12:92 Miscellaneous Autonomic Drugs

Nicotine

Introduction

C10H14N2

C10H14N2 x(C10H10C4H6O2)x

Nicotine, a naturally ocurring autonomic drug, is a ganglionic (nicotinic) cholinergic-receptor agonist.

Uses

Smoking Cessation Buccal (chewing gum, lozenge) nicotine polacrilex or a transdermal system, intranasal spray, or oral inhaler of nicotine1, 2, 3, 36, 48, 191, 244, 257, 258 is used for nicotine replacement therapy as a temporary adjunct in the cessation of cigarette smoking either unsupervised188, 189, 190, 246, 257 or in conjunction with a behavior modification program under medical or dental supervision.1, 2, 5, 6, 7, 8, 9, 10, 11, 29, 30, 31, 96, 97, 191, 192, 193, 194, 195, 196, 244, 245, 257, 258, 263 Although behavioral modification enhances clinical success and has been considered an integral component of smoking cessation therapy when any form of nicotine replacement therapy was used, and such modification generally involved supervised programs of counseling, psychologic support, and education, including detailed instructions on how to use the gum, lozenge, transdermal system, intranasal spray, or oral inhaler correctly,1, 2, 7, 9, 43, 67, 68, 76, 77, 96, 97, 101, 102, 103, 104, 115, 116, 119, 126, 131, 144, 148, 149, 167, 192, 194, 195, 196, 244, 245, 257, 258, 263 there is evidence that nicotine replacement therapy can be effective in many individuals with minimal adjuvant therapy,193, 195, 196, 258, 263 and

therefore the drug also is available for buccal or transdermal self-medication without such supervision.188, 189, 190 However, there also is evidence that intensive clinical interventions produce higher success rates and are more cost effective than less intensive interventions and should be used whenever possible.257, 258

While the over-the-counter (OTC) availability of nicotine for self-medication has increased the availability and use of replacement therapy with the drug, this does not reduce the responsibility of clinicians to intervene with smokers or with insurers and managed-care organizations to cover the costs of such therapy.257 In addition, OTC availability of these preparations may enhance the capacity of nonphysician clinicians to intervene comprehensively when treating tobacco dependence.257 All clinicians have responsibilities regarding OTC nicotine preparations, such as encouraging their use when appropriate, providing counseling and follow-up, and offering instructions on proper use.257 In addition, patients should be encouraged to abstain totally from tobacco products, to read the patient information provided by the manufacturer, and to consult their pharmacist.257 Clinicians also have an important role in advising patients of their therapeutic options, including the selection and use of OTC versus prescription therapies, and in providing or recommending counseling when OTC therapy is chosen.257

Although OTC nicotine replacement therapy employing transdermal systems of the drug has been reported to nearly double abstinence rates relative to placebo in a pooled analysis of several studies (the only adjuvant therapy was a self-help manual, the manufacturer's patient information, or written instructions for use of the transdermal system),257 evidence from one study not included in this analysis indicates that abstinence rates with OTC therapy may be relatively low.257 Therefore, additional study is needed to determine the extent to which OTC pharmacotherapy is enhanced by adjuvant therapies such as pharmacist counseling, telephone counseling, computer self-help resources, and clinical interventions.257 Despite these limitations in current evidence, however, it should be recognized that OTC replacement therapy with transdermal nicotine has been shown to be more effective than placebo and should be encouraged as appropriate.257 Because nicotine polacrilex gum or lozenge or a transdermal system or oral inhaler of nicotine is used as an adjunct to the patient's own cessation efforts, these preparations should be used in patients who strongly desire to quit smoking.2, 5, 194, 195, 196, 244

Smoking cessation therapies, including nicotine replacement, have been shown to be cost-effective preventive-health strategies.192, 194, 195, 257, 258, 241, 253 Cost-effectiveness analyses have shown that smoking cessation therapies compare favorably with routinely reimbursed medical interventions such as treatment of hypertension and hypercholesterolemia and with preventive screening interventions such as periodic mammography. 257 In addition, the more intensive the intervention the lower the cost per quality-adjusted life-year saved, indicating that intensive counseling and adjunctive

nicotine replacement (e.g., transdermal) therapy have particular merit.241, 257 Use of smoking cessation services in smokers with health insurance varies according to the extent of coverage for behavioral and nicotine replacement therapy, with the highest rates of use of such services occurring among those with full coverage.253 The US Public Health Service (USPHS) currently recommends that health-care delivery administrators, insurers, and purchasers promote the treatment of tobacco dependence through a systems approach.257, 258 Purchasers of health care (e.g., employers) should make tobacco use assessment and treatment a contractural obligation of health-care insurers and/or providers that sell services to them.257 Because both counseling and pharmacotherapy smoking cessation treatments are highly cost-effective relative to other reimbursed treatments (e.g., treatment of hyperlipidemias and mammographic screening), the USPHS recommends that they be provided to all smokers.257 In addition, because intensive smoking cessation interventions are especially efficacious and cost-effective, smokers should have ready access to these services as well as to less intensive interventions.257 Including smoking cessation treatments as a paid or covered benefit by health benefits plans can improve utilization of such therapy and reduce absenteeism rates and utilization of health resources.257 In addition, sufficient resources should be allocated for clinician reimbursement and support services to ensure the delivery of effective tobacco use treatments.257

Guidelines Nicotine (tobacco) dependence is a chronic relapsing disorder that requires ongoing assessment and often repeated intervention.196, 257, 258 Because effective nicotine dependence therapies are available, every patient should be offered effective treatment, and those who are unwilling to attempt cessation should be provided at least brief interventions designed to increase their motivation to stop tobacco use.257

US Public Health Service An expert panel convened by the US Agency for Health Care Policy and Research (AHCPR) (currently the Agency for Healthcare Research and Quality, AHRQ) had concluded that primary care clinicians were uniquely positioned to assist individuals who smoke since they have extraordinary access to the smoking population under their care.194, 195 However, primary care clinicians treat a wide variety of patients and face severe time constraints.257, 258 At least 70% of smokers visit a physician annually, more than 50% visit a dentist, and the services of other clinicians (e.g., physician assistants, nurse practitioners, nurses, physical and occupational therapists, pharmacists) are used by many smokers.194, 195, 257, 258 In addition, 70% of smokers indicate that they want to quit and smokers cite a clinician's advice as an important motivator for attempting to stop.194, 195, 257, 258 Therefore, the current USPHS guideline, which updates the earlier guideline from AHCPR (now AHRQ), considers all clinicians to be uniquely positioned to intervene against the use of tobacco by their patients.257, 258

Delineated in the current USPHS guideline are 5 brief strategies of intervention that can be provided by any clinician but that are most relevant to primary care clinicians providing service to a wide variety of patients under the constraint of limited time.257, 258 These strategies consist of asking patients if they use tobacco, advising those who use tobacco to quit, assessing their willingness to attempt to quit, assisting those who attempt to quit, and arranging follow-up to prevent relapse.257, 258

Included in the USPHS guideline are recommendations for the use of pharmacotherapy in general, firstline drugs (i.e., buccal nicotine polacrilex, transdermal nicotine, nicotine nasal spray, nicotine oral inhaler, bupropion [as extended-release tablets]) that should be considered first as part of treatment for dependence on tobacco, unless contraindicated, and second-line drugs (i.e., clonidine, nortriptyline).257 Clinicians should encourage all patients attempting to quit smoking to use effective pharmacotherapy, except in the presence of special circumstances (e.g., medical contraindications, less than 10 cigarettes smoked daily, pregnancy, breast-feeding, adolescence).257 When pregnant women are not otherwise able to quit smoking and when the likelihood of cessation, with its potential benefits, outweighs the risks of the pharmacotherapy and possible continued smoking, clinicians should consider pharmacotherapy.257 For the treatment of adolescents, nicotine replacement therapy may be considered when there is evidence of dependence on nicotine and a desire to quit the use of tobacco.257 For patients receiving treatment for chemical dependence and attempting to quit smoking, clinicians should provide effective treatments for the cessation of smoking that include both counseling and pharmacotherapy, since interventions for the cessation of smoking do not appear to interfere with recovery from chemical dependence.257 Clinicians can consider long-term pharmacotherapy for the cessation of smoking in certain patients as a strategy to reduce the likelihood of relapse.257

Buccal nicotine polacrilex, transdermal nicotine, nicotine nasal spray, and nicotine oral inhaler are effective treatments that clinicians should encourage patients to use for the cessation of smoking.257, 263 If nicotine polacrilex gum is used in highly dependent smokers, clinicians should recommend the 4mg strength, rather than 2-mg strength, because of evidence of increased efficacy.257 Nicotine replacement therapy, particularly with nicotine polacrilex gum, or bupropion (as extended-release tablets) may be most appropriate in patients greatly concerned about gaining weight after cessation of smoking since these therapies have been shown to result in delay in such gain in weight.257 If pharmacotherapy with a single first-line drug does not enable patients to quit smoking, clinicians should encourage the use of transdermal nicotine combined with a self-administered form of nicotine replacement (i.e., either buccal nicotine polacrilex or nicotine nasal spray) that they administer independently to themselves.257 Nicotine replacement therapy in such combination is more effective than when administered as a single nicotine preparation.257

Clinicians should ask all patients if they use tobacco and document their tobacco-use status regularly, advising patients strongly who use tobacco to quit and assessing their willingness to quit.257 For

patients unwilling to quit, a motivational intervention to promote cessation attempts should be given by the clinician.194, 195, 257, 258 For patients who are willing to attempt to quit the use of tobacco, effective interventions should be initiated.257 The clinician should assist the patient in the effort.194, 195, 257, 258 Help should be provided in developing a plan to quit that encompasses the patient's preparations for quitting, including setting a date to quit that should ideally be within 2 weeks, telling family, friends, and coworkers about the attempt to quit, and seeking their understanding and support.194, 195, 257, 258 Patients should be provided with practical counseling (i.e., problem solving/skills training).194, 257, 258 Social support should be provided as a part of treatment and the patient should be aided in obtaining social support outside of treatment.194, 257, 258 The use of effective pharmacotherapy should be recommended except in special circumstances.257, 258 Supplementary materials should be provided.194, 195, 257, 258 Patients attempting to quit the use of tobacco should be scheduled for follow-up contact either in person or by telephone soon after the date set for the patient to quit (e.g., during the first week), again during the month, and then as indicated.194, 195, 257, 258

Abstinence should be ascertained at the completion of treatment and subsequently during clinical visits of all patients who receive an intervention against tobacco dependence.257 Treatment to prevent relapse should be provided to abstinent patients.257 In response to relapse, patients should be assessed to determine their willingness at another attempt to quit the use of tobacco.257 Additional treatment should be provided to or arranged for patients willing to attempt again to quit.257 For patients unwilling to attempt again to quit, an intervention to promote motivation to quit should be given by the clinician.257

Because chronic relapses are inherent to dependence on tobacco, the clinician should provide brief treatment to prevent relapse in patients who quit the use of tobacco recently, particularly during the 3 months after they quit.194, 195, 257, 258 Relapse prevention interventions more intensive than minimal practice interventions may be given by the clinician during dedicated follow-up contact held in person or over the telephone, or through a specialized clinic or program.194, 195, 257, 258

American Psychiatric Association The American Psychiatric Association (APA) also has issued guidelines for the treatment of nicotine dependence; while these guidelines should be useful to any clinician caring for a nicotine-dependent patient, they focus on the groups of smokers most likely to be seen by psychiatrists, including smokers being seen for a psychiatric disorder other than nicotine dependence or withdrawal, smokers who have failed initial attempts at cessation and require more intensive treatment that could be provided by a psychiatrist, and psychiatric patients who smoke and temporarily are confined to a smoke-free

environment (e.g., hospital, residential care facility).196 The APA guidelines generally apply to all smokers, not just those meeting the DSM criteria for nicotine dependence.196

Referral or provision of adjunctive psychiatric services, when indicated, and optimizing treatment with psychosocial therapy or other pharmacologic therapy (e.g., certain antidepressants such as bupropion)240 also are important responsibilities of the clinician.196

Nicotine Replacement Therapy in Combination with Behavioral and Psychologic Support Current evidence indicates that use of nicotine replacement therapy in combination with behavioral and psychologic support is more successful than such pharmacologic therapy alone in achieving smoking cessation,43, 115, 116, 119, 144, 148, 193, 194, 195, 196, 257, 258 but the use of nicotine replacement therapy should not be conditioned on concomitant behavioral and psychologic therapy.196, 263 Although transdermal nicotine therapy may be of value even in patients who do not participate in formal smoking cessation programs,113, 114, 117, 130, 135, 193, 194, 195, 196 many patients receiving such therapy have been otherwise healthy, nicotine-dependent smokers who were described as motivated to quit smoking and who often were treated by experienced researchers in specialized clinics and/or had frequent contact with clinicians.111, 112, 114, 115, 133, 136, 144, 148

The success of nicotine polacrilex gum for smoking cessation in general medical practice, where intensive behavioral support generally is not feasible and/or patient motivation may be less than optimal, has been relatively poor,148, 149 and it has been suggested that abstinence rates reported from studies of transdermal nicotine therapy in specialized clinics may not accurately reflect the efficacy that can be expected in the general community.144 There is some evidence, however, that buccal replacement therapy with nicotine polacrilex lozenges can be highly effective in achieving smoking cessation with little face-to-face behavioral support (e.g., limited to simple reinforcement of written patient information on smoking cessation).263 Different dosing models employed for buccal gum and lozenge formulations as well as more consistent systemic delivery of the drug from the lozenge may affect the level of cessation success.263

Current data suggest that rates of smoking cessation in patients receiving transdermal nicotine therapy are higher and less variable, at least in the short term, when concomitant behavioral support is provided.101, 144, 194, 195, 196 Therefore, the manufacturers and most clinicians recommend that transdermal systems of nicotine preferably be used as part of a comprehensive program of multiple treatment strategies, including behavioral modification, to assist in the cessation of smoking.43, 44, 101, 102, 103, 104, 115, 116, 119, 126, 131, 144, 148, 149, 167, 193, 194, 195, 196, 257, 258 The quality, intensity, and frequency of such behavioral support appear to influence the outcome of attempts to quit

smoking,101, 102, 103, 104, 149, 193, 194, 195, 196, 257 although the minimum and/or essential components of a successful smoking-cessation program have not been clearly defined to date.116, 148 Even clinical interventions by clinicians lasting less than 3 minutes can increase overall tobacco cessation rates. 257, 258

The efficacy of intranasal191, 196, 202 or orally inhaled244, 245 nicotine replacement therapy as an adjunct to smoking cessation also has been demonstrated in patients who underwent concomitant psychosocial interventions (e.g., group support, individualized counseling), and therefore a comprehensive program of behavioral modification is recommended when this method of nicotine therapy is employed.

Different strategies of concomitant behavioral support influence the rate of abstinence from smoking achieved with transdermal nicotine, although evidence against differential outcome also exists.193, 194, 195, 196 An analysis of pooled data from several well-designed, controlled studies showed that the rate of abstinence from smoking was greater with counseling that was of high rather than of low intensity, as indicated by ratings on an index that reflected the importance of counseling as a goal at meetings with patients, frequency of meetings during the first 4 weeks of treatment with transdermal nicotine, number of meetings held during the first 12 weeks of abstinence from smoking, and length of meetings.257, 258Analysis of individual criteria revealed higher rates of abstinence from smoking when counseling was a primary goal of meetings with patients, when patients were met with at least weekly during the first 4 weeks of treatment with transdermal nicotine, and when at least 7 meetings were held during the first 12 weeks of abstinence. In addition, rates of abstinence from smoking were higher with group counseling than with individual counseling.

Despite these results, transdermal nicotine has been shown to be consistently more effective than placebo regardless of intensity of any adjuvant psychosocial intervention, which suggests that transdermal nicotine also is effective with minimal behavioral support.193, 195, 241 A randomized study of transdermal nicotine combined with minimal (i.e., provision of self-help pamphlet about smoking cessation), individual (i.e., provision of pamphlet along with motivational message from physician, 3 meetings less than 15 minutes long with nurse), or group (i.e., provision of pamphlet, motivational message from physician, and 8 weekly sessions of group smoking cessation counseling 1 hour long) counseling showed that the type of counseling received did not influence the rate of smoking cessation at the end of treatment with transdermal nicotine for 8 weeks and at follow-up at 26 weeks. Costeffectiveness analysis has shown that costs per quitter, life-year saved, and quality-adjusted life-years saved associated with any degree of counseling provided by a primary-care clinician or smoking cessation specialist were lower when evaluated in combination with adjunctive transdermal nicotine, and the more intensive the intervention the lower the cost per quality-adjusted life-year saved.241, 257

 Efficacy of the Various Nicotine Dosage Forms Therapy with buccal (chewing gum, lozenge) nicotine polacrilex may be useful as a temporary substitute for smoking and, when used in conjunction with other therapies, may be beneficial in overcoming manifestations of nicotine withdrawal.43, 86, 97, 195, 196, 263 Unlike nicotine transdermal systems or intranasal spray, but like orally inhaled nicotine using a smokeless cigarette-like inhaler, buccal nicotine polacrilex can provide a substitute oral activity during cigarette withdrawal.5, 77, 196, 263 In addition, buccal administration of nicotine has the potential advantage of allowing smokers to control the amount and timing of dosing, thus allowing the patient to self-titrate dosage to an appropriate level and to use acute ("rescue") dosing to combat acute craving episodes.263 By comparison, transdermal systems potentially may provide some advantages over buccal nicotine polacrilex, such as a reduction in symptoms of craving, ease of administration, absence of local oral adverse effects, fewer adverse GI effects, less frequent dosing leading to better compliance, the absence of reinforcement of addictive behavior obtained from frequent self-administration of nicotine, and effectiveness across diverse settings and populations and when used with a variety of psychosocial interventions.43, 48, 49, 109, 111, 112, 115, 116, 117, 118, 119, 121, 123, 124, 126, 130, 136, 144, 194, 195, 196

Nicotine oral inhalers provide a method of replacement that most closely mimics the behaviors (i.e., handling and inhalation through the mouth) of cigarette smoking,245 although clinical experience suggests that this mode of administration contributes at most only marginally to efficacy compared with buccal nicotine polacrilex or intranasal nicotine.245 In addition, the cigarette shape and more obvious use of the oral inhaler may carry some stigma in certain patients.263 Likewise, use of the nasal inhaler may carry some stigma in certain patients, and initially is locally very irritating.263

Any of these forms of nicotine provides an alternative source of the drug that is devoid of tars, carbon monoxide, and respiratory irritants2, 97, 257 and that may help reduce withdrawal symptoms associated with nicotine dependence.2, 50, 78, 79, 80, 97, 191, 194, 195, 196, 244, 245, 263 Some data suggest that withdrawal symptoms unrelieved with transdermal nicotine therapy alone may respond to combined therapy with transdermal nicotine and buccal nicotine polacrilex.43, 166, 196 Some clinicians state that there are insufficient data from well-designed studies to recommend one method of smoking cessation therapy (e.g., transdermal nicotine systems, nicotine gum) over another.43, 44, 144, 167, 257, 258

Buccal Nicotine Polacrilex Buccal nicotine polacrilex has been used widely as a temporary adjunct in smoking cessation therapy263 and has been shown consistently to be more effective than control interventions (e.g., psychosocial

support alone) regardless of the intensity of adjuvant psychosocial interventions, although efficacy is enhanced with intensive psychosocial intervention.1, 2, 5, 7, 8, 9, 29, 68, 89, 96, 195 The use of extemporaneously prepared buccal formulations of nicotine (e.g., nicotine salicylate lozenges ["lollipops"]) is not recommended. (See Extemporaneously Prepared Nicotine Formulations, under Uses: Smoking Cessation.) The optimal dosage and duration of buccal nicotine polacrilex therapy and optimal methods for withdrawing buccal therapy have not been clearly established,43, 86 but buccal therapy is most commonly used during the first few months of an attempt at smoking cessation, and clinicians should individualize the duration of therapy to meet the needs of the patient.195, 196, 257 There is some evidence that continuing buccal nicotine polacrilex therapy beyond (e.g., for a year or longer) the usually recommended period may increase abstinence rates.257 Although weaning from nicotine replacement therapy should be encouraged,263 continued use of such therapy is clearly preferable to a return to smoking and its health consequences.257

In several controlled studies in patients participating in behavior modification programs, buccal nicotine polacrilex has been reported to be more effective than placebo as an adjunct during smoking cessation.1, 2, 5, 7, 8, 9, 29, 68, 89, 96, 195, 257 In these studies, patients receiving nicotine polacrilex experienced less severe withdrawal symptoms and achieved higher abstinence rates than patients receiving placebo.2, 5, 7, 8, 9, 29, 89, 96, 97, 195 Because therapy with buccal nicotine polacrilex may be associated with problems of compliance,263 ease of use, social acceptability, and unpleasant taste,263 use of this form of nicotine replacement therapy depends in large part on patient preference.195

Abstinence rates in patients using nicotine polacrilex gum therapy are variable,6, 7, 8, 9, 29, 31, 33, 46, 47, 48, 76, 77, 82, 83, 84, 85, 97, 195 but the gum generally improves long-term abstinence rates by 3080% compared with control interventions.195, 257 In several controlled studies, reported rates of abstinence for nicotine polacrilex gum vs placebo were 10-63% vs 5-45% at 6 months7, 8, 9, 31, 46, 47, 48, 85 and 10-49% vs 9-37% at 12 months.7, 8, 9, 47, 48, 89, 96 In one study comparing nicotine polacrilex gum with psychologic behavior modification alone in patients with nicotine dependence, reported rates of abstinence were 59 vs 22% at 1 month, 51 vs 14% at 3 months, 45 vs 14% at 6 months, and 38 vs 14% at 1 year, respectively.6 In another study, the abstinence rate at 1 year was about 23% in patients receiving nicotine polacrilex gum.29 In a large multicenter study, long-term abstinence rates (i.e., at 6 and 12 months) in patients receiving therapy consisting of verbal and written counseling and nicotine polacrilex gum were not substantially different from those in patients receiving verbal counseling alone.48

In highly dependent smokers, the 4-mg nicotine polacrilex gum is more effective than the 2-mg gum as an aid to smoking cessation.96, 195, 196, 257, 258 In a study in patients receiving gum containing 2 or 4 mg of nicotine and undergoing psychologic behavior modification, abstinence rates in highly dependent patients at 6 weeks, 1 year, and 2 years were 54.5, 12.1, and 6.1%, respectively, for 2-mg doses and

81.5, 44.4, and 33.3%, respectively, for 4-mg doses; in those with a low to moderate degree of dependence, abstinence rates were 73.3, 38.3, and 28.3%, respectively, for 2-mg doses.96

Abstinence rates in patients using nicotine polacrilex lozenges also are variable, but the lozenges generally improve abstinence rates relative to control interventions.263 In one controlled study employing little face-to-face behavioral support (e.g., limited to simple reinforcement of written patient information on smoking cessation), reported rates of abstinence at 6 weeks for nicotine polacrilex lozenges vs placebo were 46% vs 29.7% for 2-mg doses in low-dependence smokers (dependency assessed by time to the first cigarette [TTFC] upon awakening) and 48.7% vs 20.8% for 4-mg doses in highly dependent smokers.263 Abstinence rates for the 2-mg doses were 34.4% vs 21.6%, 24.2% vs 14.4%, and 17.9% vs 9.6% at 12, 24, and 52 weeks, respectively.263 Abstinence rates for the 4-mg doses were 35.3% vs 14%, 23.6% vs 10.2%, and 14.9% vs 6.2% at 12, 24, and 52 weeks, respectively. 263 In this study, patients were only provided nicotine polacrilex or placebo lozenges through week 24 and, after a 12-week period of downwardly titrated dosing, were instructed to use them only occasionally (i.e., in situations when they might be tempted to smoke) during weeks 12-24; patients were instructed to stop lozenge use after 24 weeks.263 Patients who failed to maintain abstinence at each visit were discontinued from the study.263 High dependency was defined as a TTFC within 30 minutes of awakening and low dependency was defined as a more prolonged TTFC.263 Patients who used more lozenges achieved substantially better treatment effects in both lozenge treatment groups (i.e., low- and high- dependence patients).263 Active lozenge therapy also reduced craving at weeks 1 and 2 for both treatment groups vs placebo, but only the 4-mg group exhibited lower withdrawal symptom scores at week 2; the greater effect on withdrawal symptoms observed with the 4-mg dose probably resulted from the higher baseline nicotine dependency and associated higher likelihood of withdrawal precipitation relative to the 2-mg group.263 Most patients in this study had failed previous attempts at pharmacologic smoking cessation therapy.263

The abstinence rate in patients using buccal nicotine polacrilex may depend on the duration of therapy.5, 33, 257 The manufacturer states that use of buccal nicotine polacrilex for longer than 3 months has not been shown to increase the rate of abstinence,1 although some clinicians suggest that longer periods of therapy may be necessary to ensure a high abstinence rate.33, 43 257 Although prolonged use of buccal nicotine polacrilex may increase the risk of patients substituting the drug for cigarettes as a source of nicotine for their nicotine dependence,1 the risk of dependence on buccal nicotine polacrilex therapy appears to be low.7, 44, 90 (See Chronic Toxicity.)

Transdermal Nicotine Transdermal nicotine has been shown to be consistently more effective than placebo regardless of intensity of any psychosocial intervention, which suggests that transdermal nicotine also is effective

with minimal behavioral support.193, 195, 241, 257 However, cost-effectiveness of transdermal therapy appears to increase as the intensity of the cessation intervention increases.241, 257 (See Smoking Cessation: Nicotine Replacement Therapy in Combination with Behavioral and Psychologic Support.)

Whether transdermal nicotine administered at a higher dosage is superior to standard dosages is uncertain.196 At steady state, the percentage of nicotine replacement, in terms of blood cotinine concentration, provided by transdermal nicotine at a dosage of 44 mg/24 hours was slightly above 100% but was less than 100% with dosages of 11 and 22 mg/24 hours. At the end of treatment for 8 weeks, the likelihood of smoking cessation was increased with each increment in dose of 11 mg and with each increase of 25% in percentage of cotinine replaced, although such associations were not discerned at follow-up at 6 months or 1 year. However, evaluation of the efficacy in achievement of smoking cessation with 8 weeks of transdermal nicotine at an initial dosage of 22 or 44 mg/24 hours did not indicate the superiority of the higher dose at follow-up at 6 months. Desire to smoke, one of 8 withdrawal symptoms assessed, was less severe with transdermal nicotine at a dosage of 44 mg/24 hours than at 22 mg/24 hours during the first 4 weeks of treatment, although such difference between these dosages in the suppression of this withdrawal symptom was not discerned at subsequent evaluation and was, furthermore, not related to the rate of smoking cessation. Other data showed that during the first 6 days of treatment, severity of withdrawal symptoms (i.e., anger/irritability/frustration, anxiety or nervousness, awakening at night, difficulty concentrating, depression, hunger, impatience or restlessness, desire to smoke) considered as a whole was less with transdermal nicotine at a dosage of 44 mg/24 hours than at 22 or 11 mg/24 hours on the first day of treatment and was less with 44 or 11 mg/24 hours than with 22 mg/24 hours on the fourth day of treatment.

Although the optimal duration, dosage, and long-term efficacy and safety of transdermal nicotine therapy have not been established fully,43, 144, 148, 149, 177 current evidence indicates that extending the duration of transdermal nicotine therapy beyond 8 weeks does not appear to increase efficacy.193, 195, 196 However, based on evidence with nicotine polacrilex gum, continued therapy for periods longer than usually recommended may be appropriate for certain patients to promote extended abstinence. 257

In controlled studies of 3-6 months or less in otherwise healthy adults who generally were considered highly motivated to quit smoking and who smoked at least 0.5-1 pack of cigarettes daily, therapy with transdermal systems of nicotine has been more effective than placebo in achieving smoking cessation,43, 101, 102, 103, 109, 111, 112, 133, 136, 143, 144, 193, 194, 195 although abstinence rates with such therapy have varied considerably.144 Smoking cessation usually was defined as total abstinence from smoking as determined by patient diary and, in most studies, was verified by measurement of expired carbon monoxide concentration. 101, 102, 103, 104, 109, 111, 112, 113, 115, 118, 136, 144 With concomitant behavioral support, rates of smoking abstinence at 6 or 7 weeks

generally ranged from about 20-60% (reportedly up to 92%)2 in smokers who received therapy with either 24- or 16-hour transdermal systems of nicotine compared with about 3-46% for placebo recipients.101, 102, 103, 104, 109, 136, 144 Abstinence rates of approximately 30-53% within the first 6 weeks of treatment also have been reported in a few studies in which concomitant behavioral support was not provided.14, 18, 113, 144 Data from trials that assessed abstinence at 6 months generally indicate lower rates of smoking cessation.2, 3, 4, 11, 15, 36 Patients receiving a transdermal system of nicotine and behavioral support experienced less severe withdrawal symptoms, including less craving for cigarettes, as indicated by patients' ratings of symptom severity, and achieved higher abstinence rates than patients receiving placebo.101, 102, 103, 104, 109, 111, 112, 133, 136, 137 Reductions in the severity of symptoms such as irritability, anger, restlessness, dizziness, difficulty concentrating, and dysphoria have been reported with transdermal nicotine therapy, although hunger and weight gain do not appear to be attenuated substantially.111, 112, 136, 148, 149

Clinical studies indicate that abstinence rates in patients receiving transdermal nicotine therapy generally exceed those in placebo recipients for at least 6 months,111, 118, 136, 149, 193 but early relapse is common.118, 136, 144, 257 Although initial rates of smoking cessation with transdermal nicotine therapy may be substantial,118, 144, 148, 193 long-term (e.g., 1-year) abstinence rates in smokers receiving transdermal therapy with behavioral support generally have averaged about 25%, similar to those observed with the use of nicotine gum for comparable periods.148 In one randomized, multicenter study, the abstinence rate with transdermal nicotine therapy and behavioral support was 61% following 6 weeks of treatment with the full dosage of 21 mg/day but, while still exceeding placebo rates, had declined to 39% at 3 months following weaning with dosages of 14 and 7 mg/day and to 26% 3 months after completion of transdermal nicotine therapy.133, 136 Therefore, while abstinence rates with transdermal nicotine therapy are approximately double those in patients who receive placebo, additional measures to prevent relapse and optimize the long-term success of nicotine-replacement therapy are needed.115, 121, 148, 149, 195, 257 However, in a few studies, addition of specific relapseprevention strategies (e.g., self-observation and recording of temptation situations, role playing, thought blocking) to therapy with transdermal nicotine systems plus behavioral support has not produced substantial improvements in long-term abstinence rates.126, 141

Because transdermal systems of nicotine do not replace the pleasurable and habitual aspects of smoking,144, 149 some clinicians suggest that transdermal nicotine therapy, combined with another more rapid-acting, titratable form of nicotine replacement (e.g., buccal nicotine polacrilex, nicotine inhaler or spray) to facilitate dosage tailoring and/or prevent relapse, may constitute the most successful treatment approach; additional study is needed.43, 147, 148, 149

Reported rates of abstinence and severity of nicotine craving in patients using transdermal systems of nicotine are variable, presumably because of differences in patient motivation, concurrent illnesses,

number of cigarettes smoked daily and duration of the smoking habit, exposure to or influence of other smokers, socioeconomic status, and differences among smoking cessation clinics.101, 102, 103, 104, 113, 136 However, in a multicenter study of 9 clinics, the number of cigarettes smoked daily at baseline, number of years of smoking cigarettes, or clinic site were not predictive of response to treatment in patients receiving transdermal nicotine therapy.111, 136 Abstinence rates for patients older than 60 years of age were comparable to those for younger individuals,101, 102, 103, 104, 144 and efficacy of the transdermal nicotine systems also appears to be similar regardless of gender.113, 121, 136, 144 However, while women appear to benefit from the same smoking cessation therapies as men, women may face different stressors and barriers to quitting (e.g., greater likelihood of depression, greater weight control concerns, hormonal cycles), and there is some evidence that nicotine replacement therapy may be less effective in women.257 Although reduction in most nicotine-withdrawal symptoms does not appear to be clearly related to the dosage of nicotine delivered by transdermal systems of nicotine,43, 136, 159 limited evidence suggests that reduction in craving may be greater with higher transdermal nicotine dosages (e.g., 21 mg/24 hours).136 In some studies, reductions in craving have been apparent only after several days or weeks of therapy, rather than early in treatment when craving is most severe.113, 114, 118, 144, 167

Comparative studies currently are limited, but some evidence suggests that abstinence rates and adverse effects are similar whether a nicotine transdermal system is applied over 16 or 24 hours.44, 111, 144, 148 Nicotine transdermal systems that deliver the drug over 24 rather than 16 hours theoretically offer the advantage of maintenance of plasma nicotine concentrations adequate to minimize withdrawal symptoms in the morning,105, 123, 132, 134 while use of 16-hour transdermal systems of nicotine is intended to reduce adverse effects (e.g., insomnia) and the potential for tolerance.144, 148 However, in one randomized study in which a prototype44 transdermal system of nicotine designed to provide 24-hour systemic delivery of nicotine was applied for either 24 hours daily or only while patients were awake (approximately 16 hours daily), severity of withdrawal symptoms during the 4-week treatment period and abstinence rates 6 months after the completion of therapy were similar for both regimens, as was the frequency of adverse effects.111, 132

Some clinicians149, 195 state that nicotine replacement therapy generally should be discontinued after 6-12 weeks. Alternatively, it has been suggested that smokers optimally should receive such therapy for as long as needed to overcome the addiction,43, 116, 143, 257 although skin irritation from a transdermal system potentially may preclude such long-term use in some patients.43, 112, 115, 167, 195 (See Cautions: Local and Sensitivity Reactions.) In addition, some evidence indicates that transdermal therapy of 8 weeks or less may be as effective as longer therapy, but therapy, including duration, should be individualized.257 Complete abstinence from smoking generally is the goal of transdermal nicotine therapy.101, 102, 103, 104, 123, 195, 257 In clinical studies of such therapy, most patients who stopped smoking did so during the first month;101, 102, 103, 104, 115, 121 therefore, the manufacturers state that transdermal nicotine therapy probably should be discontinued in patients who

continue to smoke 4 weeks after initiating such treatment.101, 102, 103, 104 Adjunctive transdermal nicotine therapy may be used again in subsequent attempts to quit smoking,101, 102, 103, 104, 121 although the efficacy of such therapy following initial failure has not been demonstrated to date.43, 162, 167 If another trial of transdermal nicotine therapy is contemplated, such therapy should be initiated only after identifying and addressing reasons for failure so that success is more likely.43, 101, 102, 103, 104

It has been suggested that use of nicotine-replacement therapy to facilitate a reduction in cigarette smoking, rather than complete cessation, may be a reasonable objective in patients in whom abstinence is not possible (harm reduction therapy).123, 148 Many patients who have been unable to quit smoking entirely have experienced a substantial (e.g., 60%), dose-related reduction in cigarette consumption, or in nicotine intake during smoking, with transdermal nicotine therapy.113, 136, 148, 158, 160 However, reduction in disease (e.g., lung cancer, emphysema) associated with a reduction in the intake of tobacco smoke has not been demonstrated to date.43, 167 Additional data on the long-term safety of nicotine replacement therapy and on patterns of smoking behavior in patients receiving such therapy are needed to determine the merits of achieving a reduction in smoking as a harm reduction strategy, rather than complete cessation,43, 123, 257 and such use of transdermal nicotine therapy generally should not be encouraged.43, 144, 167, 257

Nicotine Nasal Spray Nicotine nasal spray with or without concomitant psychosocial treatment (e.g., group therapy, individual counseling) was more effective than placebo in achieving smoking cessation in controlled studies.191, 201, 202, 203, 257 Enrollment did not include patients with severe or symptomatic cardiovascular disease, hypertension, asthma, diabetes, or severe allergy.191, 201, 202 Nicotine nasal spray was used for up to 1 year at a dosage determined by the patient of up to 40 mg daily, although 3 months was recommended generally as the duration of therapy.191, 201, 202, 203 Smoking cessation usually was defined as total abstinence from smoking as reported by the patient and verified by measurement of expired carbon monoxide concentration.191, 201, 202, 203 Abstinence was achieved with nicotine nasal spray in 49-58, 41-45, 31-35, and 23-27% of patients at 6 weeks, 3 months, 6 months, and 1 year, respectively, compared with 21-32, 17-20, 12-15, and 10-15% at the respective follow-up in recipients of placebo.191, 201, 202, 203 Outcome at 1 year did not distinguish use of nicotine nasal spray limited to 6 months from therapy of longer duration.191, 203 Withdrawal symptoms and craving for cigarettes were experienced to a lesser extent with nicotine nasal spray than with placebo.191, 201 The risk of developing dependence on nicotine nasal spray appears to be greater than that with other nicotine replacement therapy but less than that with cigarette smoking.191, 196, 201, 202, 257 (See Chronic Toxicity.)

 Nicotine Oral Inhaler Nicotine inhalation therapy using an oral inhaler, with intensive (e.g., group therapy) or minimal (limited individual advice and support) concomitant psychosocial treatment, was more effective than placebo in achieving smoking cessation in controlled studies.244, 245, 246 257 Orally inhaled nicotine was used for up to 6 months at a dosage determined by the patient, but generally with a recommended minimum dosage of 4 inhaler cartridges (designed to deliver a maximum of about 4 mg each) daily and a maximum dosage of 20 cartridges daily; the recommended duration of inhalation therapy was 3 months, although patients could continue therapy for up to 6 months if they desired, preferably at reduced dosage.244, 245 Patients who continued to smoke cigarettes during nicotine replacement therapy with the oral inhaler were encouraged to continue their inhaler use and increase the dosage.256 Smoking cessation was defined as total abstinence from smoking after the initial 2 weeks of oral inhaler therapy as reported by the patient and verified by measurement of expired carbon monoxide concentration.244, 245

Abstinence was achieved with nicotine oral inhaler in 44-46, 31-37, 20-35, and 11-28% of patients at 6 weeks, 3 months, 6 months, and 1 year, respectively, compared with 14-33, 8-23, 6-19, and 5-18% at the respective follow-up in recipients of placebo.244, 245 The urge to smoke, a nicotine withdrawal symptom, was reduced during the first week of nicotine oral inhalation therapy relative to placebo.244, 245 Although not compared directly, 1-year abstinence rates with the oral inhaler were similar to those observed with nicotine polacrilex gum or intranasal nicotine in similarly designed clinical studies.245

After 2, 3, or 6 weeks of oral inhaler therapy, the percentage of nicotine replacement, in terms of salivary cotinine concentration, provided by oral inhalation of usual dosages of nicotine inhaler was about 37-43, 30-34, or 20-24%, respectively, of that provided by cigarette smoking, representing the lower availability of nicotine from the inhaler compared with cigarette smoking as well as downward self-titration of nicotine replacement during continued use of the inhaler.245, 246 Small increases (3.8 mg/dL) in serum high-density lipoprotein (HDL) cholesterol concentrations were associated with orally inhaled nicotine therapy at 3 and 6 months; similar increases were observed in placebo recipients at 3 but not 6 months.245

Extemporaneously Prepared Nicotine Formulations The US Food and Drug Administration (FDA) has become aware of the increasing promotion of certain extemporaneous formulations of nicotine salicylate intended to be used as nicotine replacement therapy to assist in the cessation of smoking.259 Such extemporaneous formulations have included buccal lozenges ("lollipops") and topical ointments for lips ("lip balm") that contain nicotine salicylate, natural sweeteners, and flavorings in a sugar-free base.259 It should be noted, however, that a

commercially available buccal (lozenge) formulation of nicotine polacrilex (Commit Lozenges) has been approved by FDA for marketing and use in the US. (See Buccal Nicotine Polacrilex, under Uses: Smoking Cessation.) The promotions on pharmacy websites that sold the extemporaneously prepared products suggested to consumers that these products help alleviate the "hand-to-mouth fixation" associated with smoking and are a "convenient, tasty way" to replace the cigarette habit.259 After careful investigation and assessment of these websites, the FDA has determined that the extemporaneously prepared nicotine "lollipop" and "lip balm" preparations are intended for use as drugs, and the agency has taken appropriate regulatory actions to remove such preparations from the US market.259 FDA is concerned that these formulations may pose a health risk to consumers because they appear to be compounded and dispensed without a prescription, contain a form of nicotine that is not used in FDA-approved commercially available nicotine dosage forms, and because these candy-like preparations present a risk of accidental use by children.259

Weight Gain and Smoking Cessation Weight gain occurs in most smokers who quit.194, 195, 196, 245, 257, 263 Although most smokers will gain less than 4.5 kg following cigarette cessation,194, 195, 196, 245, 246, 257, 263 there is a broad range of weight gain, with up to 10% of smokers gaining up to 13.5 kg following cessation.194, 195, 257 Women tend to gain more weight than men, and blacks, individuals younger than 55 years of age, and heavy smokers (more than 25 cigarettes daily) are at increased risk of substantial weight gain.194, 195, 257

Patients generally should be advised not to take strong measures (e.g., strict dieting) to counteract weight gain during smoking cessation therapy since such simultaneous measures may undermine the attempt at smoking cessation.194, 195, 196, 257 Although no strategy or treatment has been shown unequivocally to prevent postcessation weight gain, nicotine replacement (particularly with the gum)194, 195, 196, 243, 257 or bupropion smoking cessation therapy243, 257 appears to be effective in delaying postcessation weight gain.194, 195, 196, 257 In fact, there appears to be a dose-response relationship between gum use and weight suppression, although once nicotine polacrilex gum is discontinued, the ultimate weight gain appears to be about the same as if the patient had never used the gum.195 Therefore, for patients concerned greatly about gaining weight after cessation of smoking, it may be most appropriate to implement or recommend nicotine replacement therapy, particularly with nicotine polacrilex gum, or alternatively bupropion therapy.257

Postcessation weight gain appears to result both from increased caloric intake (e.g., eating, alcohol consumption) and by metabolic adjustments.257 Involvement of metabolic mechanisms suggests that patients will on average gain some weight following smoking cessation even if they do not increase their caloric intake.257 Because many patients believe that they can do little to prevent postcessation weight

gain except to return to smoking, a belief that is consistent with research findings, such concerns may be difficult to address clinically.257 However, clinicians should recommend a healthy diet and physical activity and emphasize that the health risks of postcessation weight gain are small compared with the risk of continued smoking.257 Clinicians also should recommend that patients concentrate principally on smoking cessation rather than weight control until they are confident that they will not return to smoking.257

Nicotine Replacement Therapy in Patients with Pulmonary and Cardiovascular Disease Because smokers with pulmonary disease appear to be highly nicotine dependent, nicotine replacement therapy is particularly important in such patients.196 Current evidence in patients with stable coronary artery disease indicates that transdermal nicotine therapy is effective and does not exacerbate cardiac complications (e.g., angina, arrhythmias) in such patients.102, 144, 149, 156, 196, 200, 211, 221, 242, 257 Although adverse cardiovascular effects, including myocardial infarction, have been reported rarely in patients receiving nicotine replacement therapy (e.g., in those who continued to smoke while receiving transdermal nicotine),144, 149, 164, 165, 167, 211, 212, 213, 214, 215 nicotine replacement therapy with transdermal systems does not appear to be associated with particular risk in patients with cardiovascular disease (even in patients who continue to smoke intermittently) but can be beneficial if the smoking cessation attempt were successful, and smoking cessation is considered essential as a secondary long-term prevention measure in such patients (e.g., those surviving a myocardial infarction.102, 156, 196, 200, 211, 221, 242, 256, 257 (See Cautions: Other Systemic Effects.) Because of inaccurate media coverage in the past linking transdermal nicotine replacement therapy and cardiovascular risk, it may be important to inform patients who are reluctant to use nicotine replacement therapy that there currently is no evidence of increased cardiovascular risk. 257 Nonetheless, the risks versus benefits should be considered, particularly in patients with acute cardiovascular conditions.1, 97, 101, 102, 103, 104, 144, 148, 149, 191, 257 (See Cautions: Precautions and Contraindications.)

Smoking Cessation Therapy in Inpatients and Residents of Long-term Care Facilities Because hospitals must be smoke-free environments to meet Joint Commission on Accreditation of Healthcare Organizations (JCAHO) standards, hospitalization may provide a good opportunity to attempt smoking cessation, depending on the patient's condition.194, 195, 257 For smokers who experience nicotine withdrawal manifestations during hospitalization, nicotine replacement therapy during hospitalization can reduce such symptoms and may promote continued use of replacement therapy for patients desiring to prolong their abstinence beyond the period of hospitalization.194, 195 In addition to reducing or preventing withdrawal manifestations, there is evidence that smoking cessation interventions that are undertaken in hospitalized patients increase abstinence rates.195, 257

The use of nicotine replacement therapy to alleviate nicotine withdrawal manifestations may be considered for inpatients who smoke and who will not consent to hospitalization without treatment for nicotine withdrawal because of concern about its occurrence.196 Such prophylactic use may be advantageous compared with allowing breaks for smoking since nicotine replacement therapy is of low risk.196 Among the advantages of buccal nicotine polacrilex are that patients can titrate the dosage of nicotine and that use can stop immediately before intermittent smoking (e.g., at breaks).196, 263 Daily use of a few doses of buccal nicotine polacrilex is sufficient in many patients to prevent manifestations of nicotine withdrawal.196 Transdermal nicotine offers the advantages of better compliance and stable delivery of nicotine, which may by especially advantageous in differentiating nicotine withdrawal from other psychiatric symptoms.196 A disadvantage of either route of administration is that patients may smoke during such therapy.196 However, substantial adverse effects do not appear to be likely with this undesirable combination.196, 200

Prophylactic pharmacotherapy generally is not a consideration for inpatients who smoke because nicotine withdrawal is often less severe than they anticipated because of such factors as the absence of cues that elicit smoking, distraction of the primary problem, and the effects of drugs.196 The use of nicotine replacement therapy (e.g., transdermal system, buccal dosage form) to alleviate nicotine withdrawal manifestations usually should be considered only when such manifestations stimulate complaints from the patient or are observed.196 Although inpatients who decide to stop smoking may not need nicotine replacement therapy while hospitalized, they should be followed carefully after discharge to determine whether such therapy is indicated because many patients experience nicotine withdrawal manifestations when they return to their usual environment.196

Nicotine replacement therapy is not recommended for use in patients while hospitalized for management of acute myocardial infarction because of the potentially deleterious effects of the sympathomimetic effects of nicotine.256 However, because the dose of nicotine in the gum and transdermal systems of the drug is substantially lower than that provided by cigarettes, nicotine replacement therapy may be considered preferable to cigarette smoking in patients experiencing nicotine withdrawal.256 (See Cautions: Cardiovascular Effects and also Precautions and Contraindications.) Smoking cessation, however, is essential as a secondary long-term (i.e., following hospital discharge) prevention measure in patients surviving a myocardial infarction.256

Residents in long-term care facilities also should receive effective tobacco dependence interventions. 257

Efficacy for Noncigarette Tobacco Cessation

The efficacy of nicotine as an adjunct in cessation therapy for other forms of nicotine dependence (e.g., smoking a pipe or cigar, chewing tobacco) has not been established to date.43, 44, 144 Specifically, studies conducted with nicotine polacrilex gum or transdermal nicotine have failed to show increased abstinence rates in users of smokeless tobacco.257 Despite the lack of current evidence establishing efficacy of nicotine replacement therapy of other pharmacotherapies for tobacco cessation in patients dependent on noncigarette forms of tobacco, smokeless/spit (chewing tobacco, snuff) tobacco users, and those using cigars, pipes, or other noncigarette combustible forms of tobacco should be identified, strongly urged to quit, and treated with the same counseling cessation interventions recommended for cigarette smokers.257 In addition, clinicians delivering dental health services should provide at least brief interventions to all smokeless/spit tobacco users.257 Like cigarette smoking, smokeless or spit tobacco produces addiction to nicotine and has serious health consequences; health risks include teeth abrasion, gingival recession, periodontal bone loss, leukoplakia, oral cancer, and cardiovascular disease.257 Cigar smoking also poses serious health risks, including coronary heart disease, chronic obstructive pulmonary disease (COPD), and lung and other cancers.257 Additional study is needed to determine the efficacy of pharmacotherapy, alone or combined with counseling and behavioral therapies, in promoting tobacco abstinence among users of noncigarette tobacco.257

Nicotine Dependence and Withdrawal Some evidence indicates that nicotine replacement therapy may be most likely to be effective in patients with a high degree of dependence on nicotine (i.e., heavy smokers)1, 2, 8, 30, 33, 67, 68, 263 and a high degree of motivation.5 However, the decision to use nicotine replacement as an adjunct to smoking cessation does not depend on establishing a diagnosis of nicotine dependence.195, 196 In a study comparing buccal nicotine polacrilex gum vs placebo, 6-week abstinence rates were 46% vs 9% in patients highly dependent on nicotine and 29% vs 13% in those with a low degree of dependence.68 However, it currently is unclear whether the likelihood of achieving smoking cessation with transdermal nicotine systems depends substantially on the patient's degree of nicotine dependence.111, 113, 114, 136, 144 Neither the number of cigarettes smoked per day, nor scores on the Fagerstrom Tolerance Questionnaire, at baseline appeared to influence the rate of smoking cessation after 8 weeks of treatment with transdermal nicotine at a dosage of 22 or 44 mg/24 hours and at follow-up at 26 weeks. Limited data suggest that highly dependent smokers may benefit from therapy with nicotine nasal spray.191, 201

Some clinicians suggest that dependence on nicotine is probable in patients who smoke more than 15 cigarettes per day, smoke cigarettes with a nicotine yield greater than 0.9 mg/cigarette, usually inhale the smoke frequently and deeply, smoke their first cigarette within 30 minutes of arising,263 find that the first cigarette in the morning is the most difficult to give up, smoke more frequently during the morning than the rest of the day, find it difficult to refrain from smoking in places where it generally is not permitted (e.g., church), or smoke even when they are so ill that they are confined to bed.1, 2, 8

Although most individuals who have quit smoking have done so spontaneously without the aid of an organized smoking cessation program such as one that includes therapy with nicotine polacrilex or transdermal nicotine,35, 74, 75, 86, 97 without social support procedures directed specifically at maintenance of abstinence, abstinence rates generally have been low.34, 35, 42, 56, 63, 97 Individuals most likely to quit spontaneously or with minimal intervention appear to be psychologically healthier, smoke less heavily and for fewer years, are generally more skillful in controlling their own behavior, and are well motivated.34, 35 Light smokers who may not be dependent on nicotine may only require psychologic behavior modification to discontinue cigarette smoking.5, 11, 34, 48, 56

Other Uses Nicotine polacrilex reportedly has provided temporary relief (for about 1 hour after chewing a piece of the gum) of hemidystonia in a patient with severe dystonia of the left hand and athetoid movements of both feet.71

Nicotine also has been administered transdermally in the management of ulcerative colitis.125, 204, 205, 206, 207, 208, 209, 210 Transdermal nicotine appeared to produce therapeutic benefit in patients who also were receiving conventional pharmacologic therapy (e.g., mesalamine with or without corticosteroids) for active ulcerative colitis.204, 205, 206, 207, 235, 236, 237 Clinical improvement, as indicated by scores on a disease activity index, was observed in a greater proportion of patients treated with transdermal nicotine at a dosage titrated up to 22 mg daily for 4 weeks than with placebo.204 Improvement from baseline in stool frequency, sigmoidoscopic results, and global assessment by the physician were each distinctive of the superiority of transdermal nicotine over placebo after 4 weeks of such treatment.204 Transdermal nicotine in a dosage of up to 25 mg daily for 6 weeks produced greater improvement than did placebo in the global clinical grade, daily stool frequency, abdominal pain, and fecal urgency in patients with active ulcerative colitis that relapsed during conventional pharmacologic therapy.206, 208, 209 In addition, improvement in the histologic score of rectal biopsies was greater with transdermal nicotine than with placebo after 6 weeks of treatment.206, 208, 209 Transdermal nicotine alone was not effective in the maintenance of patients with ulcerative colitis in remission.205, 208, 210 The number of relapses that occurred during 6 months of treatment in such patients did not distinguish transdermal nicotine from placebo.205, 210 Additional study is needed to adequately determine the role of nicotine in the management of this condition.204, 205, 208, 209, 210

Dosage and Administration

Administration

Buccal Administration Buccal nicotine polacrilex is administered orally as a chewing gum or lozenge; the gum or lozenge should not be swallowed.1 In addition, the lozenge should not be bitten or chewed like a hard candy.260, 263, 264 To obtain optimum results, patients should be provided self-help materials, advice, and instructions in the proper use of the gum or lozenge.1, 194, 195, 196, 198, 241, 257 Patients should be given a copy of the patient information provided by the manufacturer and should be instructed to read and keep this information.1, 190, 264 Patients should be instructed to stop smoking immediately prior to initiating buccal nicotine polacrilex therapy and to not eat or drink anything other than water for 15 minutes before and during chewing of the gum or sucking on the lozenge.1, 190, 257, 263, 264 However, some clinicians suggest that some carefully selected heavy smokers may benefit from a cessation program that includes a gradual reduction in cigarette smoking and concomitant use of nicotine polacrilex;58 additional evaluation of such concomitant use is needed.257

Patients receiving buccal nicotine polacrilex therapy with the gum should chew one piece of gum whenever they have the urge to smoke.1 They should be instructed to chew the gum very slowly until the distinctive peppery taste of nicotine, minty or orange taste of the flavored gum, or a slight tingling in the mouth is perceived, and to then stop chewing and park the gum between the cheek and gum; once this tingling is almost gone (usually within about 1 minute), this chewing procedure should be repeated intermittently for about 30 minutes or until the taste dissipates.1, 257 The initial taste or tingling usually is perceived after about 15 chews but its onset exhibits interindividual variation.1 This chewing technique provides constant, slow, buccal absorption of nicotine from the gum.1, 257 Patients should be advised that chewing the gum will not provide the same rapid satisfaction that smoking tobacco provides.1 Chewing the gum too rapidly can cause excessive release of nicotine, resulting in adverse effects similar to those of oversmoking (e.g., nausea, hiccups, irritation of the throat).1

Patients receiving buccal nicotine polacrilex therapy with the lozenge should be instructed to suck on the lozenge until it dissolves.263, 264 The lozenge should be allowed to dissolve slowly in the mouth over 20-30 minutes, periodically moving the lozenge (e.g., with the tongue) from one side of the mouth to the other; patients should be advised to minimize swallowing while the lozenge is dissolving in the mouth.263, 264 The lozenges are self-administered in response to the patient's cravings for nicotine during the day, with the frequency of administration expected to decline over time as nicotine cravings and/or withdrawal symptoms decline.263, 264 (See Dosage: Buccal Dosage in Dosage and Administration.)

For information on buccal administration via oral inhalation of nicotine, see Administration: Oral Inhalation, in Dosage and Administration.

Transdermal Administration If the protective pouch containing a transdermal nicotine system is damaged, the system should not be used because of the possibility that tampering has occurred.101, 102, 103, 104 To expose the adhesive surface of a nicotine transdermal system, the protective liner should be peeled and discarded just prior to application.101, 102, 103, 104, 129 The transdermal system should be applied immediately after removal from its protective pouch and removal of the protective liner to avoid loss of nicotine through volatilization.101, 102, 103, 104

Nicotine transdermal systems should be applied to clean, dry, hairless areas of skin on the trunk or upper outer arm at the same time each day, usually after awakening.101, 102, 103, 129, 167, 188, 189, 257 The application site should not be oily, damaged, or irritated;43, 101, 129 if necessary, hair may be clipped, but the area should not be shaved.167 The transdermal system usually is applied as soon as the patient wakes up; for patients who experience sleep disruption while receiving a 24-hour transdermal system, the system can be removed prior to bedtime or the patient can be switched to application of a 16-hour system after awakening.257 The manufacturer states that each Nicotrol transdermal system should not be applied for longer than 16 hours daily; patients who forget to remove these systems at bedtime may experience vivid dreams or other sleep disturbances.262

With the adhesive side touching the skin, the transdermal system should be pressed firmly in place with the palm of the hand for about 10 seconds, ensuring good contact, particularly around the edges.101, 129, 167 If the system should inadvertently come off during the period of use, the manufacturers recommend that a new system be applied;101, 102, 103, 104, 167 the application schedule employed may either be continued or changed so that the next system would be applied 24 hours later.129

To minimize and/or prevent potential skin irritation, application sites for the transdermal systems should be rotated; an interval of at least 1 week should be allowed between application at a given site.101, 102, 103, 129 After removal, used transdermal systems should be folded so that the adhesive side adheres to itself, placed in the empty protective pouch of the system just applied, and then disposed of immediately to prevent access by children or pets.101, 102, 103, 104, 129, 264 (See Cautions: Precautions and Contraindications.) After handling a nicotine transdermal system, patients should wash their hands with water alone since soap reportedly may enhance percutaneous absorption of the drug; patients should avoid touching their eyes prior to handwashing.43, 101, 102, 103, 104, 129, 167

Intranasal Administration Nicotine nasal solution is administered intranasally via a metered-dose spray pump.191 A 1-mg dose is delivered by administering 1 metered spray into each nostril (i.e., 2 sprays total).191, 257 (See Dosage: Intranasal Dosage, in Dosage and Administration.) Patients should be instructed carefully regarding the proper use of the nasal spray and their questions should be answered.191 They should be advised to tilt their head back slightly when administering nicotine nasal spray and to not sniff, swallow, or inhale nasally during administration since these may increase the irritating effects.191, 257 Comprehension by the patient of the directions for the use of nicotine nasal spray and safe disposal of spent containers should be ensured.191 Patients should be instructed to stop smoking completely upon initiation of therapy with nicotine nasal spray.191

Oral Inhalation Nicotine oral inhaler is administered as an inhaled vapor from cartridges containing porous plugs impregnated with the drug.244, 245, 246, 247, 248 Patients should be carefully instructed in the proper use of the oral inhaler.244, 250 To obtain optimum results, patients also should be given a copy of the patient instructions provided by the manufacturer and should be instructed to stop smoking completely.244, 250

Only a small portion of the dose is released from the inhaler with each inhalation, and the amount of nicotine released depends on the volume and temperature of the air passing through the inhaler.244, 245, 246, 247, 248 At room temperature, the inhaler releases approximately 13 ng of nicotine per rapid shallow (about 50-mL) inhalation or about 1 mg per 80 inhalations;245 however, intense deep inhalations can release up to 4 mg of the drug from the plug per 80 inhalations.244, 247

Patients should be advised that puffing on the inhaler for about 5 minutes at a time will provide about 4 uses per inhaler cartridge.250 Oral inhalation over 5 minutes using rapid shallow sucking/puffing ("buccal mode") has been shown to produce delivery of the drug comparable to that using slow deep inhalation ("pulmonary mode").248 Therefore, because the deep inhalation technique requires considerable effort but does not result in substantially increased drug delivery or other benefits,248 the shallow puffing method generally is preferred.244, 248, 250 257

Patients should be advised that while use of the oral inhaler mimics that of smoking cigarettes, deep inhalation via the inhaler is not necessary for effective absorption of nicotine but more frequent puffing of the inhaler generally is required.244, 245, 248 Patients also should be advised that optimum results generally are achieved by frequent continuous puffing of the inhaler over 20 minutes.244 Patient

tolerance of the local irritant effects of orally inhaled nicotine generally improves with continued therapy.244

Nicotine is used up from each cartridge after about four 5-minute sessions of inhalation or one 20minute session of active puffing.250 After a few days of use, patients will become aware of what method and frequency of oral inhalation works best for them as well as knowing when the cartridge is used up.250 After complete use of a given cartridge, the mouthpiece should be separated carefully from the inhaler and the cartridge removed and disposed of properly.244, 250 (See Cautions: Precautions and Contraindications.) After use, the mouthpiece should be stored in the plastic storage case for further use.244 The mouthpiece is reusable and should be cleaned regularly with soap and water.244

Dosage Buccal Dosage Dosage of nicotine polacrilex is expressed in terms of nicotine.1, 264 Dosage of nicotine polacrilex should be individualized by the patient after careful instruction and, unless self-administered without supervision,190 should be assessed periodically by the clinician.1, 43, 195 Supervised or unsupervised (self-medication) nicotine polacrilex therapy can be initiated with either the 2- or 4-mg (of nicotine) gum or lozenge, but should be individualized depending on the patient's degree of nicotine dependence.1, 190, 195, 257, 263, 264

Nicotine Polacrilex Gum In most cases, nicotine replacement therapy with nicotine polacrilex gum is initiated with the 2-mg (of nicotine) gum.195 Initial therapy with the 4-mg gum generally is preferred for heavy (highly dependent) smokers (e.g., as determined by a Fagerstrom Tolerance Questionnaire [FTQ] score of 7 or greater, current smoking history of more than 20-25 cigarettes per day, smoking within 30 minutes of awakening, or difficulty refraining from smoking in places where it is forbidden). In addition, some patients initially receiving the 2-mg gum may benefit from substitution of the 4-mg gum (e.g., those who fail to stop smoking with the 2-mg gum, those whose withdrawal symptoms with the 2-mg gum remains so strong as to threaten relapse).

Patients often do not use enough nicotine polacrilex gum to obtain maximum benefit; they chew too few pieces daily and do not use the gum for a sufficient number of weeks. 257 Because of evidence that abstinence rates may be improved when nicotine polacrilex gum is administered on a regular schedule rather than on an as-needed ("prn") basis, it may be preferable to follow a fixed dosing schedule such as

instructing patients to chew at least one piece of gum at 1- to 2-hour intervals for at least 1-3 months.257 Alternatively, when nicotine polacrilex therapy is initiated, patients can be instructed to chew one piece of gum whenever the urge to smoke a cigarette occurs,1 and to titrate their daily use of the gum according to tolerance and response.1 To minimize adverse effects, it is important that patients be instructed carefully regarding the need to self-titrate their dosage of the gum and to chew the gum slowly (see Dosage and Administration: Administration), since adverse effects are related principally to the balance between the individual's degree of nicotine tolerance and the rate and extent of absorption of nicotine from the gum.1

During the first month of smoking-cessation therapy with nicotine polacrilex, most patients require approximately 9-12 pieces of 2-mg (of nicotine) gum (18-24 mg of nicotine) daily, one piece at a time.1 This dosage has been reported to approximate usual nicotine doses attained from smoking 20 cigarettes daily.5, 43 Most patients receiving the 4-mg gum respond to 9-12 pieces (36-48 mg of nicotine) daily.

The maximum dosage of nicotine polacrilex should not exceed 30 pieces (60 mg of nicotine) of 2-mg gum daily under the supervision of a clinician1, 195 or 24 pieces (48 mg of nicotine) daily when unsupervised during self-medication,190, 257 and maximum dosage of the 4-mg gum should not exceed 24 pieces (96 mg of nicotine) daily, whether supervised or not.190 When supervised, patients should be evaluated at intervals of no more than 1 month to determine their smoking status and whether adjunctive therapy with nicotine polacrilex gum should be continued.1 As the patient's urge to smoke decreases, the number of pieces of gum used each day should be reduced gradually.1, 190

Attempts to gradually reduce nicotine polacrilex dosage generally should begin after 2-3 months of successful smoking abstinence. In patients who are successfully abstaining from smoking after 3 months of therapy, nicotine polacrilex generally should be discontinued or, when the patient is using more than 2 pieces of gum daily at this time, gradually withdrawn.1 In general, gradual withdrawal of the gum can be accomplished by instructing the patient to reduce their consumption by one or more pieces daily at 4- to 7-day intervals as tolerated. Alternatively, patients can reduce the chewing time for each piece of gum from the usual 30-minute duration (see Dosage and Administration: Administration) to 10-15 minutes for 4-7 days, and to subsequently begin reducing the daily consumption of pieces of gum as described. Some patients also may benefit from a withdrawal schedule that involves decreasing the number of daily pieces of gum chewed while increasing the duration of chewing for each piece to periods that exceed 30 minutes. Substituting nonmedicated sugarless chewing gum for discontinued doses of nicotine polacrilex gum may aid in successful withdrawal of the drug. For patients receiving the 4-mg gum, substitution of the 2-mg gum for individual doses and any of the previously described procedures also could be followed. Some clinicians state that it may be possible to discontinue nicotine polacrilex therapy prior to 3 months in some patients (e.g., those who are confident that they can

remain abstinent if therapy is discontinued, those who have titrated their dosage of the gum to 2 or fewer pieces daily).43

When nicotine polacrilex gum is used for self-medication, the manufacturer recommends a 12-week schedule of gradually decreasing dosage.190 In this schedule, the usual initial dosage of the gum in adults 18 years of age or older is one 2- or 4-mg piece chewed at 1- to 2-hour intervals during weeks 1-6, followed by this dose administered at 2- to 4-hour intervals during weeks 7-9 and then at 4- to 8-hour intervals during weeks 10-12.190 If the patient feels the need for continued use of the gum after this period, a clinician should be consulted.190 If problems of the mouth, jaw, or teeth develop during selfmedication with buccal nicotine polacrilex, use of the gum should be stopped and a clinician consulted.190Use of the gum also should be stopped and a clinician consulted if an irregular heart beat or palpitations develop or if manifestations of nicotine overdosage (e.g., nausea, vomiting, dizziness, weakness, rapid heartbeat) develop.190

Use of the gum for longer than 3 months is discouraged by the manufacturer and the benefit of continued therapy should be weighed against the risk of nicotine dependence.1, 81 If the drug is used for 3 months or longer, withdrawal from the gum should be gradual and should be completed by 6 months; use of nicotine polacrilex for longer than 6 months is not recommended by the manufacturer.1 (See Chronic Toxicity.) Since most patients who have returned to smoking during participation in a smoking-cessation program that included nicotine polacrilex therapy have done so within 6 months after initiation of the gum and because the efficacy of continuing therapy with the gum has not been established, the manufacturer recommends that nicotine polacrilex be withdrawn gradually in patients who have not spontaneously reduced their consumption of the gum after 6 months of therapy.1 Although use of nicotine polacrilex for longer than 6 months is not recommended by the manufacturer,1 many clinicians state that therapy for longer than 6 months may be beneficial in some patients and the need for continued use should be determined mainly by the patient's preference, since such continued use is not associated with substantial risk and almost all patients eventually will discontinue use of the gum.9, 43, 65, 96, 98, 195, 196, 257 In addition, there is some evidence that continuing nicotine polacrilex therapy beyond (e.g., for a year or longer) the usually recommended period may promote long-term abstinence in some patients.257 Although weaning from nicotine replacement therapy should be encouraged, continued use of such therapy is clearly preferable to a return to smoking and its health consequences.257

Nicotine Polacrilex Lozenges The initial replacement dosage of nicotine polacrilex lozenges for self-administration should be determined by the patient's level of nicotine dependency as indicated by the time to smoking their first cigarette [TTFC] upon awakening.263, 264 Patients who smoke their first cigarette within 30 minutes of

awakening are considered to have high dependence and should initiate therapy with the 4-mg lozenges, and those who smoke their first cigarette later than 30 minutes after awakening are considered to have low dependence and should initiate therapy with the 2-mg lozenges.263, 264

During the first 6 weeks of therapy with nicotine polacrilex lozenges, low- or high-dependence smokers should receive 2 or 4 mg of nicotine, respectively, every 1-2 hours, with a recommended minimum use of 9 lozenges daily.263, 264 Taking at least 9 lozenges daily during this initial phase of therapy appears to optimize the likelihood of success.263, 264 During weeks 7-9, low- or high-dependence smokers should receive 2 or 4 mg of nicotine, respectively, every 2-4 hours, and during weeks 10-12, they should receive the respective dose every 4-8 hours.263, 264

Generally, patients should discontinue nicotine polacrilex replacement therapy with the lozenges after 12 weeks,263, 264 although some patients may require occasional use of the lozenges over weeks 12-24 for situations when they might be tempted to smoke.263 In addition, the patient's clinician may recommend a regimen that extends beyond the initial 12 weeks.264 Patients should be advised to contact their clinician if they feel the need for continued nicotine replacement therapy beyond the usual 12-week regimen.264

Patients should be instructed not to exceed 5 nicotine polacrilex lozenges in any 6-hour period nor to exceed 20 lozenges daily.263, 264 In addition, patients should be instructed not to use more than one lozenge simultaneously nor to use them in uninterrupted sequence since the risk of certain adverse effects (e.g., hiccups, dyspepsia, nausea) may be increased with such administration.264

Transdermal Dosage Transdermal systems of nicotine are applied only once daily; after the prescribed duration of daily use (e.g., 16 or 24 hours), the system in use is removed and discarded and a new system is applied at a different site.101, 102, 103, 104, 129, 167, 188, 189, 257 The Nicotrol transdermal system is designed to provide systemic nicotine delivery of nicotine over 16 hours; this system is applied daily after awakening and removed before retiring.104, 257 Patients should be instructed not to use the same Nicotrol transdermal system for longer than 16 hours.188 The duration of daily use for NicoDerm CQ is 16- 24 hours; patients who crave a cigarette upon awakening should wear this transdermal system for 24 hours.189 Patients who experience vivid dreams or other disturbances of sleep with application of NicoDerm CQ for 24 hours should remove the transdermal system after about 16 hours of application, before retiring.189, 257, 262 Patients should be instructed not to use the same NicoDerm CQ transdermal system for longer than 24 hours.189

Self-medication For self-medication as a temporary adjunct in the cessation of cigarette smoking in adults who smoke more than 10 cigarettes daily, transdermal nicotine therapy with NicoDerm CQ is initiated with the 21-mg/day strength.189 The usual dosage schedule consists of 4-6 weeks of therapy with a transdermal system delivering 21 mg/day of nicotine, followed by 2 weaning periods in which systems delivering 14 and 7 mg/day are each used for 2 weeks, for a total duration of therapy of 10 weeks; therapy is then discontinued.189, 257 In adults who smoke 10 or fewer cigarettes daily, therapy with NicoDerm CQ is initiated with the 14-mg/day strength.189 The dosage schedule recommended by the manufacturer in such patients consists of 6 weeks of therapy with a transdermal system delivering 14 mg/day of nicotine, followed by one weaning period in which a system delivering 7 mg/day is used for 2 weeks, for a total duration of therapy of 8 weeks; therapy is then discontinued.189 For self-medication with Nicotrol in adults who smoke more than 10 cigarettes daily, the usual dosage schedule consists of 6-8 weeks of therapy with a transdermal system delivering 15 mg/day; therapy is then discontinued.188, 257 Alternatively for self-medication with Nicotrol in adults, a step-down regimen can be followed in which a transdermal delivery system delivering 15 mg/day is administered daily for 6 weeks (step 1), a system delivering 10 mg/day is administered daily for 2 weeks (step 2), and a system delivering 5 mg/day is administered daily for 2 more weeks.

If the patient feels the need for continued transdermal nicotine therapy after completion of selfmedication with NicoDerm CQ or Nicotrol, a clinician should be consulted.188, 189 If application of a transdermal system of nicotine during self-medicationresults in local erythema that persists longer than 4 days, or if edema or rash develops, transdermal nicotine therapy should be discontinued and a clinician consulted.188, 189 Transdermal nicotine self-medication also should be discontinued and a clinician consulted if irregular heart rate or palpitations develop or if manifestations of nicotine overdosage (e.g., nausea, vomiting, dizziness, weakness, rapid heart rate) develop.188, 189

Supervised Therapy For supervised therapy, the usual initial adult dosage in otherwise healthy patients is one transdermal system, delivering the largest available dosage of nicotine (highest strength) in its dosage series, applied once daily.101, 102, 103, 104, 144, 149, 167 Supervised therapy with a NicoDermCQ transdermal system generally is initiated with the 21-mg/day strength;101, 102 the initial dosage for the Nicotrol104 system is 15 mg/day.104 Patients who weigh less than 45 kg, those who smoke less than 10-15 cigarettes daily, and/or those who have cardiovascular disease generally should receive lower initial dosages.101, 102, 103, 196 The recommended initial dosage of nicotine using the NicoDermCQ transdermal system102 in such patients is 14 mg/day. With all transdermal nicotine systems, the need for dosage adjustment should be assessed over the initial 2 weeks of therapy, recognizing that some

symptoms of excessive intake of nicotine (as might occur in patients who continue to smoke) may be similar to those of nicotine withdrawal.43, 101, 102, 103, 104, 167 (See Cautions: Systemic Effects.)

Once an appropriate initial dosage for supervised therapy has been established, the manufacturers recommend continuation of transdermal nicotine therapy at that dosage for up to 4-12 weeks, depending on the transdermal system used.101, 102, 103, 104, 144 Subsequently, patients who have abstained successfully from smoking generally receive one or more periods of supervised therapy at a reduced dosage over the subsequent 2-8 weeks, followed by discontinuance of therapy.43, 101, 102, 103, 104 The dosage schedule recommended by the manufacturer of NicoDermCQ for otherwise healthy patients consists of 4-6 weeks of supervised therapy with a transdermal system delivering 21 mg/day of nicotine, followed by 2 weaning periods in which systems delivering 14 and 7 mg/day are each used for 2-4 weeks; therapy is then discontinued.101, 102 The duration of supervised therapy, including any weaning period(s), with the NicoDerm CQ transdermal nicotine system generally should not exceed 12 weeks.44, 101, 102, 103, 104, 167, 196 Continuation of therapy beyond this period has not been studied and is not recommended by the manufacturer.101, 102, 103, 104

Other Considerations Some clinicians have suggested that a total of 6-8 weeks of transdermal nicotine therapy is sufficient time for abatement of withdrawal symptoms and acquisition of skills necessary to maintain abstinence.149 While some clinicians have suggested transdermal therapy for longer than 12 weeks and even nicotine maintenance with such therapy in some cases, other clinicians recommend a duration of 6-12 weeks for transdermal therapy, with tapering of dosage beginning at 4-6 weeks, since increased efficacy for periods beyond this has not been established.196

A variety of therapeutic methods, such as counseling and behavioral modification, have been used concurrently for the duration of transdermal nicotine therapy.101, 102, 103, 104, 116, 119, 195 Patients should stop smoking completely while receiving transdermal nicotine therapy.101, 102, 103, 104, 188, 189, 195 If patients have not stopped smoking after 4 weeks of transdermal nicotine therapy, such therapy probably should be discontinued, but a new course can be initiated after discussion and/or elimination or reduction of the factors responsible for failure.43, 101, 102, 103, 104, 144

Intranasal Dosage The metered pump of nicotine nasal solution delivers a metered 50-L spray that contains 0.5 mg of the drug per actuation.191, 257 The commercially available pump containing 100 mg (10 mg/mL) of nicotine delivers approximately 200 sprays (i.e., 100 doses).191, 257 A 1-mg dose of nicotine is delivered by

administering 1 spray of the nasal solution via the metered pump into each nostril (i.e., 2 sprays total).191, 257 The dosage of nicotine nasal spray should be individualized depending on the patient's dependence on nicotine and whether symptoms of excessive intake of nicotine occur.191 Therapy with the nasal spray usually is initiated in adults with 1-mg doses administered once or twice per hour.191 This initial dosage may be increased according to patient tolerance and response to a maximum of five 1-mg doses per hour to administer a maximum hourly dose of 5 mg and daily dose of 40 mg (i.e., 80 sprays).191, 257 To achieve optimal therapeutic results, patients should be encouraged to administer at least the minimum recommended dosage of 8 mg daily since lower dosages are unlikely to be effective.191, 257 Use of the spray regularly during the first week of therapy may allow adaptation to the irritant effect of nicotine nasal spray.191

Nicotine dosage with the nasal spray can then be adjusted in patients with manifestations of nicotine withdrawal or excessive intake of nicotine, recognizing that some symptoms of excessive intake (as might occur in patients who continue to smoke) may be similar to those of nicotine withdrawal.191 In clinical studies of nicotine replacement therapy, excessive intake of nicotine appeared to be more often manifested by palpitations, nausea, and sweating and those of nicotine withdrawal by anxiety, nervousness, and irritability.191 When nicotine withdrawal was experienced most strongly, nicotine nasal spray was used liberally, up to the maximum dosage recommended of 40 mg daily in some heavy smokers, by patients who achieved cessation of smoking in clinical studies.191

Once an appropriate dosage has been established, the manufacturer recommends continuation of therapy with nicotine nasal spray at that dosage for up to 8 weeks in patients who have abstained successfully from smoking.191 Therapy should then be discontinued sometime over the subsequent 4-6 weeks.191 An optimal schedule of tapering the dosage to discontinuance was not identified in clinical studies; therapy simply was discontinued by many patients at their last clinic visit.19 The manufacturer recommends several strategies that patients can use to discontinue therapy with nicotine nasal spray including halving each dose (i.e., to 1 spray [0.5 mg]) administered, reducing the frequency of use, tallying daily administration, targeting a steady reduction in dosage, skipping a dose by deviating from hourly administration, or setting a date for discontinuance of therapy.191 Therapy can be discontinued abruptly in some patients, although gradual reduction of the dosage may be preferable in others.191 Continued therapy with nicotine nasal spray beyond 12-14 weeks has not been shown to improve outcome, and safety of use beyond 6 months has not been established.191

Complete abstinence is the goal of therapy with nicotine nasal spray.191 If patients have not stopped smoking after 4 weeks of therapy with nicotine nasal spray, such therapy probably should be discontinued.191 Unsuccessful patients should be counseled and probably should receive a break from smoking cessation therapy before another attempt is tried.191 Such patients may benefit from

adjunctive interventions to enhance the possibility of success on the next attempt.191 Another attempt to quit smoking should be encouraged by a more favorable context.191

Oral Inhalation Dosage Nicotine oral inhaler cartridges labeled as containing 10 mg of nicotine deliver a maximum of approximately 4 mg total with repeated inhalation.244, 247, 250, 257

Initial dosage of nicotine via oral inhalation should be individualized.244 Patients may self-titrate the orally inhaled dosage to the level of nicotine replacement they require.244 In clinical studies, most successful patients used between 6-16 cartridges daily.244, 245, 246, 257 Patients generally increased their daily nicotine dosage from the first to the second week of oral inhalation therapy, and then subsequently decreased their daily consumption somewhat but not substantially over the next 4 weeks.245 The recommended duration of therapy is 3 months, after which patients may be weaned from oral inhalation therapy by gradual reduction of the daily dosage over 6-12 weeks.244, 245, 257 Safety and efficacy of oral inhalation therapy have not been established beyond 6 months244, 245 and therefore such prolonged use is not recommended by the manufacturer.244

For optimal results, patients should be instructed to use at least 6 cartridges daily at least for the initial 3-6 weeks of nicotine oral inhalation therapy, with the likelihood of success increasing with daily doses exceeding this amount.244 Additional daily doses may be required to control the urge to smoke, but the manufacturer recommends that daily consumption not exceed 16 nicotine cartridges (about 64 mg of delivered nicotine) for up to twelve weeks.244 Dosage should be adjusted if manifestations of nicotine withdrawal or excess develop.244 Initial treatment generally should continue for about 12 weeks, after which oral inhalation therapy may be gradually withdrawn.244

After completion of a course (generally up to 12 weeks) of nicotine oral inhalation therapy, most patients require a gradual reduction in daily cartridge consumption, although abrupt discontinuance may be possible in some patients.244, 245 Gradual dosage reduction may extend over 6-12 weeks.244 Recommended strategies for discontinuing therapy include recommending that the patient decrease the frequency of daily use of the oral inhaler, keep a tally of daily usage, try to meet a steadily reducing target, or set a planned quit date for discontinuing oral inhalation therapy.244

Nicotine oral inhalation therapy provides the smoker with adequate amounts of nicotine to reduce the urge to smoke, and may provide some degree of comfort by providing a hand-to-mouth ritual similar to

smoking.244 The goal of nicotine oral inhaler therapy is complete abstinence from cigarette smoking.244 If the patient is unable to stop smoking completely by the fourth week of oral inhalation therapy, the manufacturer states that treatment probably should be discontinued.244 Patients who fail to quit on any attempt may benefit from interventions to improve their chances with subsequent attempts.244 After an unsuccessful attempt, the patient should be counseled and probably should be given a treatment break before another attempt.244 Once conditions are more favorable, a new attempt at smoking cessation using orally inhaled244 or another form1, 101, 102, 103, 104, 191 of nicotine replacement therapy can be initiated.

Cautions

Adverse Effects Adverse effects associated with buccal nicotine polacrilex therapy are usually mild and transient, and include systemic effects resulting from the pharmacologic actions of the drug and local effects.1, 5, 257, 263, 264 Patients who are not highly motivated may become noncompliant because of initial adverse effects.5, 33, 195 In a placebo-controlled study with nicotine polacrilex lozenges, 61.8% of patients reported adverse effects, and those receiving the drug were more likely to report adverse effects than those receiving placebo lozenges; 17% of patients experienced severe adverse effects and 7.1% discontinued therapy because of adverse effects.263 The most common adverse effects reported with the lozenges were GI and respiratory complaints, but only dyspepsia, hiccup, and nausea occurred substantially more often with drug than placebo with both the 2- and 4-mg dosing regimens.263

Transdermal systems of nicotine appear to be well tolerated.109, 111, 113, 114, 115, 133, 136, 195, 257 In clinical studies, the most commonly reported adverse effects associated with the use of these systems were mild and transient dermatologic (i.e., application site) reactions. 101, 102, 103, 104, 109, 111, 112, 113, 114, 115, 118, 126, 136, 167, 257 In general, the reported incidences of adverse effects with transdermal nicotine therapy reflect those reported with the highest dosages of commercially available transdermal systems.43, 101, 102, 103, 104, 167 In a study of transdermal nicotine administered at a dosage of 11, 22, or 44 mg/24 hours, a positive association was found between dose and the occurrence of weakness during the first 6 days of treatment. Other data showed that erythema and edema at the site of application, nausea, and vomiting also are dose related, occurring more often with a dosage of 44 mg/24 hours than with 22 mg/24 hours.

Adverse effects associated with intranasal202, 257 or orally inhaled244, 245, 246, 257 nicotine also usually are transient and mild to moderate or mild, respectively, and include systemic and local effects.

 Local and Sensitivity Reactions Nicotine Polacrilex Gum Adverse local effects of nicotine polacrilex gum are related principally to the mechanical effects of gum chewing and include traumatic injury to the oral mucosa and/or teeth;1, 68, 257 irritation and/or tingling of the tongue, mouth, and throat;1, 5, 9, 27, 29, 68, 85, 89, 95, 96 ulceration of the oral mucosa, including traumatic and aphthous ulcers;1, 5, 6, 7, 29, 68, 89, 96 esophagitis;43 jaw-muscle ache;1, 5, 6, 7, 29, 68 eructation (belching) resulting from unintentional swallowing of air during chewing;1, 68, 95 gum sticking to teeth;89 and unpleasant taste.5, 85, 95 A pruritic, maculopapular rash occurred periorally in at least one patient receiving nicotine polacrilex therapy.92 Some oral mucosal changes such as stomatitis, glossitis, gingivitis, pharyngitis, aphthous ulcers, and alterations in taste perception can occur during smoking cessation efforts with or without nicotine polacrilex therapy.1

Initially, very few smokers enjoy the chewing gum, and it is usually slightly aversive.5 Although the initial local irritation and dislike of the taste may deter some patients from continuing therapy,5 most adverse local effects of nicotine polacrilex are transient, usually subsiding after the first few days of therapy, and may be minimized or avoided by modifying the chewing technique (see Dosage and Administration: Administration).1, 5, 7, 9, 68, 196, 257

Nicotine Polacrilex Lozenges Unlike the adverse effect profile observed with buccal nicotine polacrilex gum where adverse local effects are most common,1 local effects occur less commonly than systemic effects with buccal lozenges of the drug.263 Adverse local effects reported with nicotine polacrilex lozenges in a placebo-controlled study were limited to sore throat, which occurred in 3.6% of patients receiving the drug.263

Transdermal Nicotine Transient and localized pruritus, burning, or erythema on at least one occasion occurred in 35-54% of patients receiving transdermal nicotine therapy in controlled clinical trials.101, 102, 103, 104, 113, 114, 115, 118, 126, 136, 137, 195, 257 Pruritus or burning generally occurred just after application of a transdermal system and lasted no longer than 30 minutes.111, 113, 114, 118, 136 Local erythema, which generally resolved without treatment within 24 hours,43, 167 was observed at least once following removal of a transdermal system in 7-25% of patients in clinical studies.101, 102, 103, 104, 113, 114, 115, 118, 136 Some degree of edema at the site of application was observed in 3-8% of patients using transdermal systems of nicotine.101, 102, 103, 104, 113, 114

Allergic contact sensitization to nicotine, confirmed by rechallenge in some patients,136 has been reported in 2-3% of patients receiving the drug via a transdermal system;101, 102, 103, 104, 126, 136, 144, 163 however, resumption of smoking by 7 patients with rechallenge-confirmed contact sensitization in one study did not result in systemic manifestations of hypersensitivity.136 Vasculitis manifested by such signs and symptoms as purpuric lesions on the lower extremities, fever, and arthralgia has occurred after several days of transdermal nicotine therapy, resolved after discontinuance of therapy, and recurred with subsequent application of a transdermal system of nicotine.231 Generalized rash has been reported occasionally with transdermal nicotine therapy.102, 103, 104, 109, 111, 112, 137 Systemic and/or severe dermatologic reactions (e.g., severe erythema, bullae, erosions) have occurred infrequently, usually after at least 2-5 weeks of continuous treatment.43, 112, 115, 136, 144, 167

Adverse dermatologic effects that required discontinuance of transdermal nicotine therapy (e.g., eczema) were reported in 1-7% of patients receiving such therapy in clinical studies.101, 102, 103, 104, 113, 114, 118, 144, 161, 257 Dermatologic reactions attributable to the gel and/or adhesive components of the transdermal nicotine systems also have occurred.44, 109, 115, 144 When treatment for local dermatologic reactions is required, use of topical corticosteroids and/or oral antihistamines generally appears to be effective.43, 112, 144, 149, 195

Intranasal Nicotine Intranasal administration of nicotine solution commonly produces local nasopharyngeal and ocular irritation.191, 202 257 During the initial 2 days of intranasal nicotine therapy, nearly all patients experience nasal irritation, which usually is moderate to severe.191, 202, 257 Both the incidence and severity of nasal irritation decrease with continued intranasal therapy,191, 202, 257 but it still is experienced by about 80% of patients after 3 weeks of therapy, usually as mild to moderate in severity.191, 257Other common local effects of intranasal administration include runny nose,191, 196, 202, 203 throat irritation,191, 196, 201, 202, 203 watery eyes,191, 196, 201, 202, 203 sneezing,191, 196, 201, 202, 203 and cough.191, 196, 201, 202, 203 Less commonly, nasal congestion, subjective comments about the taste or use of the spray, sinus irritation, transient epistaxis, ocular irritation, transient changes in the sense of smell or taste, pharyngitis, nasal or oral numbness, nasal or ocular burning, earache, facial flushing, hoarseness, nasal ulcer or blister, and paresthesia of the nose, mouth, or head have been reported with the nasal spray.191 257

Topical application of either nicotine or tobacco products can cause irritation of the nasal mucosa, and therefore the risks and benefits of intranasal nicotine therapy must be considered both before initiating

such therapy and in assessing the merits of continuance.191 Following 1 month of intranasal nicotine in 39 cigarette smokers, random biopsies at the completion of therapy revealed persistence of preexisting dysplasia in one patient and newly diagnosed dysplasia in another.191 In both patients, dysplasia had resolved 8 weeks later.191 In a study of patients who received intranasal nicotine for longer than 6 months, ear, nose, and throat examinations 1-3 months after discontinuance of the spray did not reveal persistent mucosal injury attributable to the spray despite complaints of local irritation by most patients during therapy.191 Although the clinical importance of these findings is not known, the manufacturer recommends that intranasal nicotine therapy not continue beyond 6 months.191 Use of intranasal nicotine is not recommended for patients with a history of chronic nasal disorders (e.g., allergy, rhinitis, nasal polyps, sinusitis) or severe reactive airway disease since safety has not been established in such patients.191, 257

Nicotine Oral Inhalation Oral inhalation of nicotine from the inhaler commonly produces oropharyngeal irritation.244, 245, 246, 257 About 32-50% 244 of patients experience oropharyngeal irritation such as coughing and mouth and throat irritation;244, 245, 246, 257 in controlled studies, such effects occurred in about 12-18%244 of placebo inhalation recipients.244, 246 Such irritation appears to be dose related, occurring in 66% of patients receiving higher than currently recommended dosages in clinical studies.244 At usual dosages, cough occurred in 27-32% of patients during the first week,244, 245, 257 and mouth and throat irritation occurred in 15% of patients; these effects generally were mild.245 Such local irritation decreases with continued oral inhalation therapy.244, 245 Rhinitis, another effect of local irritation, occurred in 23% of patients.244, 257 Other effects possibly related to local irritant effects of nicotine oral inhalation and occurring in greater than 3% of patients include taste disturbances, jaw and neck pain, tooth disorders, and sinusitis.244 Local irritant effects generally have been mild and decline in frequency with continued use,257 but such effects occasionally may be severe enough to result in discontinuance of nicotine oral inhalation therapy.245

Allergic reactions have been reported in greater than 3% of patients receiving orally inhaled nicotine.244

Systemic Effects The incidence and severity of adverse systemic effects associated with the use of buccal nicotine polacrilex gum are quite variable and may depend on the patient's individual chewing technique.1, 5 The incidence of adverse systemic effects associated with transdermal, intranasal, or orally inhaled nicotine therapy is difficult to ascertain because the adverse GI and nervous system effects associated with nicotine withdrawal in patients who quit smoking are similar to those produced by excessive intake of nicotine (e.g., in patients who continue to smoke during transdermal nicotine therapy), and

investigators in clinical trials generally did not attempt to identify the cause of these reactions.101, 102, 103, 104, 136, 191, 244 In controlled clinical studies, nicotine toxicity reportedly was manifested more frequently by abnormal dreams, insomnia, dizziness, rash, sweating, and/or abdominal pain, while withdrawal was characterized more often by irritability, anxiety, depression, somnolence, and/or flatulence.101, 102, 103, 104, 136, 191 In general, adverse systemic effects are not severe and usually do not require discontinuance of transdermal, intranasal, or orally inhaled nicotine therapy.43, 144, 191, 244, 245

The risk of adverse systemic nicotine effects and toxicity may be increased in patients who apply more than one transdermal system at a time and in those who continue to smoke while using transdermal therapy.100, 101, 102, 103, 104, 167, 196, 230, 233, 234 Patients in whom buccal,263 transdermal, or orally inhaled nicotine therapy is initiated should be urged to stop smoking completely and advised that they may experience adverse effects from elevated plasma nicotine concentrations if they continue to smoke while receiving such therapy.101, 102, 103, 104, 167, 244, 250

Although a causal relationship and potential mechanism were not established, an association between strenuous physical activity (e.g., squash, karate, hockey) and nicotine toxicity (e.g., nausea, vomiting, disorientation, severe fatique, palpitations, chest heaviness or pain, insomnia, tremor) was reported in several patients who were using a transdermal system during such activity; it was postulated that transdermal absorption of nicotine may have been enhanced by increased skin temperature and peripheral cutaneous vasodilation and perfusion during exercise.196 However, in a study in healthy smokers who were refraining from smoking while wearing a transdermal system of nicotine that delivered 21 mg/24 hours, no difference was apparent in the incidence of adverse effects on the day on which these individuals exercised by cycling on an ergometer for 20 minutes at 80% of their maximal heart rate compared with the previous day that served as baseline.238 The adverse effects that occurred during exercise and the period of recovery were headache, dizziness, and nausea that were each reported as severe, although discontinuance of transdermal nicotine was not necessary.238

The most common adverse effects reported with buccal nicotine polacrilex lozenges were systemic (e.g., GI, respiratory) effects.263

GI Effects Adverse GI effects occur frequently during the first week of therapy with buccal nicotine polacrilex gum.1, 5 Some adverse GI effects may result from a local action of nicotine, increasing in frequency as the amount of drug swallowed increases.94 The most frequent adverse systemic effects associated with nicotine polacrilex gum are indigestion (e.g., dyspepsia, heartburn)1, 7, 27, 85, 96, 257 and nausea,1, 6,

9, 27, 68, 85, 95 which reportedly occur in about 20-40% of patients receiving the drug.1, 96 Vomiting has also occurred in patients receiving nicotine polacrilex gum.1, 96 These adverse GI effects are caused in part by excessive chewing which releases nicotine from the gum too rapidly and subsequently causes excessive salivation and swallowing of nicotine;5, 94 modification of the chewing technique may minimize these effects.1, 5, 7, 9, 27, 257 Excessive salivation may also result from the autonomic effect of the drug.1, 4, 94 Other less frequent adverse GI effects of nicotine polacrilex gum include dry mouth,1 anorexia,1, 68 diarrhea,1, 96 constipation,1 and flatulence.5, 89, 96 Hiccups reportedly occur in 15-23% of patients receiving buccal nicotine polacrilex gum,1, 7, 68, 89, 94, 96, 257 and appear to be dose related, occurring more frequently in patients receiving 4- rather than 2-mg doses.94, 96

The most common adverse GI effects reported with buccal nicotine polacrilex lozenges were nausea, flatulence, dyspepsia, hiccup, and diarrhea, which occurred in 12.2, 9.8, 5, 3.5, and 3.5%, respectively, of patients receiving 2-mg dosing regimens and in 15.1, 10.4, 5.8, 8.4, and 5.3%, respectively, of patients receiving 4-mg dosing regimens.263

Adverse GI effects that generally appeared to be dose related or occurred more frequently in patients receiving a transdermal system of nicotine than in those receiving placebo in clinical studies include diarrhea,101, 102 dyspepsia,103, 137 abdominal pain,103 and dry mouth.101, 102, 109, 137 Constipation,101, 102, 103, 104, 111 flatulence,104 nausea,101, 102, 103, 104, 118, 137 and vomiting101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 also have been reported in patients receiving transdermal nicotine, although a causal relationship to the drug has not been established. Adverse GI effects reported with intranasal nicotine include nausea,191, 203 flatulence,191 abdominal pain,191 dry mouth,191 and diarrhea.191

The most common nicotine-related adverse effect in patients receiving orally inhaled therapy with the drug is dyspepsia,244, 246 occurring in 18% of those receiving the drug versus 9% of those receiving placebo in clinical studies.244 Other nicotine-related effects of oral inhalation therapy that occurred in greater than 3% of patients and included nausea,244, 245, 246 diarrhea,244 and hiccups.244 Flatulence also has been reported in greater than 3% of patients receiving orally inhaled nicotine.244

Nervous System Effects Adverse nervous system effects of buccal nicotine polacrilex gum include dizziness and lightheadedness,1, 27 headache,1, 68 insomnia,1 and irritability,1, 68 which reportedly occur in 1-25% of patients. Euphoria reportedly occurs in less than 1% of patients.1 Confusion, seizures, depression, numbness, paresthesia, syncope, and weakness also have occurred during therapy with the drug.1

263 The only adverse nervous system effect reported in a placebo-controlled study with buccal nicotine polacrilex lozenges was headache, which occurred in 5 or 8% of patients receiving 2- or 4-mg dosing regimens, respectively.263 However, this effect occurred more frequently with the drug relative to placebo only in patients receiving 4-mg dosing regimens with the lozenges.263

Adverse nervous system effects that generally were dose related or reported more frequently with transdermal systems of nicotine than with placebo include insomnia,102, 136, 137 abnormal dreams/nightmares,101, 102, 136, 137 somnolence,101, 103 dizziness,104, 109 and nervousness.102 Headache,101, 102, 103, 104, 109, 111, 118, 137 paresthesia,102, 109 impairment of concentration,101, 104 depression,104 vertigo,118, 137 and fatigue109, 111, 137 also have been reported. Psychotic disorder has occurred with use of a transdermal system of nicotine by patients who continued to smoke.233, 234

Adverse nervous system effects reported with intranasal nicotine include headache, back pain, confusion, aphasia, amnesia, migraine, and numbness.191

The most common adverse nervous system effect associated with orally inhaled nicotine therapy is headache,244, 246 occurring in 26% of those receiving the drug versus 15% of those receiving placebo in clinical studies.244 Nervous system effects reported in greater than 3% of patients receiving orally inhaled nicotine therapy and attributed to manifestations of nicotine withdrawal included dizziness, anxiety, sleep disorder, mental depression, withdrawal syndrome, drug dependence, fatigue, and myalgia.244 Other adverse nervous system effects occurring in greater than 3% of patients receiving orally inhaled nicotine include pain, back pain, and paresthesias.244

Cardiovascular Effects Adverse cardiovascular effects, including myocardial infarction,144, 149, 164, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257 atrial fibrillation,165, 211 and cerebral ischemia (e.g., reversible cerebral arterial narrowing, stroke),211, 214, 215 have been reported rarely during transdermal nicotine therapy in patients with or without cardiovascular disease and who were abstinent or continued to smoke; whether such events were related to excessive nicotine intake or associated with underlying cardiovascular disease in these patients has not been established.43, 44, 144, 149, 164, 167, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220 However, nicotine replacement therapy with transdermal nicotine does not appear to be

associated with particular risk in patients with cardiovascular disease.102, 156, 196, 200, 211, 221, 242 257

In patients with stable coronary artery disease, the weekly frequency of angina did not differ between the group who received transdermal nicotine in a dosage of 14-21 mg daily or placebo for 5 weeks.156, 200, 211 Heart rate, hourly number of ventricular premature complexes or supraventricular premature beats, number of atrial or ventricular arrhythmias, and number of ischemic episodes (e.g., evidenced by ST-segment depression) during treatment with transdermal nicotine did not differ from baseline in the patients evaluated with ambulatory 24-hour ECG monitoring during the first and last week of treatment.200 In patients with at least one cardiovascular condition (e.g., history of myocardial infarction, history of coronary-artery bypass surgery or angioplasty, clinical history of angina, peripheral vascular disease), therapy over 10 weeks with transdermal nicotine at a dosage of 21 mg daily for 6 weeks, 14 mg daily over the next 2 weeks, and 7 mg daily during the final 2 weeks did not differ from placebo in the incidence of serious adverse effects, including the primary end points of death, myocardial infarction, cardiac arrest, or admission as an inpatient (because severity of angina increased or for arrhythmia or congestive heart failure) and the secondary endpoints of admission as an inpatient (for peripheral vascular disease, cerebrovascular disease, or other indications) or as an outpatient (because atherosclerotic cardiovascular disease [e.g., angina, arrhythmia, congestive heart failure] increased in severity).211, 221 Of the patients who continued to smoke during treatment with transdermal nicotine or placebo, a primary or secondary endpoint occurred in a greater proportion of smokers who received placebo.221 Of the group treated with transdermal nicotine, a primary or secondary endpoint occurred in a similar proportion of patients who achieved abstinence or who continued to smoke.221 The cardiovascular safety of transdermal nicotine therapy also is suggested by the observation that in smokers with coronary artery disease, the extent of exercise-induced myocardial ischemia, as indicated by total left ventricular perfusion defect size, was reduced compared with baseline during administration of transdermal nicotine initiated at 14 mg daily and then increased to 21 mg daily.211, 222, 223

Edema,1 flushing,1 hypertension,1 palpitation,1, 6, 96 tachyarrhythmias,1, 34 and tachycardia1, 34, 95 have been reported in patients receiving buccal nicotine polacrilex gum. Potentially serious cardiac irritability, which is an established effect of cigarette smoking, has occurred rarely in patients receiving the resin complex; in at least one patient receiving nicotine polacrilex gum, cardiac irritability resulted in reversible atrial fibrillation.1 Atrial fibrillation has been reported rarely with nicotine polacrilex gum.211, 224 However, the cardiovascular safety of nicotine polacrilex gum was indicated by analysis of data from over 3300 patients with chronic obstructive pulmonary disease.211, 225 Nicotine replacement therapy with nicotine polacrilex gum was not related to the occurrence of hospitalization or death secondary to cardiovascular disease over 5 years in these patients.225

Nicotine nasal spray with or without a cigarette smoked concomitantly did not affect either myocardial oxygen demand, as indicated by the product of heart rate and systolic arterial pressure, or the minimal luminal diameter of normal or stenosed coronary arteries in smokers who had smoked a first cigarette 20 minutes earlier.226 Since myocardial oxygen demand was increased and coronary arterial diameter was decreased after the first cigarette was smoked, the development of acute cardiovascular tolerance to nicotine is suggested by the lack of effect observed after nicotine nasal spray was administered and the second cigarette was smoked.226

Hypertension occurred in greater than 3% of patients receiving orally inhaled nicotine but was attributed to cigarette smoking rather than to nicotine replacement therapy.244 A trend toward decreased blood pressure and pulse rate has been associated with orally inhaled nicotine therapy.245 However, tachycardia and palpitations have been reported occasionally in patients receiving orally inhaled nicotine.244

Other Systemic Effects Hoarseness, sneezing, wheezing, breathing difficulty, and cough have been reported in less than 1% of patients receiving buccal nicotine polacrilex gum.1 Tinnitus also has been reported with the gum.1, 68 Systemic nicotine intoxication requiring hospitalization has occurred in at least one patient receiving the resin complex.1 (See Acute Toxicity.) Alterations in liver function tests also have occurred during therapy with the gum.1

Respiratory complaints reported with buccal nicotine polacrilex lozenges include upper respiratory tract infections, cough, and sore throat, occurring in 12, 4.1, and 2.6%, respectively, of patients receiving 2mg dosing regimens and in 9.8, 5.6, and 5.1%, respectively of those receiving 4-mg dosing regimens.263 Only cough was dose related, but only in those receiving 4-mg dosing regimens.263

Long-term (longer than 11 months) use of nicotine polacrilex gum has been associated with insulin resistance and hyperinsulinemia in healthy, non-obese, middle-aged men; the decrease in insulin sensitivity correlated with the extent of nicotine use, as determined by plasma cotinine concentrations.254

Other adverse effects that were dose related and/or reported more frequently with transdermal nicotine therapy than with placebo in clinical trials include arthralgia,101, 102, 103, 104, 105, 106, 107,

108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 myalgia,101, 102, 136 and diaphoresis.102, 103, 104, 109 Other adverse effects for which a causal relationship to transdermal nicotine therapy has not been definitely established include increased cough,136 pharyngitis,101, 102, 103 sinusitis,101, 102, 103, 104 and pain in the back,101, 102, 103, 104 chest,102, 109 or at other sites.102, 103, 104, 137 Dysmenorrhea,101, 102, 103, 104 dysgeusia,102, 104, 111 allergy,101 hypertension,101 and cerebral hematoma232 also have been reported.

Other adverse effects reported with intranasal nicotine and occurring in 2-5% of patients include dyspnea, arthralgia, menstrual disorder, palpitation, tooth disorder, gum problems, myalgia, acne, dysmenorrhea, and pruritus.191 Less commonly, peripheral edema, pain, numbness, allergy, hiccups, purpura, bronchitis, bronchospasm, increased sputum, rash, and vision abnormality have been reported with intranasal nicotine.191 Exacerbation of bronchospasm has occurred with intranasal nicotine in patients with preexisting asthma.191 Therefore, the use of the nasal spray is not recommended for patients with severe reactive airway disease.191 257

Chest discomfort and bronchitis occurred in greater than 3% of patients receiving orally inhaled nicotine but was attributed to cigarette smoking rather than to nicotine replacement therapy.244 Other adverse effects reported with orally inhaled nicotine and occurring in greater than 3% of patients include influenza-like symptoms and fever.244 Blood hemoglobin concentrations decreased by 5.2 mg/dL at 3 and 6 months of orally inhaled nicotine therapy.245

Precautions and Contraindications Patients with cardiac disease, recent myocardial infarction, or irregular heart rate should consult their clinician before initiating self-medication with nicotine preparations.188, 189, 190 A clinician also should be consulted prior to self-medication if the patient has peptic ulcer disease, is receiving insulin for the management of diabetes mellitus, or has uncontrolled hypertension or if they are receiving drug therapy for depression or asthma (since nicotine may alter the pharmacokinetics of such concomitant drugs)188, 189, 190 and, for the transdermal systems, if they are allergic to adhesive tape or have a dermatologic condition.188, 189 Nicotine preparations should not be used for self-medication in patients who will continue to smoke, chew tobacco, or use snuff or other nicotine-containing preparations.188, 189, 190

The risks of nicotine in patients with certain cardiovascular, peripheral vascular, and/or endocrine diseases should be weighed carefully against the benefits of including nicotine polacrilex or transdermal, intranasal, or orally inhaled nicotine therapy in a smoking cessation program in these patients.1, 97, 191, 244, 257 Although possible cardiac complications have been reported rarely in patients with

underlying cardiovascular disease who continued to smoke during transdermal nicotine therapy,144, 149, 164, 165, 211, 212, 213, 214, 215 transdermal nicotine therapy does not appear to be associated with particular risk in patients with cardiovascular disease.102, 156, 196, 200, 211, 221, 243, 257 (See Cautions: Cardiovascular Effects.) Despite the current lack of an established causal relationship between nicotine therapy and cardiac complications, nicotine polacrilex or the transdermal, intranasal, or orally inhaled drug should be used with caution and only after careful evaluation in patients with coronary artery disease (i.e., those with a history of myocardial infarction and/or angina pectoris), serious cardiac arrhythmias, or vasospastic diseases (e.g., Buerger's disease, Prinzmetal variant angina, Raynaud's phenomenon).101, 102, 103, 104, 144, 148, 149, 191, 244, 257 Because tachyarrhythmias occasionally have been reported during nicotine replacement therapy, discontinuance of such therapy is recommended if an increase in adverse cardiovascular effects occurs.1, 101, 102, 103, 104, 191, 244

Nicotine replacement therapy should be used with caution in patients with accelerated hypertension and only when the benefits of including such therapy in a smoking cessation program outweigh the risks, since nicotine is a risk factor for the development of malignant hypertension in these patients.1, 101, 102, 103, 104, 191, 244 Because cigarette smoking is believed to have a perpetuating role in hypertension, nicotine replacement therapy also should be used with caution in other patients with systemic hypertension.

It should be kept in mind that cessation of smoking, with or without nicotine replacement therapy, can affect the pharmacokinetics of certain concomitantly administered drugs.101, 102, 103, 104, 167, 191 (See Drug Interactions.)

Patients receiving nicotine polacrilex gum should be warned that chewing the gum too rapidly may result in effects similar to those associated with smoking a cigarette too rapidly or those experienced by nonsmokers when they inhale a cigarette for the first time.1 These effects include lightheadedness, nausea and vomiting, irritation of the throat and mouth, hiccups, and indigestion.1 Patients should also be advised about other adverse effects (e.g., mouth ulcers, jaw-muscle ache, headache, palpitation, hypersalivation) that may occur during nicotine polacrilex therapy, especially during the first few days of therapy.1 Patients should be warned that nicotine overdosage may occur if many pieces of the gum are chewed simultaneously or in rapid succession1 or if the gum is used concomitantly with cigarettes or other nicotine-containing products (e.g., chewing tobacco).43 Patients should also be advised to not attempt discontinuing therapy with nicotine polacrilex until their craving is satisfied by 1 or 2 pieces of the gum daily but to not continue therapy for longer than 6 months,1 unless otherwise instructed by their physician.9, 43, 65 Women who are or may become pregnant or who may consider nursing an infant should receive appropriate precautions regarding nicotine therapy.1, 191, 244 (See Cautions: Pregnancy, Fertility, and Lactation.)

Patients receiving nicotine polacrilex gum or lozenges should be instructed to contact their clinician or local poison control center immediately if they accidentally take an overdose of the drug or if a child or pet accidentally chews or swallows one or more pieces of the gum or lozenge.1, 264 Patients receiving buccal, transdermal, intranasal, or orally inhaled nicotine therapy should be advised regarding proper handling, storage, and disposal of these preparations and cautioned to keep the gum and lozenges as well as both unused and used systems, intranasal containers, and oral inhaler cartridges out of the reach of children and pets.101, 102, 103, 104, 191, 244 The amount of nicotine in both used and unused transdermal systems, intranasal spray containers, or oral inhaler cartridges could be toxic or fatal if applied or ingested by children or pets.101, 102, 103, 104, 191, 244 (See Acute Toxicity.) All other components of the nicotine oral inhaler system also should be kept out of reach of children and pets to avoid accidental swallowing and choking.244 Inhaler cartridges can be detected radiographically.244 Buccal formulations of the drug also could cause nicotine toxicity in children or pets.

Nicotine polacrilex preparations and transdermal, intranasal, or oral inhaler preparations of the drug should be used with caution in patients with hyperthyroidism, pheochromocytoma, or type 1 (insulindependent) diabetes mellitus, since nicotine stimulates the release of catecholamines from the adrenal medulla101, 102, 103, 104, 191, 244 and tolerance to this effect of nicotine apparently does not occur. The possibility that prolonged nicotine replacement therapy could result in hyperinsulinemia and insulin resistance should be considered.254

Because cigarette smoking delays healing of peptic ulcers, nicotine polacrilex preparations and transdermal, intranasal, or orally inhaled nicotine should be used with caution in patients with active or inactive peptic ulcer disease and only when the benefits of including such therapy in a smoking cessation program outweigh the risks.101, 102, 103, 104, 191, 244 Nicotine polacrilex gum also should be used with caution in patients with a history of esophagitis and in those with oral or pharyngeal inflammation1, 97 or a dental condition that might be exacerbated by chewing gum.1

Patients receiving nicotine polacrilex lozenges should be advised to discontinue the lozenges and contact a clinician if they develop mouth problems, persistent indigestion, severe sore throat, irregular heartbeat, palpitations, or symptoms suggestive of overdosage such as nausea, vomiting, dizziness, diarrhea, weakness, and rapid heartbeat.264 Commercially available nicotine polacrilex lozenges contain aspartame, which is metabolized in the GI tract to phenylalanine following oral administration.264 Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that each lozenge provides 3.4 mg of phenylalanine.264

Because the viscosity of nicotine polacrilex chewing gum is greater than that of normal chewing gum, use of the resin complex gum may cause occlusal stress when it is chewed for a long period of time which may displace dental restorations and/or result in loosening of dental inlays or fillings.1, 72 Although nicotine polacrilex reportedly has been used safely in patients wearing dentures,27, 43 the gum may stick to dentures, dental caps, or partial bridges.1, 72 The degree to which nicotine polacrilex gum sticks to dental material may depend on its composition and other factors such as the amount of saliva present, dryness of the mouth, salivary constituents, and possible interaction with denture adhesives or dental cleaning compounds.1 If excessive sticking or damage to dental work occurs, the patient should discontinue nicotine polacrilex therapy and consult a physician or dentist.1

Toxicity and addiction are possible with the use of nicotine from any source.101, 102, 103, 104, 244 Sustained use of nicotine polacrilex preparations or transdermal or orally inhaled nicotine should not be encouraged because chronic consumption of nicotine may result in intoxication and dependence (addiction).1, 81, 101, 102, 103, 104, 244 (See Chronic Toxicity.) In deciding whether to initiate therapy with nicotine polacrilex preparations or transdermal or orally inhaled nicotine, regardless of the presence of disease or pregnancy, the risk of nicotine replacement in a smoking-cessation program should be weighed against the hazard of continued smoking concurrent with nicotine-replacement therapy and the likelihood of achieving smoking cessation without such pharmacologic management.101, 102, 103, 104, 244

Patients who develop a severe or persistent skin reaction (e.g., severe erythema, pruritus, edema) at the site of application of a transdermal system of nicotine or a generalized skin reaction (e.g., urticaria, hives, rash) should be instructed to discontinue use of the transdermal system promptly and contact their physician.101, 102, 103, 104, 129 If contact sensitization to a transdermal system of nicotine occurs, patients should be advised that smoking or exposure to other products containing nicotine could result in a serious reaction.101, 102, 103, 104 (See Cautions: Local and Sensitivity Reactions.) Skin irritation with transdermal systems of nicotine may be more likely to occur in patients with certain dermatologic conditions, such as psoriasis or atopic or eczematous dermatitis.101, 102, 103, 104 Because nicotine can be a dermal irritant and cause contact sensitization, health-care workers should avoid unnecessary contact with transdermal systems of nicotine.101, 102, 103, 104 Health-care workers who handle a transdermal system of nicotine should avoid touching their eyes prior to handwashing and should wash their hands with water alone since soap reportedly may enhance percutaneous absorption of nicotine.101, 102, 103, 104, 167

The pharmacokinetics of nicotine have not been studied in patients with renal or hepatic impairment.101, 102, 103, 104, 244 However, the possibility that nicotine clearance could be reduced in

the presence of hepatic dysfunction should be considered since the drug is metabolized extensively in the liver and its systemic clearance depends principally on hepatic blood flow.101, 102, 103, 104, 244 Because nicotine is only minimally excreted in urine, altered renal clearance of the drug or its metabolites would be expected only in patients with severe renal failure.44, 101, 102, 103, 104, 244 (See Pharmacokinetics: Elimination.)

Nicotine oral inhaler has not be studied specifically in patients with asthma or chronic pulmonary disease.244 Nicotine is an airway irritant and might cause bronchospasm,244 and local irritation occurs commonly with orally inhaled nicotine.244, 245, 246 Therefore, nicotine replacement therapy via oral inhalation should be undertaken with caution in patients with bronchospastic disease, and other forms of replacement therapy might be preferable in patients with severe bronchospastic airway disease.244

Nicotine replacement therapy usually is contraindicated during the initial recovery phase of myocardial infarction (see Smoking Cessation: Smoking Cessation Therapy in Inpatients, under Uses), in patients with severe or worsening angina pectoris, in patients with life-threatening arrhythmias, and in women who are or may become pregnant (see Cautions: Pregnancy, Fertility, and Lactation);1, 43, 191, 244, 257 some clinicians suggest that use of a smoking cessation program that includes nicotine may be considered in some of these patients in whom other methods of smoking cessation are ineffective, but only when the potential benefits of nicotine therapy clearly justify the possible risks to the patient compared with the risks of continued cigarette smoking.43, 257 Nicotine polacrilex gum also is contraindicated in patients with temporomandibular joint disease, and transdermal, intranasal, or orally inhaled nicotine therapy also is contraindicated in patients with hypersensitivity or allergy to nicotine or to any other component in the respective preparations.101, 102, 103, 104, 191, 244 Intranasal nicotine also is not recommended for use in patients with a history of chronic nasal disorders (e.g., allergy, rhinitis, polyps, sinusitis) nor in patients with severe reactive airway disease.191, 257Nicotine oral inhalers also should not be used in patients with known hypersensitivity to menthol.244

Pediatric Precautions Safety and efficacy of nicotine polacrilex preparations264 or transdermal, intranasal, or orally inhaled nicotine in children and adolescents who smoke cigarettes have not been established,1, 101, 102, 103, 104, 191, 196, 244 and use of these preparations in pediatric patients currently is not recommended by the manufacturers.1, 43, 101, 102, 103, 104, 191, 244 However, the US Public Health Service (USPHS) states that nicotine replacement therapy may be considered for tobacco cessation therapy in adolescents when there is evidence of nicotine dependence and a desire to quit the use of tobacco.196, 257 Before instituting nicotine replacement therapy though, clinicians should be confident of the patient's dependence on tobacco and intention to quit, given the psychosocial and behavioral aspects of smoking in adolescents.257 Clinicians should consider such factors as degree of dependence on nicotine,

number of cigarettes smoked daily, and the patient's weight.257 While pharmacotherapy (e.g., nicotine replacement therapy, extended-release bupropion) can be considered for adolescents dependent on nicotine and there currently is no evidence of harm from such therapy in the pediatric population, the USPHS currently only recommends considerations of counseling and behavioral interventions in younger children.257

Clinicians in a pediatric setting also should offer smoking cessation advice and interventions to parents to limit exposure of children to second-hand smoke.257

Tobacco use in the pediatric population in the US is a major concern.257 It is estimated that more than 6000 children and adolescents try their first cigarette each day in the US, and that more than 3000 become daily smokers each day.257 Among adults who have ever smoked, about 90% tried their first cigarette and about 70% were daily users by age 18 years.257 Because tobacco use often begins during preadolescence, clinicians should routinely assess and intervene in this population.257 Young individuals vastly underestimate the addictiveness of nicotine.257

Geriatric Precautions The pharmacokinetics of nicotine have not been studied specifically in geriatric patients.101, 102, 103, 104, 244 However, smoking cessation interventions that have been shown to be effective in the general population also have been shown to be effective in adults 50 years of age and older. 257 The abstinence rates and adverse effects with transdermal or orally inhaled nicotine therapy in patients 60 years of age and older are comparable to those of younger adults.101, 102, 103, 104, 144, 196, 244

Mutagenicity and Carcinogenicity It is not known if nicotine is mutagenic or carcinogenic in humans.34, 43, 44, 66 Neither nicotine nor cotinine (the principal metabolite of nicotine) demonstrated evidence of mutagenicity in a microbial test system (Ames Salmonella test).101, 102, 103, 104 However, nicotine has induced repairable DNA damage in an E. coli test system and demonstrated genotoxicity in Chinese hamster ovary cells.101, 102, 103, 104 Although nicotine reportedly is not carcinogenic in animals, the drug and its metabolites increased the incidences of tumors in the cheek pouches of hamsters and in the forestomach of rats when administered with tumor initiators.101, 102, 103, 104, 244 In a study for which the results could not be replicated, cotinine appeared to cause lymphoreticular sarcoma in the large intestine of rats.101, 102, 103, 104, 244

The role of nicotine in initiating or promoting tumors in humans (e.g., cigarette smokers) has not been determined. Although the US Surgeon General has concluded that smoking is a major cause of lung cancer and of cancers of the larynx, oral cavity, bladder, and esophagus and is a contributing factor in the development of cancers of the pancreas, cervix, and kidney and that the risk of lung cancer is correlated positively with the tar and nicotine content of cigarettes,34, 35, 69 it is not known whether nicotine alone is carcinogenic.43, 44, 66, 97 Most evidence suggests that nicotine is not directly carcinogenic; however, the carcinogenic potential of nicotine-derived nitrosamines in the amounts achieved during nicotine polacrilex therapy remains to be determined.97

Pregnancy, Fertitlity and Lactation Pregnancy Nicotine may cause fetal harm when administered to pregnant women.1, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 101, 102, 103, 104, 191, 244 257 Although the exact mechanism has not been determined, cigarette smoking during pregnancy has been associated with fetal growth retardation, an increased risk of spontaneous abortion, and increased perinatal mortality.1, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 26, 34, 97, 99, 191, 244 Substantial evidence indicates that decreased birthweight in neonates born to women who smoke is in part caused by a direct vasoconstrictive effect of nicotine on uterine vasculature resulting in fetal hypoxia;14, 20, 21, 22, 23, 24, 34, 97, 196 the effects of carbon monoxide in cigarette smoke also have been implicated.1, 196

Rapid IV infusion of nicotine (up to 2 mg/kg) in pregnant rhesus monkeys caused acidosis, hypercarbia, and hypotension (fetal and maternal nicotine concentrations were about 20 times those achieved after smoking one cigarette in 5 minutes).1, 101, 102, 103, 104, 244 Reduction of fetal respiratory movement was observed in the fetal lamb after IV injection of nicotine in the ewe at a dose equivalent to smoking one cigarette every 20 seconds for 5 minutes (0.25 mg/kg).1, 101, 102, 103, 104, 244 In pregnant rhesus monkeys, IV infusion of nicotine at a dosage of 0.2 mg/kg over 20 minutes (equivalent to smoking 120 cigarettes over 20 minutes) reduced uterine blood flow by about 30%.1, 101, 102, 103, 104, 244 Spontaneous abortion rates may be higher in women who smoke and the frequency appears to be related directly to the number of cigarettes smoked.1, 14, 26, 34, 244 Although a direct causal relationship has not been established, at least one spontaneous abortion reportedly occurred during nicotine polacrilex therapy.1 Nicotine has produced skeletal abnormalities in the progeny of mice given the drug subcutaneously or intraperitoneally at a dose known to be toxic to the dams (25 mg/kg).101, 102, 103, 104 Studies in rats and monkeys using nicotine doses similar to those associated with cigarette smoking have not revealed evidence of teratogenicity.1

The teratogenic potential of cigarette smoking or nicotine in humans has not been clearly established.101, 102, 103, 104, 128, 139, 244 Although several studies suggest that tobacco smoke has transplacental carcinogenic effects, the role of nicotine in the transplacental effects of tobacco smoke has not been fully elucidated.34, 35 Cigarette smoking and use of nicotine polacrilex gum during the latter stage of pregnancy have both been associated with decreased fetal breathing movement, possibly resulting from a nicotine-induced decrease in placental perfusion;1, 101, 102, 103, 104, 128 increased fetal total aortic blood flow and heart rate and decreased uterine blood flow also have been noted.1, 101, 102, 103, 104 Nicotine polacrilex (administered as one or two 2- or 4-mg pieces of gum delivering 1-4 mg of nicotine) reportedly had less effect on these parameters than cigarette smoking.1 However, in a limited study of pregnant (e.g., between 24-36 weeks of gestation) women who continued to smoke at least 10 cigarettes daily for 5 days or who discontinued smoking and began taking nicotine polacrilex gum for 5 days at a dosage of at least 6 pieces of 2-mg gum (up to 30 pieces) daily chewed at a rate not to exceed 2 pieces hourly, there were no differences between the groups in changes in maternal or fetal hemodynamic measurements (e.g., maternal heart rate and mean arterial pressure, fetal heart rate, uterine resistance index, umbilical resistance index).227 The maternal serum cotinine concentration after 5 days was decreased with nicotine polacrilex gum but did not change with continuance of smoking.227 Peak and trough maternal serum nicotine concentrations after 5 days were lower with nicotine polacrilex gum than with continuance of smoking.227 Spontaneous abortion has been reported during nicotine replacement therapy; as with smoking, nicotine as a contributing factor cannot be ruled out.191, 244

The effects of nicotine delivered by a transdermal system have been studied in a limited number of pregnant women.228 In pregnant (e.g., between 27-38 weeks of gestation) smokers who did not smoke cigarettes during the study, application for 6 hours of a transdermal system that delivered nicotine at a rate of 21 mg/24 hours did not result in changes in measures of fetal well-being (e.g., biophysical profiles, heart rate, umbilical artery Doppler examination, uterine activity) nor were maternal vital signs affected adversely.228 The effects of nicotine delivered intranasally have not been studied in pregnant women.191 Some clinicians have suggested that the risk to the fetus may be less with nicotine replacement therapy than with cigarette smoking because plasma nicotine concentrations with nicotine polacrilex or transdermal or intranasal nicotine therapy usually are similar to or lower than those produced by cigarette smoking and neither mother nor fetus is exposed to carbon monoxide or other hazardous substances in cigarette smoke.128, 140, 194, 195 Women who do not stop smoking on their own early in pregnancy are likely to be highly nicotine dependent.196

Smoking cessation programs consisting of behavioral and educational rather than pharmacologic interventions should be tried in pregnant women before nicotine polacrilex or transdermal, intranasal, or orally inhaled nicotine therapy is considered.1, 101, 102, 103, 104, 128, 191, 194, 195, 196, 244, 257, 264 Therapy with nicotine polacrilex or transdermal, intranasal, or orally inhaled nicotine should be used during pregnancy only if the increased likelihood of smoking cessation, with its potential benefits,

justifies the potential risk to the fetus and patient of nicotine replacement and possible continued smoking.1, 101, 102, 103, 104, 128, 191, 194, 195, 196, 244, 257, 264 Smoking cessation without nicotine replacement therapy may be difficult in women who experience withdrawal symptoms after attempting to quit.196 Patients who receive therapy with nicotine polacrilex or transdermal, intranasal, or orally inhaled nicotine during pregnancy or who become pregnant while receiving such treatment should be informed of the potential hazard to the fetus.196 In general, relatively low doses and short durations as well as dosage forms that yield intermittent rather than continuous drug exposure (e.g., nicotine polacrilex gum rather than transdermal nicotine) should be employed if nicotine replacement is used during pregnancy so that potential fetal exposure to nicotine can be minimized.196, 257 Although smoking cessation prior to conception or early in pregnancy is most beneficial, health benefits result from cessation at anytime; therefore, efforts to encourage smoking cessation should persist for women who continue smoking after conception.195, 196 257

Postpartum follow-up of women who stop smoking during pregnancy is important since there is a high rate of relapse during the postpartum period, even for women who maintained total abstinence for 6 months or longer during pregnancy.195, 196, 257 Relapse may be decreased by continued emphasis on the relationship between maternal smoking and poor health outcomes (e.g., sudden infant death syndrome, respiratory infections, asthma, middle ear disease) in infants and children.195 257

Fertility Reproduction studies in female rats have shown a decrease in litter size in those animals receiving nicotine during the time of fertilization.1, 101, 102, 103, 104 Nicotine inhibits DNA synthesis in rats and rabbits, which has resulted in delayed or inhibited implantation.101, 102, 103, 104 The effects of nicotine on the mother and fetus during labor are not known, and the use during labor and delivery of nicotine polacrilex or a transdermal nicotine system is not recommended by the manufacturers.101, 102, 103, 104

Lactation Nicotine is distributed into milk in a milk to plasma ratio averaging 2.9.1, 34, 70, 73, 101, 102, 103, 104, 191, 244, 257 Proper use of nicotine polacrilex preparations or transdermal, intranasal, or orally inhaled nicotine would be expected to produce lower concentrations of nicotine in milk than would cigarette smoking because of lower maternal plasma nicotine concentrations with nicotine-replacement therapy.1, 101, 102, 103, 104, 191, 244 Although some clearance of orally absorbed nicotine in infants will occur through first-pass metabolism in the liver, the efficiency of nicotine removal probably is lowest at birth.1, 101, 102, 103, 104, 191, 244 The safety of nicotine replacement therapy in infants who are breast-feeding has not been evaluated.1, 101, 102, 103, 104, 191, 244 Whether to use nicotine

polacrilex or transdermal, intranasal, or orally inhaled nicotine in a nursing woman should be based on comparison of the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke from continued smoking by the mother, and those associated with use of such nicotine replacement therapy alone or concomitantly with continued smoking.1, 101, 102, 103, 104, 191, 244

Drug Interactions

Smoking Cessation Cessation of smoking, with or without subsequent administration of nicotine replacement therapy, may alter the response to concomitant administration of various drugs in patients who previously smoked.1, 93, 191, 244 Smoking, via enzyme induction, has been shown to increase the metabolism of some drugs including caffeine, theophylline, imipramine, oxazepam, pentazocine, and certain -adrenergic blocking agents (e.g., propranolol), thereby increasing elimination and decreasing blood concentrations of these drugs.1, 34, 57, 93, 191, 244Cigarette smoke is a complex mixture of substances,34, 57 and only a few of its components have been studied for their effects on drug disposition;57 although polycyclic aromatic hydrocarbons are thought to be principally responsible for enzyme induction by cigarette smoke,57, 93 nicotine also has been shown to be an enzyme inducer.34, 53, 57 Cessation of smoking may result in increased blood concentrations of these drugs.1, 34, 93, 191 Cessation of smoking also may decrease the metabolism of propoxyphene during first pass through the liver and may decrease the absorption of glutethimide.1, 57 Therefore, the effect of cessation of smoking in patients receiving nicotine polacrilex or transdermal, intranasal, or orally inhaled nicotine therapy should be considered when the patient is receiving other drugs concomitantly.43, 44, 101, 102, 103, 104, 191, 244 Since smoking decreases the diuretic effects of furosemide and antagonizes the decreased cardiac output and hypotensive effect induced by propranolol, possibly as a result of nicotine's hormonal (i.e., secretion of vasopressin) and sympathomimetic effects, cessation of smoking may reverse these actions.1, 57, 191

Nicotine polacrilex does not appear to affect theophylline elimination.93 In otherwise healthy smokers (1 pack or more daily), abstinence from smoking for 1 week reduced total body clearance of theophylline from plasma by 32-38% and increased elimination half-life by 36-40%; subsequent use of nicotine polacrilex gum for 1 week (4 mg hourly for 12 hours daily) did not affect theophylline clearance or elimination half-life.93 Because plasma theophylline concentrations may increase to toxic levels during smoking cessation, with or without nicotine polacrilex, in previously stabilized smokers, plasma theophylline concentrations should be monitored closely and dosage adjusted accordingly during smoking cessation or short-term abstinence.93

 Bupropion The manufacturer of extended-release bupropion states that patients can receive the drug concomitantly with transdermal nicotine therapy if indicated for smoking cessation.240 If combined therapy is employed, the usual precautions of each drug should be considered.240 In the principal clinical study that initially established the efficacy of bupropion for smoking cessation, current use of nicotine replacement therapy was an exclusion criteria for eligibility to participate in the study; therefore, the risks and benefits of combined therapy were not assessed by this study.243 However, the manufacturer of bupropion reported a possible increased risk of hypertension during combined therapy (2.5% alone versus 6.1% combined), and the possibility of treatment-emergent hypertension should be considered when nicotine replacement therapy is used concomitantly with bupropion.240

Sympathomimetic and Sympatholytic Drugs Because smoking and nicotine can increase circulating plasma concentrations of cortisol and catecholamines, it may be necessary to adjust dosage of sympathomimetic (adrenergic) or sympatholytic (adrenergic blocking) agents according to changes in nicotine therapy or smoking status.1 Absorption of nicotine from a transdermal system was delayed substantially in adult male smokers who received concomitant IV infusion of nicotine as part of a bioavailability study, suggesting that drugs producing cutaneous vasoconstriction (e.g. sympathomimetic agents) or vasodilation (e.g., antihypertensive agents) potentially may alter the absorption of nicotine from transdermal systems.45

Other Drugs Subcutaneous insulin absorption may increase following smoking cessation.191

Use of a nasal vasoconstrictor can delay achievement of peak nicotine concentrations following intranasal administration of nicotine.191

Food Acidic beverages (e.g., coffee, juices, carbonated soft drinks) may inhibit buccal absorption of nicotine from nicotine polacrilex gum or orally inhaled drug by transiently decreasing the pH of the saliva below that necessary for optimum absorption of the drug.100, 257 Eating and drinking anything other than water should therefore be avoided for 15 minutes before and during chewing of nicotine polacrilex gum.1, 100 257

Acute Toxcicity

Limited information is available on the acute toxicity of nicotine polacrilex,1 transdermal systems of nicotine after either oral ingestion or topical administration,1, 2, 3, 36, 37 nasal solutions of nicotine after either oral ingestion or topical (to the nose, eyes, ears, or oral mucosa) administration,191 or cartridges of the oral inhaler after either oral ingestion or topical (to the oropharyngeal or bronchopulmonary mucosa) administration.244

Pathogenesis Nicotine is one of the most toxic of all poisons, and toxic effects develop rapidly following acute overdose.36 The minimum acute lethal dose of nicotine in adults is reported to be 40-60 mg orally (less than 1 mg/kg).1, 191 Oral nicotine doses of 0.6-0.9 mg/kg are probably lethal in humans.36 Toxicologic studies in animals have shown that the oral LD50 of nicotine exhibits species variability, exceeding 24 mg/kg in rodents and 5 mg/kg in dogs.1, 191 In rodents, lethal doses of nicotine produce respiratory paralysis.1

Although overdosage with nicotine polacrilex can occur if many pieces of the gum are chewed simultaneously or in rapid succession or if the gum is used concomitantly with cigarettes or other nicotine-containing products (e.g., chewing tobacco), the risk of overdosage as a result of swallowing the gum is minimal since, in the absence of chewing, GI absorption of nicotine from the intact gum is slow and incomplete,1, 2, 25, 43 and nicotine that is released from the gum undergoes extensive metabolism during first pass through the liver;4, 5, 12, 34 in addition, nicotine-induced nausea and vomiting would be likely to prevent substantial absorption of the drug from the GI tract.1 No adverse effects were seen in healthy adults following simultaneous ingestion (i.e., swallowing without chewing) of 10 pieces of 4-mg nicotine polacrilex gum (40 mg of nicotine total).2 The resulting blood nicotine concentrations in these individuals were similar to those achieved following smoking of one cigarette.2

A used Habitrol, Nicoderm, Nicotrol, or Prostep transdermal system delivering 21, 21, 15, or 22 mg/day contains approximately 60, 73, 40, or 27% of its initial drug content, corresponding to 32, 83, 10, or 8 mg of nicotine.101, 102, 103, 104 In a study in adult smokers with an average weight of 74 kg, oral ingestion of a gel matrix (i.e., Prostep) containing 8 mg of nicotine produced peak plasma nicotine concentrations averaging 9.5 ng/mL 2 hours after administration and resulted in some adverse GI effects (e.g., burning after ingestion, nausea).103 Plasma nicotine concentrations in these individuals declined to baseline within 8 hours.103

A full container of nicotine nasal spray (Nicotrol NS) contains 100 mg of the drug, which is a lethal dose, and some nicotine may remain in the bottle once it is discarded.191

The effects of orally inhaling nicotine from several cartridges of the inhaler in rapid succession currently are not known.244 Because each cartridge delivers only about 4 mg of the drug when inhaled orally, excessive overdosage is unlikely in adult smokers via inhalation.244 However, the amount of nicotine that can be tolerated by an adult smoker can produce manifestations of nicotine toxicity and could prove fatal if the nicotine from cartridges were inhaled, ingested, or buccally absorbed by a child or pet.244 A used Nicotrol inhaler cartridge contains approximately 60% of its initial content, corresponding to about 6 mg of nicotine.244

Manifestations Although toxicity from nicotine polacrilex overdosage will most likely be minimized as a result of the early nausea and vomiting that occur following excessive nicotine exposure, systemic toxicity may occur.1 Systemic nicotine intoxication requiring hospitalization has occurred in at least one patient receiving the nicotine polacrilex.1 The patient fully recovered after 4 days, but suddenly died 1 month later; the patient did not receive nicotine polacrilex during this 1-month interval.1 A direct causal relationship between nicotine polacrilex and the patient's death has not been established.1

In general, overdosage of nicotine polacrilex gum or transdermal systems, nasal solutions, or oral inhalers of nicotine may be expected to produce effects that commonly are associated with acute nicotine intoxication.1, 191, 244 Signs and symptoms of acute nicotine intoxication include nausea, hypersalivation, abdominal pain, vomiting, diarrhea, perspiration, headache, dizziness, hearing and visual disturbances, mental confusion, and marked weakness.1, 4, 36, 97, 191, 244 Syncope, prostration, dyspnea, seizures, hypotension, and a weak, rapid, irregular pulse subsequently may occur.1, 4, 36, 191, 244 Lethal doses rapidly produce seizures, and death may occur within a few minutes following severe nicotine overdosage as a result of respiratory failure secondary to paralysis of respiratory muscles.1, 4, 36, 97, 191, 244

Acute nicotine intoxication has occurred after simultaneous application of multiple (2-20) transdermal systems of nicotine that delivered 21 or 22 mg/24 hours, although concurrent ingestion of other drugs may have been responsible for some of the manifestations.230 Neurologic manifestations included ataxia, coma, confusion, incoherence, diabetes insipidus, dizziness, lethargy, increased sleeping, seizures that were refractory to anticonvulsant agents, slurring of speech, stupor, and weakness.230 GI manifestations included nausea and vomiting.230 Dermatologic manifestations included flushing, paleness, and perspiration.230 Cardiovascular manifestations included arrhythmias, prolongation of the

QT interval, high blood pressure, and low blood pressure.230Aspiration pneumonitis and impairment of respiratory function that required mechanical ventilation briefly also occurred.230 Cardiac arrest has resulted possibly for acute nicotine intoxication while wearing a transdermal system of nicotine.229

Nicotine nasal solution would be expected to be irritating if sprayed into the eyes, oral mucosa, or ears.191 The risk of systemic overdosage with such exposure is not known.191 Intranasal overdosage would be expected to produce typical manifestations of nicotine toxicity.191

Treatment Oral Overdosage The manufacturers state that treatment of acute overdosage with nicotine polacrilex gum or transdermal systems, nasal solutions, or oral inhaler cartridges of nicotine generally involves symptomatic and supportive care and should include measures that are used for the treatment of acute nicotine intoxication; there is no specific antidote for nicotine intoxication.1, 43, 101, 102, 103, 104, 191, 244 Cases of oral ingestion of transdermal systems or oral inhaler cartridges of nicotine should be treated in a health-care facility.101, 102, 103, 104, 244 If vomiting has not occurred following acute ingestion of an overdose, the stomach should be emptied immediately by inducing emesis or by gastric lavage.1, 4 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage with a widebore tube may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.101, 102, 103, 104, 244 Because acute nicotine intoxication can result in seizures, activated charcoal should be administered following gastric lavage and/or emesis to decrease absorption of nicotine.101, 102, 103, 104, 244 If a transdermal system or oral inhaler cartridge has been ingested, activated charcoal should be administered repeatedly for as long as the system or cartridge remains in the GI tract because nicotine release from the system or cartridge will continue for many hours.101, 102, 103, 104, 244 Administration of a saline cathartic or sorbitol may be used to increase GI transit of the gum, transdermal system, or oral inhaler cartridge or of the activated charcoal. Vigorous fluid support and/or other appropriate therapy should be instituted if hypotension and/or cardiovascular collapse occur.1, 191, 244 Seizures usually may be controlled by IV administration of a benzodiazepine (e.g., diazepam) or short-acting barbiturate.101, 102, 103, 104, 191, 244 Atropine may be given for bradycardia, excessive bronchial secretions, or diarrhea.43, 101, 102, 103, 104, 191, 244 Assisted pulmonary ventilation may be necessary for the management of respiratory paralysis following severe nicotine intoxication.101, 102, 103, 104, 191, 244

Topical Overdosage If signs or symptoms of acute nicotine intoxication occur in patients receiving transdermal nicotine therapy, the transdermal system should be removed promptly and immediate medical care sought.101,

102, 103, 104 The skin may be flushed with water to remove nicotine and then dried, but soap should not be used because it reportedly may increase dermal absorption of the drug.101, 102, 103, 104, 167 It should be kept in mind that systemic absorption of nicotine from a transdermal system will continue for several hours after removal of the system because of the presence of a skin depot of the drug.101, 102, 103, 104

If the nasal solution of nicotine is sprayed inadvertently into the eye, the affected eye(s) should be treated with copious irrigation (e.g., with water) for 20 minutes.191 Irritation also can result from inadvertent exposure of the oral mucosa or inner ear to the nasal spray.191

Although the risk of excessive overdosage following oral inhalation of nicotine from inhaler cartridges that deliver about 4 mg of drug is low in adult smokers, if manifestations of acute nicotine intoxication occur following oral inhalation of the drug, a clinician or poison control center should be contacted immediately for emergency information.244 The possibility that severe, potentially fatal overdosage could occur following oral inhalation of nicotine in a child should be considered.244

Chronic Toxcicity

Pathogenesis Tolerance and psychologic and physical dependence may occur in patients who smoke cigarettes.1, 2, 12, 34, 54, 97 Nicotine is the dependence-producing component in tobacco;12, 34, 51, 54, 97 however, other factors such as social reinforcement, environmental factors (e.g., advertising), and learning behavior may contribute to tobacco dependence.12, 43, 50, 54, 67, 78 All patients who smoke cigarettes do not become dependent on nicotine; however, most patients who habitually smoke more than 10-15 cigarettes per day (particularly cigarettes with a nicotine yield of 0.9 mg or more) develop some degree of dependence.1, 2, 43

The possibility of transference of nicotine dependence exists during nicotine replacement therapy.1, 81, 87, 88, 90, 96, 97, 98, 191, 195, 244 257

Some smokers who use nicotine polacrilex as an adjunct for smoking cessation may develop physical and/or behavioral dependence on the gum.1, 87, 88, 195, 196 Withdrawal symptoms similar to those associated with withdrawal of cigarette smoking have occurred when nicotine polacrilex was

discontinued abruptly.87, 88, 196 In addition, some patients may continue using nicotine replacement for prolonged periods beyond the time when they were advised to stop the gum.5, 6, 7, 88, 90, 91, 96, 98, 195 In a study in patients receiving nicotine polacrilex gum for smoking cessation, patients who continued to use the gum at 1 year after initiation were heavier and more dependent smokers and used substantially more gum during the prescribed 3 months of therapy than those not using gum at 1 year.98 Studies also suggest that 15-20% of successful smoking abstainers given free access to nicotine polacrilex gum will continue to use the gum for a year or longer.98, 195

Tolerance to the adverse CNS-mediated effects of hiccups, nausea, and emesis associated with the use of small doses of nicotine usually develops in patients who smoke; however, overdosage will produce toxic symptoms even in nicotine-dependent patients who have developed tolerance.1, 12, 97 Tolerance to all effects of nicotine does not develop uniformly; patients who smoke cigarettes reportedly do not develop substantial tolerance to the catecholamine-releasing effects of nicotine.1, 97 Although the exact mechanism of tolerance to nicotine has not been determined, it has been suggested that nicotine may induce its own metabolism34, 57 and that the number of central nicotine receptors may decrease during prolonged use;50, 59 behavioral tolerance also has been shown to occur during nicotine use.50

The potential for abuse of transdermal or orally inhaled nicotine is likely to be low compared with cigarette smoking because absorption of nicotine is slower, plasma nicotine concentrations are lower and exhibit less fluctuation, and, in the case of the transdermal systems, the systems are applied only once daily.101, 102, 103, 104, 136, 244 Results of a randomized study in a limited number of smokers who received transdermal nicotine therapy in a dosage of 22 or 44 mg (i.e., one or 2 systems) daily for 7 days suggest that these systems have a low potential for abuse (as measured by "liking" scores).103, 122 Local irritant effects of orally inhaled nicotine might discourage abuse of the preparation.255 However, the potential exists for transference of nicotine dependence from cigarette smoking to transdermal or orally inhaled nicotine.101, 102, 103, 104, 244

The potential for abuse and dependence of nicotine nasal spray appears to be greater than that for other formulations of nicotine (i.e., nicotine polacrilex gum, transdermal nicotine systems) but less than that of cigarettes.191, 196, 201, 202, 257 Such variation results from differences between these sources of nicotine in the characteristics of pharmacokinetics and dosing that are associated commonly with dependence and abuse.191, 201, 202 More rapid onset of effect, greater capacity for patients to titrate the dosage, and frequent and rapid fluctuations in plasma nicotine concentration distinguish nicotine nasal spray from nicotine polacrilex gum and transdermal systems of nicotine.191, 201, 202 However, local irritant effects of the nasal spray might discourage abuse of the preparation.255 In clinical studies, dependence on nicotine nasal spray occasionally occurred, which may represent transference of nicotine dependence from cigarette smoking.191, 196, 201, 202 Feeling dependence on the nasal spray was reported by 32 or 13% of patients who received nicotine nasal spray or placebo, respectively.191

Nicotine nasal spray was continued for 6-12 months by 10-20% of treated patient studied191, 202 in clinical trials in which 3 months was recommended as the duration of therapy,191, 201, 202 while a higher dosage than recommended was administered by 5% of the patients.191 Anxiety about discontinuance of therapy was experienced or craving for nicotine nasal spray rather than for cigarettes was reported by some of these patients.191 At follow-up at 1 year in studies in which the recommended duration of nicotine nasal spray therapy was 3 months, 29-43% of the patients who achieved abstinence with nicotine nasal spray had not discontinued its use.191, 201, 202 Probable dependence on nicotine nasal spray was observed in several of these patients.191

Pathogenesis Withdrawal symptoms (which usually appear within 24 hours of abstinence) are extremely variable in character, severity, and duration and may include craving for tobacco, irritability, anxiety, difficulty in concentrating, restlessness, impatience, mental depression, hostility, frustration, headache, drowsiness, and GI disturbances.2, 54, 78, 79, 80, 87, 88, 97, 191, 244 In addition, decreases in heart rate and blood pressure, increased skin temperature, and various EEG changes have occurred.2, 54, 79, 80, 88, 97 In general, abstinence symptoms persist for several days to weeks following withdrawal of nicotine.2, 54, 97 However, craving to smoke tobacco, which is the most common and clinically important withdrawal symptom, may persist for years; some patients who have been abstinent for up to 9 years reportedly continue to have occasional cravings to smoke tobacco.2 It may be difficult to distinguish between withdrawal symptoms and the emergence of psychologic traits that were suppressed, controlled, or altered by nicotine.54

Pathogenesis Treatment of nicotine dependence includes behavioral approaches and combined behavioral and pharmacologic therapy.97, 194, 195, 196 Behavioral approaches are most successful when they include multiple components such as aversive smoking, group support, skills training, and self-reward, although too many components may reduce the success.97 Nicotine replacement therapy can be used as one such component to treat nicotine dependence resulting from tobacco use (see Uses: Smoking Cessation),97, 196 since such therapy has been shown to reduce withdrawal symptoms associated with such dependence2, 50, 78, 79, 80, 97, 196 and may enhance the efficacy of behavioral therapy.1, 2, 5, 7, 8, 9, 29, 68, 89, 96, 97, 196 However, transference of dependence to nicotine replacement therapy may occur.1, 81, 87, 88, 90, 96, 97, 98, 191, 195, 196

To minimize withdrawal symptoms87 and the risk of dependence on nicotine, patients should be encouraged to withdraw gradually or discontinue use of nicotine polacrilex gum or transdermal or intranasal nicotine after 2-3 months,1, 2, 3, 36, 191, 195, 244 if therapy has not already been

discontinued.43 Although weaning from nicotine replacement should be encouraged,1, 195, 244 continued use of nicotine replacement clearly is preferable to a return to smoking with respect to health consequences,195 and therefore some patients may benefit from more prolonged therapy.9, 43, 65, 96, 98, 195, 244 Progressive reduction of the transdermal nicotine dosage every 2-4 weeks prior to cessation of nicotine replacement therapy has not been found to result in increased craving for nicotine.136

Pharmacology

Nicotine is a ganglionic (nicotinic) cholinergic-receptor agonist.1, 4, 34, 50, 97, 169, 171 The pharmacologic actions of nicotine are complex and include a variety of effects mediated by stereospecific binding to receptors in autonomic ganglia, the adrenal medulla, the neuromuscular junction, and the brain.1, 4, 34, 43, 97, 101, 102, 103, 104, 169, 170, 171, 172 The effects of the drug are generally dose related; large doses can produce toxic symptoms1, 4, 97 (see Acute Toxicity). Chronic use of nicotine may result in psychologic and physical dependence, and tolerance to some of the pharmacologic effects may occur.1, 2, 12, 34, 50, 97 (See Chronic Toxicity.) As adjuncts in the cessation of cigarette smoking, nicotine polacrilex and transdermal systems of nicotine provide alternative sources of nicotine that help reduce the withdrawal symptoms associated with nicotine dependence.1, 2, 50, 78, 79, 80, 97, 101, 102, 103, 104 (See Chronic Toxicity). It also has been suggested that chewing the resin complex-containing gum may act as a substitute oral activity in behavior modification.5

Nervous System Effects Nicotine exhibits both stimulant and depressant effects in the peripheral and central nervous systems.1, 4, 34, 43, 50, 97, 172

Peripheral Nervous System The principal pharmacologic effect of small doses of nicotine is initial, transient stimulation of autonomic ganglia; large doses or prolonged neuronal receptor exposure to nicotine results in subsequent persistent depression of receptor activity.4, 43, 50, 97, 172 Although nicotine has similar dose-related effects at the myoneural (neuromuscular) junction, rapidly developing skeletal muscle paralysis obscures the stimulant phase.4 The muscle-relaxant properties of nicotine may be mediated through stimulation of Renshaw cells and pulmonary afferent nerves, which results in inhibition of skeletal muscle motor activity; such relaxant effects may contribute to the behavior-reinforcing effects of the drug.97, 172 Small doses of nicotine directly stimulate sympathetic ganglia and facilitate

neurotransmission;4, 97 however, large doses produce initial ganglionic stimulation, which is quickly followed by inhibition of neurotransmission.4, 97

Nicotine has a dose-related, biphasic action on the adrenal medulla.4 Nicotine reportedly stimulates the release of catecholamines from myocardial chromaffin tissue and from the adrenals.34, 97 At low concentrations, nicotine causes the release of catecholamines, while at high concentrations, the drug inhibits the release of catecholamines in response to splanchnic neuronal stimulation.4 Nicotine also causes the release of catecholamines from other sites, resulting in a sympathomimetic response that may be blocked by sympatholytic agents.4 Tolerance to the catecholamine-releasing effects of nicotine reportedly does not occur.1, 97

Like acetylcholine, nicotine directly stimulates a variety of peripheral sensory receptors including mechanoreceptors that respond to stretch or pressure of the skin, mesentery, tongue, lung, and stomach; chemoreceptors of the aortic and carotid bodies; thermal receptors of the skin and tongue; and pain receptors.4

Central Nervous System Nicotine produces marked CNS and respiratory stimulation.4, 50, 97, 172 Nicotine-induced CNS stimulation may result in tremors; with increasing doses (i.e., toxic doses), seizures may subsequently develop.4, 36, 97 Delirium may also occur at toxic doses.1 The effect of nicotine on respiration following large doses is mediated via a direct effect on the medulla oblongata; however, small doses of the drug reflexly stimulate respiration via stimulation of chemoreceptors of the aortic and carotid bodies.4, 171 Nicotine-induced CNS stimulation is followed by depression; following exposure to large doses of the drug, death may occur as a result of respiratory failure secondary to centrally mediated paralysis and peripheral blockade of the muscles of respiration.4, 97, 171

Some evidence suggests that the behavior-reinforcing properties of nicotine may be the result of stimulant effects (e.g, increased alertness and cognitive performance) in the cerebral cortex and "reward" effects mediated through the mesolimbic dopaminergic system.1, 101, 102, 103, 104, 169, 171, 173, 174, 175 The stimulant effects of nicotine reportedly predominate at low doses, while high doses provide reward effects.1, 101, 102, 103, 104

Nicotine produces emesis by direct stimulation of the medullary chemoreceptor trigger zone (CTZ) and via stimulation of vagal and spinal nerves that transmit afferent impulses from the GI tract to the vomiting center in the lateral reticular formation.4, 171

Cardiovascular Effects The cardiovascular effects of nicotine generally are dose dependent and are mediated principally via stimulation of sympathetic ganglia and the adrenal medulla and via release of catecholamines from neuronal tissue (e.g., sympathetic neurons, chromaffin cells).4, 34, 43, 50, 172 At low doses similar to those associated with cigarette smoking, the cardiovascular effects of nicotine appear to be mediated principally by the CNS, through activation of chemoreceptor afferent pathways or by direct effects on the brain stem.97, 172 At higher doses, the drug may act directly on the peripheral nervous system, producing ganglionic stimulation and adrenal catecholamine release.97, 172 The sympathomimetic activity of nicotine is also mediated via the drug's effects on chemoreceptors of the aortic and carotid bodies.1, 4, 34 Relatively small doses of nicotine produce peripheral vasoconstriction and increase heart rate, myocardial contractile force, cardiac output, stroke volume, velocity of myocardial contraction, and blood pressure, resulting in an increase in cardiac work and oxygen consumption;1, 4, 34, 171, 172 however, large doses of the drug may cause hypotension.1, 4, 172

Results of studies comparing the cardiovascular effects of nicotine polacrilex with those induced by cigarette smoking have shown that each source of nicotine produces similar dose-dependent effects;1 however, when nicotine polacrilex (2 mg/piece) is used by former smokers at a rate not exceeding 1 piece/hour, the cardiovascular effects produced by the gum are similar to those of placebo or baseline.1, 95 In patients with coronary artery disease, 4-mg doses of nicotine polacrilex may decrease myocardial contractility in ischemic myocardial regions, with an overall reduction in contractility in patients with severe disease.97 Such doses increased contractility in healthy individuals.97 Small increases in heart rate and blood pressure generally have been noted in patients receiving therapy with various transdermal systems of nicotine.101, 102, 103 In one study, patients receiving therapy with a Nicoderm transdermal system delivering 21 mg per 24 hours and patients who smoked cigarettes every 30 minutes during waking hours over a 5-day period had similar increases in heart rate (approximately 10 bpm) and blood pressure (approximately 5 mm Hg) over a 24-hour period, including during sleep, compared with measurements during an abstinence period.102

In a study of healthy smokers who were refraining from smoking and were on their fourth hour of application of a transdermal system of nicotine that delivered 21 mg per 24 hours, concurrent administration of nicotine polacrilex at 4 hours as a single dose of 4 mg chewed over 30 minutes resulted in transient increases in systolic and diastolic blood pressure and heart rate.238 Such effects also were observed when the dose of nicotine polacrilex was followed immediately by 10 minutes of

smoking a cigarette that delivered 1.2 mg of nicotine,238 but the increases in systolic and diastolic blood pressure and heart rate over the 2 hours of observation were not clinically important.238 Exercising for 20 minutes at 80% of maximal heart rate resulted in heart rate becoming increased compared with measurements obtained at the start of such exercise in healthy smokers who were refraining from smoking and were on their fourth hour of application of a transdermal system of nicotine that delivered 21 mg per 24 hours;238 however, the increases in heart rate over the 2 hours of observation that included the period of exercise were not clinically important.238

GI Effects Unlike the cardiovascular effects, the effects of nicotine on the GI tract are mediated principally via cholinergic stimulation.4 Nicotine-induced stimulation of parasympathetic ganglia and cholinergic nerve endings results in increased tone and motor activity of GI smooth muscle.4 Nausea, vomiting, and diarrhea may occur following systemic absorption of nicotine.4, 97 (See Central Nervous System in Pharmacology: Nervous System Effects.) The relative importance of local effects of nicotine (e.g., resulting from swallowing nicotine polacrilex) and systemic effects of the drug on the risk of peptic ulcer formation, delayed healing and relapse, and on esophageal reflux has not been elucidated.97

Other Effects Nicotine exhibits antidiuretic activity, which is mediated by stimulating the secretion of vasopressin (antidiuretic hormone) via a direct effect on the hypothalamic-pituitary system.97, 171, 172

Nicotine produces an initial increase in salivary and bronchial secretion; however, the drug subsequently produces an inhibitory effect on exocrine glands.4 Nicotine also has a local (e.g., gastric) irritant effect.36, 44

Pharmacokinetics

Absorption The pharmacokinetics of various commercially available dosage forms of nicotine and nicotine polacrilex differ principally in the rate, site, and extent of absorption of the drug, with absorption being most rapid with intranasal administration of the spray (peak concentrations achieved within 4-15 minutes), followed by chewing the gum (peaks within 25-30 minutes) or oral inhalation (peaks within 15-30 minutes), and then being substantially slower with the transdermal systems (peaks within 2-10

hours).44, 102, 119, 142, 147, 151, 196, 244, 246, 247, 252 Plasma nicotine concentrations fluctuate least with the transdermal systems and are least like those produced by cigarette smoking,123, 144, 147 whereas those produced by intranasal administration mimic those of cigarette smoking most closely, although the role of their rise is still somewhat slower and peaks achieved generally are lower than with cigarettes.152, 153, 154, 191, 252

Buccal Nicotine Polacrilex Nicotine is readily absorbed from the buccal mucosa when nicotine polacrilex gum is chewed or the lozenge is sucked;1, 2, 5, 25, 27, 28, 94, 97 however, when the gum is used properly, buccal absorption of nicotine from the gum is much slower than that achieved after oral inhalation of cigarette smoke.1, 2, 5, 27, 28, 34 The rate and extent of absorption of nicotine from nicotine polacrilex gum depend on many factors, including surface area (e.g., respiratory tract vs buccal mucosa),5, 34, 50 blood flow,50 membrane permeability,34, 43 and pH.2, 5, 12, 34, 97 Although it has been reported that up to 90% of the nicotine is released from nicotine polacrilex gum during a 20- to 30-minute period of chewing,1, 2, 5, 25, 27 other data indicate that nicotine release is less complete (e.g., averaging 53-55% from the commercially available 2-mg gum during a 20- to 30-minute period of chewing).94, 95 In a study in smokers who chewed a single piece of commercially available nicotine polacrilex gum at a vigorous, paced rate (i.e., reportedly greater than that recommended with normal use and likely to produce maximum plasma nicotine concentrations achievable with the gum), approximately 70 or 85% of the nicotine in a 2- or 4-mg piece, respectively, was released during a 30-minute period of chewing.1 The rate of release of nicotine from the resin complex is variable and depends greatly on the vigor and duration of chewing.1, 97 Only minimal amounts of nicotine are released from the ion-exchange resin when the gum is swallowed.1, 2 Nicotine is absorbed only minimally from the GI tract and is metabolized rapidly and extensively during first pass through the liver.4, 5, 12, 97, 196 Commercially available nicotine polacrilex chewing gum is buffered to pH 8.5 to enhance buccal absorption of the drug;2, 55, 97 acidic beverages (e.g., coffee, juices, wine, soft drinks) may interfere with the buccal absorption of nicotine from the gum.1, 100 (See Drug Interactions: Food.)

Blood nicotine concentrations obtained during use of nicotine polacrilex gum are variable and depend on the vigor and duration of chewing, the amount of saliva generated during chewing, the fraction of an extracted dose held within the mouth and accessible for buccal absorption versus the fraction swallowed, and the fraction of an extracted dose expectorated.1, 5, 25, 27, 94 The pronounced early peak in blood nicotine concentrations attained following oral inhalation of cigarette smoke is not attained by chewing nicotine polacrilex gum;1, 2, 5, 12, 27, 28 however, following repeated administration of the gum, relatively constant blood nicotine concentrations similar to those achieved during cigarette smoking are attained.2, 5, 27 Results from studies comparing the blood nicotine concentrations produced by nicotine polacrilex gum with those attained during cigarette smoking have shown that trough blood nicotine concentrations achieved by smoking one cigarette per hour are at

least twice those achieved by chewing one piece of nicotine polacrilex gum (containing 2 mg of nicotine) every hour.5, 27, 28, 29, 94 In one study in patients with chronic obstructive pulmonary disease, hourly chewing of 2- or 4-mg pieces of nicotine polacrilex gum resulted in mean steady-state plasma nicotine concentrations of 11.8 or 23.2 ng/mL, respectively;27 in these patients, hourly or usual (as desired) smoking of cigarettes with a 1.1-mg nicotine yield produced mean trough plasma nicotine concentrations of 18.3 or 15.7 ng/mL, respectively.27

Nicotine from the polacrilex lozenges is absorbed systemically more extensively following buccal administration of the lozenge vs gum, with approximately 25-27% more of an equivalent dose being absorbed transmucosally with the lozenge.263 Such differences in systemic absorption of buccal nicotine from these 2 formulations are thought to result from the dependency of drug release from the gum on mechanical chewing, which usually results is incomplete release from the gum relative to complete dissolution of the lozenges in the mouth and delivery of the drug to the oral mucosa.263

Nicotine Transdermal Systems Nicotine is well absorbed percutaneously following topical application of a transdermal system. 101, 102, 103, 104, 108, 109, 120 A Habitrol, NicoDerm, Nicotrol, or Prostep transdermal system reportedly delivers nicotine at a rate of 29, 40, 31, or 130 mcg/cm2 per hour, respectively; the rate of delivery at currently marketed dosages is linearly dependent on the active surface area of the applied system.43, 44, 101, 102, 103, 104, 167 Each transdermal system contains an excess amount of drug, which establishes a concentration gradient to promote delivery of the drug out of the system and into the skin,44, 167 and a substantial amount of nicotine (approximately 30-70% of the original content)101, 102, 103, 104, 120, 146, 150 remains in the system at the end of the normal application period (i.e., 16 or 24 hours).101, 102, 103, 104, 120, 146, 150

The manufacturers state that the labeled dose of nicotine absorbed over 24 hours from a Habitrol, NicoDerm, or Prostep transdermal system or over 16 hours from a Nicotrol system averages 98, 68, 98, or 95% of the amount of drug released from the respective system.101, 102, 103, 104, 108, 109, 120 In one study, the absolute bioavailability of nicotine (e.g., based on the assumption that the amount of drug absorbed systemically is a fraction of the amount remaining in the system after use) with a transdermal system containing 52.5 mg of nicotine averaged 82%.120, 144 Plasma nicotine concentration and area under the concentration-time curve (AUC) produced by a given transdermal dose of nicotine (given as NicoDerm) were similar whether the dose was administered as a single system labeled as delivering 21 mg/day or as 2 systems (1 system each) labeled as delivering 14 or 7 mg/day (21 mg/day total).102, 151

Differences in the amount of nicotine released from transdermal systems and the amount absorbed may occur as a result of loss of nicotine from the edges of the systems;102, 104, 144 the adhesive qualities of the system that maintain contact of the drug reservoir with the skin and the composition of the drug reservoir also may affect drug release and absorption.43, 107, 120, 144, 167 Conditions or agents that alter penetration of nicotine through the skin (e.g., dermatologic damage, shaving) or alter skin blood flow (e.g., sympathomimetic/sympatholytic agents) also may influence transdermal absorption of nicotine.43, 101, 102, 103, 104, 144, 145, 155 (See Acute Toxicity: Topical Overdosage, and also see Drug Interactions.) Although varying the site of application (e.g., hip, abdomen, upper torso, upper arm) does not appear to substantially affect nicotine delivery from transdermal systems,101, 102, 103, 104, 122, 142, 144 the systems generally should be applied to sites recommended by the respective manufacturers.167

Following initial application of a transdermal system of nicotine, a depot of the drug apparently is formed in the skin beneath the system.101, 102, 103, 104, 122 In contrast to the high, rapidly achieved plasma nicotine concentrations produced by cigarette smoking,108, 147 plasma nicotine concentrations produced by commercial transdermal systems generally increase slowly, reaching a peak within 4-9 hours after application, and then decline gradually. 101, 102, 103, 104, 105, 106, 107, 108, 109, 118, 120, 121, 142, 144, 150, 151 This slow decline in plasma nicotine concentrations during the latter period of system application reportedly reflects the slow release of nicotine from these trandermal systems compared with the more rapid rate of absorption of residual drug from the skin.101, 102

Peak plasma concentrations of nicotine following topical application of a Habitrol, NicoDerm, or Prostep transdermal system labeled as delivering 21, 21, or 22 mg/24 hours, respectively, reportedly average approximately 17, 23, or 16 ng/mL at 6, 4, or 9 hours after system application;101, 102, 103, 151 such plasma nicotine concentrations reportedly are similar to trough plasma concentrations achieved during moderate to heavy cigarette smoking.108, 120, 149 Peak plasma nicotine concentrations produced by application of a Nicotrol system labeled as delivering 15 mg over 16 hours reportedly average 13 ng/mL and are achieved at 8 hours.104 Plasma concentration and AUC for nicotine generally are proportional to dose for most transdermal systems of the drug.101, 102, 103, 105, 108, 121, 151 With some transdermal systems (e.g., NicoDerm), peak nicotine concentrations may occur within as little as 2-4 hours because of an initial rapid release of drug from the adhesive layer of the system;44, 102, 142, 151 with other systems, a delay of up to 4 hours may occur before any increase in plasma nicotine concentration is detected.101, 106, 107, 120, 144, 146

Steady-state plasma nicotine concentrations with sequential application of nicotine transdermal systems over 24 hours are achieved after 2-4 days.101, 102, 103, 105, 106, 144, 146, 150, 151 Although the manufacturers of Habitrol, NicoDerm, and Prostep state that plasma nicotine concentrations at steady state average approximately 25-30% higher than those following single 24-hour applications of

these systems,22, 101, 102, 103, 150, 167 substantial accumulation of nicotine (as determined by AUCs) generally has not been reported with repeated applications of 24-hour transdermal nicotine systems.105, 106, 108, 144 Nicotine concentrations following single or multiple applications of a Nicotrol transdermal system over 16 hours reportedly do not differ substantially.104

Plasma nicotine concentrations produced by application of a transdermal system generally are lower and fluctuate less than those produced by smoking cigarettes;123, 144 these low, relatively constant levels are sufficient to relieve or diminish the intensity of nicotine withdrawal symptoms in most patients while avoiding the dependence-reinforcing stimulatory and euphoric effects associated with rapid delivery of nicotine to the brain.43, 144, 148, 149, 167 Preliminary data from a study in otherwise healthy male smokers indicate that plasma nicotine concentrations produced during therapy with a transdermal system delivering nicotine 21 mg/24 hours average approximately 50% of those produced by smoking a cigarette either every 30 minutes or as desired over a 15-hour period.44, 110, 144, 196 In otherwise healthy adult smokers, a transdermal system of nicotine delivering approximately 14 mg of nicotine per 24 hours produced steady-state plasma nicotine concentrations that were comparable to trough plasma nicotine concentrations but lower than peak concentrations produced by hourly cigarette smoking.105, 121

Limited data suggest that peak plasma nicotine concentrations resulting from transdermal administration generally are similar to those achieved with nicotine polacrilex gum but may occur earlier.8, 110, 122, 144 In one study, a transdermal system of nicotine that delivered 22 mg/24 hours produced peak and trough plasma nicotine concentrations of 13.8 and 5.9 ng/mL, respectively, compared with peak and trough concentrations of 11.9 and 0.3 ng/mL, respectively, attained by chewing 2 mg of nicotine gum over 30 minutes every hour for 15 hours.108, 122, 144 Application of a transdermal system delivering approximately 14 mg of nicotine per 24 hours reportedly produced average plasma nicotine concentrations similar to those achieved by chewing 2 mg of nicotine gum every 65-100 minutes for 15 hours.110, 144

Following application of a transdermal system of nicotine that delivered 21 mg/24 hours alone, in combination with nicotine polacrilex gum administered 4 hours later as a single dose of 4 mg chewed over 30 minutes, or in such combination followed immediately after nicotine polacrilex gum was discarded by 10 minutes of smoking a cigarette that delivered 1.2 mg of nicotine, the mean peak plasma nicotine concentration and AUC of the drug over 4-6 hours were increased with each additional source of nicotine compared with the transdermal system alone.238 Smoking a cigarette in addition to receiving transdermal nicotine and nicotine polacrilex gum resulted in the highest peak plasma concentration and AUC over 4-6 hours.238 The transdermal system of nicotine alone, in combination with nicotine polacrilex gum, or in combination with nicotine polacrilex gum and smoking a cigarette

produced peak plasma nicotine concentrations of 30.2, 36, or 48 ng/mL, respectively, and an AUC over 4-6 hours of 48, 63, or 74 ngh/mL, respectively.238

Peak plasma concentration and AUC for nicotine following application of a transdermal system are inversely related to total body weight;102, 104, 176 these values were substantially lower in obese men (mean weight: 112 kg) than in men of normal weight (mean weight: 76 kg) using Nicoderm.44, 102, 176

Nicotine Intranasal Inhalation Nicotine is rapidly absorbed and produces plasma concentrations similar to those achieved with cigarette smoking when the drug is administered intranasally as an aerosol or spray.152, 153, 154, 191, 252 Following intranasal administration of 2 sprays (1 mg) of nicotine, approximately 53% of the dose is absorbed systemically.191 Deposition of the spray on various parts of the nasal mucosa does not appear to affect the rate or extent of systemic absorption.191

Following intranasal administration of a 1-mg dose, maximum plasma concentrations of 2-12 ng/mL are achieved within 4-15 minutes; however, there is wide interindividual variation.191, 252 As a result, only about 20% of individuals receiving a 1-mg intranasal dose reach peak plasma nicotine concentrations similar to those achieved by smoking one cigarette.191 The extent of intranasal nicotine absorption and peak plasma concentrations are decreased slightly, and the time to peak is delayed, by the presence of the common cold or rhinitis.191 The time to peak plasma concentrations of the drug following intranasal administration of nicotine may be delayed further by use of a nasal vasoconstrictor (e.g., xylometazoline).191

Nicotine Oral Inhalation Nicotine is absorbed readily from the buccal mucosa following oral inhalation;196, 244, 247, 248, 249, 251 however, when the drug is administered via the oral inhaler, the absorption characteristics of nicotine differ substantially from those associated with oral inhalation of cigarette smoke.244, 248, 249, 250 With oral inhalation from the inhaler, most of the nicotine released from the porous plug (drug reservoir) is deposited in the mouth for absorption,244, 248, 249, 251whereas with oral inhalation of cigarette smoke, most of the drug is deposited in the pulmonary system for absorption.244, 247, 248, 249 Release of nicotine from the porous plug is substantially lower than that from a cigarette,244, 250 being about 14% of a dose over 5 minutes of oral inhalation with the plug and 93% over 3.5 minutes of cigarette smoke inhalation in one healthy smoker.249

When radiolabeled nicotine was administered via oral inhalation from a vapor inhaler in healthy smokers, the extent of drug deposition in the mouth following oral inhalation over 5 minutes using rapid shallow sucking/puffing ("buccal mode") versus slow deep inhalation ("pulmonary mode") was similar, averaging 49 and 40% of the released dose, respectively.248 The portion of the nicotine dose released from the porous plug during inhalation averaged about 14 and 17% with each respective inhalation method, exhibiting considerable interindividual variation (range: 6-25%); however, no intraindividual differences in released dose between the inhalation methods was observed.248 Deposition in the oral cavity is closely followed a linear temporal pattern over 5 minutes of inhalation, followed by rapid loglinear elimination from the mouth (presumed absorption) with a half-life of about 18 minutes; only about 8% of the released dose remains in the mouth 45 minutes after completion of inhalation.248 Systemic absorption of nicotine also has been shown to be comparable for these 2 methods of oral inhalation in healthy smokers,247 with about 60% of a dose being absorbed systemically within 45 minutes after a 5-minute inhalation period.248

A substantial portion of an inhaled dose of nicotine (e.g., 20%) also appears to be swallowed following oral inhalation via the inhaler but not via cigarette smoke.249 Smaller portions of an inhaled dose from the oral inhaler are deposited in esophagus (about 10%), lungs (about 5%), bronchi (about 2%), and trachea (about 1%).248 Compared with intranasal inhalation of nicotine from a spray, oral inhalation of drug released from the porous cartridge appears to produce slower and lower plasma nicotine concentrations.196, 246

Absorption of nicotine following oral inhalation via an inhaler appears to result principally through the mucosa, which is much slower than that achieved after oral inhalation of cigarette smoke; absorption from cigarette smoke occurs principally from the pulmonary system.244, 247, 248, 249 As a result, absorption following oral inhalation via the inhaler is relatively slow compared with the high and rapid rise in arterial plasma nicotine concentrations that occurs with inhalation of cigarette smoke.196, 244 In addition, release of nicotine from cigarettes is far more efficient than that from the oral inhaler.196, 249 Peak plasma nicotine concentrations are typically achieved within 15 minutes following the end of oral inhalation via the inhaler,244 averaging about 40-49 ng/mL at steady state with a regimen of 80 deep inhalations over 20 minutes per hour for 10 hours and varying depending on the ambient temperature (increasing with increasing temperature).244 Mean and trough plasma nicotine concentrations at steady state average 23-34 and 11-24 ng/mL with such inhalation and also vary with the ambient temperature.244, 247 Less intense (i.e., as needed) self-administration of orally inhaled nicotine typically produces plasma nicotine concentrations of about 6-8 ng/mL, which are about one-third those achieved with cigarette smoking.244 Absolute (compared with IV administration) oral bioavailability of nicotine from a 10-mg oral nicotine inhaler that released approximately 4 mg of the drug over a 20minute inhalation period averaged 51-56%.247

 Distribution The reported volume of distribution of nicotine following IV administration is approximately 2-3 L/kg.1, 101, 102, 103, 104, 191, 244 Following IV administration of nicotine in animals, the drug is rapidly distributed into most body tissues and fluids with highest concentrations in the cerebral cortex12, 32, 60 and adrenal medulla60 and lower concentrations in spleen, adrenal cortex, kidney, and pancreas.60 In animals, peak nicotine concentrations in the brain occur within 1 minute following IV administration and are approximately 5 times greater than those in plasma.12, 30, 32, 97 Evidence from animal studies suggests that brain cells have the ability to bind or retain nicotine against a concentration gradient.12 Nicotine is less than 5% bound to plasma proteins.191, 244

Nicotine crosses the placenta14, 70, 97 and is freely distributed into milk, reportedly producing concentrations in breast milk averaging 2.9 times those in plasma.101, 102, 103, 104 Nicotine concentrations in amniotic fluid, placental tissue, and fetal serum exceed corresponding maternal serum concentrations in women who smoke cigarettes, apparently as a result of ion trapping of alkaline nicotine in these acidic compartments.70 Small amounts of nicotine appear in serum and urine of infants of nursing women who smoke cigarettes.70, 73

Elimination Plasma concentrations of nicotine appear to decline in a biphasic manner.12 The half-life of nicotine in the initial phase (t1/2a) is reportedly about 2-3 minutes and the half-life in the terminal phase (t1/2) reportedly averages about 2 hours (range: 1-4 hours).1, 4, 12, 38, 39, 43, 45, 97, 101, 102, 103, 104, 171, 172, 244 The clearance of nicotine from the body appears to exhibit interindividual variation.28, 63

Following removal of a transdermal system of nicotine, plasma nicotine concentrations decline with an apparent half-life averaging 3-6 hours, which exceeds that of nicotine given IV;101, 102, 103, 104, 106, 107, 108, 109, 20, 142, 144, 146, 150, 151 the slow decline in plasma nicotine concentrations following removal of a transdermal system appears to result from continued absorption of residual drug in the skin.101, 102, 103, 104, 122, 127, 144, 151 Plasma nicotine concentrations generally are undetectable 10-12 hours after removal of a transdermal system of nicotine in most patients who have stopped smoking cigarettes.101, 102, 103, 104, 144

Metabolism of nicotine is qualitatively similar following buccal absorption from nicotine polacrilex gum or nicotine oral inhalation and from oral inhalation of cigarette smoke,1, 244 and reportedly following application of nicotine transdermal systems.43 Although the exact metabolic fate of nicotine is not clearly established, the drug is metabolized extensively to more than 20 metabolites, but principally in

the liver via oxidation of the a-carbon and N-oxidation of the pyrrolidine ring to cotinine and nicotine-1N-oxide, respectively.4, 12, 97, 191, 244 These metabolites are not pharmacologically active in humans at blood concentrations attained during cigarette smoking; however, cotinine has been reported to be pharmacologically active in animals, but its potency at equivalent molar concentrations is substantially less than that of nicotine.12, 34, 40, 56 Cotinine is the major metabolite and has a plasma half-life of about 10-40 hours.40, 41, 97, 244 Nicotine may also be metabolized to a lesser extent in the kidneys and lungs.1, 4, 12, 97, 191, 244

Substantial metabolism of nicotine by the skin following application of transdermal systems of the drug has not been demonstrated.101, 102, 103, 104, 122

Nicotine and its metabolites are excreted in urine.1, 4, 5, 12, 97, 244 Approximately 10-20% of an absorbed dose of the drug is excreted unchanged.1, 244 Urinary excretion of nicotine is pH dependent;1, 4, 12, 28, 45, 50, 97, 244 excretion of the drug is increased in an acid urine and by high urine output.1, 12, 28, 50, 97, 244 Nicotine-1-N-oxide is reduced to nicotine by bacterial flora in the large intestine via an N-oxide reductase system and subsequently undergoes enterohepatic circulation and repeat metabolism in the liver.12, 97

Chemistry and Stability

Chemistry

nicotine polacrilex

Nicotine is a naturally occurring autonomic drug.36 The drug is commercially available as the base in transdermal systems, an oral inhaler, and a nasal solution and as the polacrilex in chewing gum.

Nicotine is a pyridine alkaloid;3, 12, 97 the nicotine present in transdermal systems or oral inhaler or in the cation-exchange resin is a highly purified extract obtained from the dried leaves of the tobacco plant (Nicotiana tabacum [Fam. Solanaceae]).2, 3, 244 The drug occurs as a basic, colorless to pale yellow, very hygroscopic, oily, volatile liquid and has an unpleasant, pungent odor and a sharp, burning, persistent taste.3, 12, 244 Nicotine is soluble in water and in alcohol.3, 12 The drug has a pKa1 of about 7.8-7.9 and a pKa2 of about 3 at 15C.12, 244

Nicotine Polacrilex Nicotine polacrilex is a resin complex of nicotine and polacrilin.61 Polacrilin is a unifunctional low-crosslinked carboxylic cation-exchange resin prepared from methacrylic acid and divinylbenzene.62

Nicotine polacrilex is commercially available in a sugar-free, flavored chewing-gum base and occurs as beige (2 mg) or yellow (4 mg) squares.1 The nicotine-containing chewing gum has a distinct,2 tobaccolike,43 slightly peppery49 taste and contains sorbitol as a sweetener.2 The commercially available chewing gum also contains buffering agents to enhance buccal absorption of nicotine.2 Each 2- or 4-mg piece of gum contains approximately 0.44 or 0.57 mEq of sodium, respectively.2, 44

Nicotine polacrilex also is commercially available in sugar-free lozenges that dissolve completely in the mouth over a 20-30 minute period.263, 264 The lozenges contain aspartame as a sweetener.264 (See Cautions: Precautions and Contraindications.)

Nicotine Transdermal Systems Commercially available transdermal systems of nicotine generally consist of an impermeable backing layer, a drug-containing reservoir, an adhesive layer, and a removable protective liner; nicotine in the systems is delivered via a rate-controlling membrane, matrix, or adhesive.111, 112, 113, 127, 136, 144 In the Habitrol transdermal system, a methacrylic acid copolymer solution of nicotine dispersed in a pad of nonwoven viscose and cotton and sandwiched between 2 layers of pressure-sensitive acrylate adhesive is used.101 The NicoDerm transdermal system consists of a drug reservoir containing nicotine in an ethylene-vinyl acetate copolymer matrix that delivers the drug via a rate-controlling polyethylene membrane.102 The Nicotrol transdermal system employs a middle layer of rate-controlling adhesive, a structural nonwoven material, and nicotine.104 The Prostep transdermal system uses a nicotinehydrogel matrix for drug delivery.103

Nicotine Nasal Solution

Nicotine nasal solution is available in a metered-spray pump containing the drug in an aqueous vehicle.191 The vehicle also contains polysorbate (Tween 80), phosphate buffers, citric acid, parabens, edetate disodium, sodium chloride, and aroma; the spray does not contain chlorofluorocarbons.191 The solution is isotonic and has a pH of 7. The size of the droplets produced by the pump exceed 8 m.

Nicotine Oral Inhaler For oral inhalation, nicotine is commercially available as an oral inhaler that delivers the drug via an inhaled vapor from a porous plug (drug reservoir) impregnated with nicotine base and menthol.244, 245, 246, 247, 248 The oral inhaler consists of a mouthpiece and a plastic cartridge containing a porous plug impregnated with 10 mg of the drug that can deliver a maximum total dose of about 4 mg of nicotine with repeated inhalations.244, 247, 250 Only a small portion of the dose is released with each inhalation, and the amount released depends on the flow and temperature of the air passing through the inhaler.244, 245, 246, 247, 248 Thus, nicotine delivery from the device is not constant but instead depends principally on inhalation intensity and environmental temperatures.247 At room temperature, the inhaler delivers approximately 13 ng of nicotine per rapid shallow (about 50-mL) inhalation or about 1 mg per 80 inhalations;245 however, intense deep inhalations release about 4 mg of the drug from the plug per 80 inhalations over 20 minutes.244, 247 The mouthpiece of the inhaler is reusable, but the plastic cartridge containing the drug is not.244, 250

Stability Nicotine is photosensitive and will gradually turn brown when exposed to light or air.3, 12

Nicotine Polacrilex Commercially available nicotine polacrilex chewing gum should be protected from light and stored at room temperature less than 30C.1

Nicotine polacrilex lozenges should be protected from light and stored at a room temperature of 2025C.264

Nicotine Transdermal Systems Commercially available transdermal systems of nicotine should be stored unopened (in their protective pouches) at a temperature less than 30C because the systems (i.e., nicotine) are sensitive to heat.101, 102, 103, 104 A nicotine transdermal system should be applied promptly after removal from its

protective pouch because nicotine is volatile and may evaporate from the system.44, 101, 102, 103, 104, 167 Slight discoloration of the systems does not appreciably affect their potency or efficacy.44, 101, 102, 103, 104

Nicotine Nasal Solution Containers of nicotine nasal solution should be stored at a room temperature not exceeding 30C.191

Nicotine Oral Inhaler Nicotine oral inhaler cartridges containing the drug should be stored at room temperatures not exceeding 30C; the cartridges should be protected from light.244, 250 Because delivery of nicotine from the inhaler declines with declining ambient temperatures below 40C, patients should be advised to store the inhaler and cartridges in an inside pocket or warm area during cold weather. 257 Nicotine cartridges should be left in an automobile with caution since interior temperatures can increase rapidly.250

Because release of nicotine as a vapor from the cartridge depends on inhalation intensity and environmental temperature, precise time periods when release of the drug will have been completed cannot be defined;247 however, patients can be advised that nicotine from each cartridge will be used up after about 20 minutes of active inhalation (e.g., inhalation for 5-minute periods will exhaust the releasable drug from the cartridge after 4 uses), and that with experience they will be able to determine more precisely when the supply of nicotine has been used up.250 Patients also should be advised to properly dispose of used cartridges so that children and pets cannot reach them since a potentially toxic dose of nicotine remains in the porous plug of the cartridge even after drug can no longer be vaporized with inhalation; chewing or swallowing the cartridge could be toxic.250

Preparations

Nicotine

Nasal

Solution

0.5 mg/metered spray Pfizer

Nicotrol NS, (with parabens)

Oral Inhalation

Inhalant

4 mg/metered spray Pfizer

NicotrolInhalaer,

Topical

Transdermal System 15 mg/16 hours (8.3 mg/10 cm2) Pfizer

Nicotrol Step 1,

10 mg/16 hours (16.6 mg/10 Nicotrol Step 2, cm2 ) Pfizer

15 mg/16 hours (24.9 mg/30 Nicotrol Step 3, cm2 ) Pfizer

7 mg/24 hours

Nicotine Transdermal System, Watson

7 mg/24 hours (36 mg/7 cm2 Nicoderm CQ Clear Step 3, ) GlaxoSmithKline

NicoDerm CQ Step 3, GlaxoSmithKline

11 mg/24 hours Perrigo

Nicotine Transdermal System,

14 mg/24 hours Watson

Nicotine Transdermal System,

14 mg/24 hours (78 mg/15 cm2 Nicoderm CQ Clear Step 3, ) GlaxoSmithKline

NicoDerm CQ Step 2, GlaxoSmithKline

21 mg/24 hours Watson

Nicotine Transdermal System,

21 mg/24 hours (114 mg/22 cm2 ) GlaxoSmithKline

NicoDerm CQ Step 1,

Nicotine Polacrilex

Buccal or Transmucosal

Lozenges

2 mg (of nicotine)

Commit, (with aspartame)

GlaxoSmithKline

4 mg (of nicotine)

Commit, (with aspartame)

GlaxoSmithKline

Pieces, chewing gum

2 mg (of nicotine)

Nicorette, (sugar-free)

GlaxoSmithKline

Nicotine Polacrilex Gum, Watson

4 mg (of nicotine)

Nicorette DS, (sugar-free)

GlaxoSmithKline

Nicotine Polacrilex Gum, Watson

References

1. SmithKline Beecham. Nicorette and Nicorette DS (double strength) (nicotine polacrilex) prescribing information and patient information dated 1993 Nov. In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:2458-62.

2. Merrell Dow Pharmaceuticals Inc. Questions and answers about nicotine gum. Cincinnati, OH; [undated].

3. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 28th ed. London: The Pharmaceutical Press; 1982:1732.

4. Taylor P. Agents acting at the neuromuscular junction and autonomic ganglia. In: Gilman AG, Rall TW, Nies AS et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:166-86.

5. Russell MAH, Raw M, Jarvis MJ: Clinical use of nicotine chewing-gum, Br Med J 1980 280: 1599-602

6. Raw M, Jarvis MJ, Feyerabend C: Comparison of nicotine chewing-gum and psychological treatments for dependent smokers, Br Med J 1980 281: 481-2

7. Jarvis MJ, Raw M, Russell MAH: Randomized controlled trial of nicotine chewing-gum, BMJ 1982 285: 537-40

8. Fagerstrom K-O: A comparison of psychological and pharmacological treatment in smoking cessation, J Behav Med 1982 5: 343-51

9. Schneider NG, Jarvik ME, Forsythe AB: Nicotine gum in smoking cessation: a placebo-controlled, double-blind trial, Addict Behav 1983 8: 253-61

10. Wilhelmsen L, Hjalmarsson A: Smoking cessation experience in Sweden, Can Fam Physician 1980 26: 737-43

11. Russell MAH, Merriman R, Stapleton J: Effect of nicotine chewing gum as an adjunct to general practitioners' advice against smoking, BMJ 1983 287: 1782-5

12. Russell MAH, Feyerabend C: Cigarette smoking: a dependence on high-nicotine boli, Drug Metab Rev 1978 8: 29-57

13. Kalter H, Warkany J. Congenital malformations (second of two parts). N Engl J Med. 1983; 308:491-7 (IDIS 165815)

14. Johnston C: Cigarette smoking and the outcome of human pregnancies: a status report on the consequences, Clin Toxicol 1981 18: 189-209

15. Landesman-Dwyer S, Emanuel I: Smoking during pregnancy, Teratology 1979 19: 119-26

16. Abel EL: Smoking during pregnancy: a review of effects on growth and development of offspring, Hum Biol 1980 52: 593-625

17. Gennser G, Marsal K, Brantmark B: Maternal smoking and fetal breathing movements, Am J Obstet Gynecol 1975 123: 861-7

18. Dougherty CRS, Jones AD: The determinants of birth weight, Am J Obstet Gynecol 1982 144: 190-200

19. Chernick V, Childiaeva R, Ioffe S: Effects of maternal alcohol intake and smoking on neonatal electroencephalogram and anthropometric measurements, Am J Obstet Gynecol 1983 146: 41-7

20. Meyer MB: How does maternal smoking affect birth weight and maternal weight gain?: evidence from the Ontario perinatal mortality study, Am J Obstet Gynecol 1978 131: 888-93

21. Lehtovirta P, Dorss M: The acute effect of smoking on intervillous blood flow of the placenta, Br J Obstet Gynaecol 1978 85: 729-31

22. Persson PH, Grennert L, Gennser G: A study of smoking and pregnancy with special reference to fetal growth, Acta Obstet Gynecol Scand 1978 78: Suppl 33-9

23. Butler NR, Goldstein H, Ross EM: Cigarette smoking in pregnancy: its influence on birth weight and perinatal mortality, Br Med J 1972 2: 127-30

24. Davies DP, Gray OP, Ellwood PC: Cigarette smoking in pregnancy: association with maternal weight gain and fetal growth, Lancet 1976 1: 385-7

25. Ferno O, Lichtneckert SJA, Lundgren CEG: A substitute for tobacco smoking, Psychopharmacologia 1973 31: 201-4

26. Ashton H: Teratogenic drugs, Adverse Drug React Bull 1983 : 101 372-5

27. McNabb ME, Ebert RV, McCusker K: Plasma nicotine levels produced by chewing nicotine gum, JAMA 1982 248: 865-8

28. Feyerabend C, Russell MAH: Effect of urinary pH and nicotine excretion rate on plasma nicotine during cigarette smoking and chewing nicotine gum, Br J Clin Pharmacol 1978 5: 293-7

29. Russell MAH, Wilson C, Feyerabend C: Effect of nicotine chewing-gum on smoking behaviour and as an aid to cigarette withdrawal, Br Med J 1976 2: 391-3

30. Brantmark B, Ohlin O, Westling H: Nicotine containing chewing gum as an anti-smoking aid, Psychopharmacologia 1973 31: 191-200

31. Puska P, Bjorkqvist S, Koskela K: Nicotine-containing chewing gum in smoking cessation: a double blind trial with half-year follow-up, Addict Behav 1979 4: 141-6

32. Stalhandske T: Effects of increased liver metabolism of nicotine on its uptake, elimination, and toxicity in mice, Acta Physiol Scand 1970 80: 222-34

33. Glantz LA: Nicotine chewing gum not for all smokers, Clin Pharm 1984 3: 236

34. US Department of Health, Education, and Welfare. US Surgeon General's report on smoking and health. DHEW Publ. No. [PHS] 79-50066. Washington, DC: US Government Printing Office; 1979:1-1164.

35. Koop CE, Luoto J: "The health consequences of smoking: cancer," overview of a report of the Surgeon General, Public Health Rep 1982 97: 318-24

36. Gosselin RE, Hodge HC, Smith RP et al. Clinical toxicology of commercial products: acute poisoning. 5th ed. Baltimore: Williams & Wilkins Co; 1984:II237, III311-4.

37. Nicotine. From: TDB, Toxicology Data Bank (database). Bethesda, MD: National Library of Medicine, 1984; TDB No 1107.

38. Issac PF, Rand MJ: Cigarette smoking and plasma levels of nicotine, Nature 1972 236: 308-10

39. Rosenberg J, Benowitz NL, Jacob P: Disposition kinetics and effects of intravenous nicotine, Clin Pharmacol Ther 1980 28: 517-22

40. Benowitz NL, Kuyt F, Jacob P: Cotinine disposition and effects, Clin Pharmacol Ther 1983 34: 604-11

41. Langone JJ, Gjika HB, Van Vunakis H: Nicotine and its metabolites: radioimmunoassays for nicotine and cotinine, Biochemistry 1973 12: 5025-30

42. Evans D, Lane DS: Long-term outcome of smoking cessation workshops, Am J Public Health 1980 70: 725-7

43. Reviewers' comments (personal observations).

44. Marion Merrell Dow, Kansas City, MO: Personal communication.

45. Benowitz NL. The use of biologic fluid samples in assessing tobacco smoke consumption. In: Grabowski J, Bell CS, eds. Measurement in the analysis and treatment of smoking behavior. NIDA Research Monograph 48. DHHS Pub No. [ADM] 83-1285. Washington, DC: US Government Printing Office; 1983:6-26.

46. Malcolm RE, Sillett RW, Turner JAM: The use of nicotine gum as an aid to stopping smoking, Psychopharmacology 1980 70: 295-6

47. Fee WM, Stewart MJ: A controlled trial of nicotine chewing gum in a smoking withdrawal clinic, Practitioner 1982 226: 148-51

48. British Thoracic Society: Comparison of four methods of smoking withdrawal in patients with smoking related diseases, BMJ 1983 286: 595-7

49. Anon: Nicotine gum, Med Lett Drugs Ther 1984 26: 47-8

50. Henningfield JE. Behavioral pharmacology of cigarette smoking. Adv Behav Pharmacol. (in press).

51. Henningfield JE, Miyasato K, Jasinski DR: Cigarette smokers self-administer intravenous nicotine, Pharmacol Biochem Behav 1983 19: 887-90

52. Henningfield JE, Goldberg SR: Nicotine as a reinforcer in human subjects and laboratory animals, Pharmacol Biochem Behav 1983 19: 989-92

53. Dawson GW, Vestal RE: Smoking and drug metabolism, Pharmacol Ther 1982 15: 207-21

54. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980:159-60, 176-8.

55. Merrell Dow Pharmaceuticals Inc. Data on file. Cincinnati, OH.

56. Food and Drug Administration. Smoking deterrent drug products for over-the-counter human use; establishment of a monograph. [Docket No. 81N-0027] Fed Regist. 1982; 47:490-500.

57. Jusko WJ: Role of tobacco smoking in pharmacokinetics, J Pharmacokinet Biopharm 1978 6: 7-39

58. Fuhrmann C (personal observations); 1984 Jun 7.

59. Falkeborn Y, Larsson C, Nordberg A: Chronic nicotine exposure in rat: a behavioural and biochemical study of tolerance, Drug Alcohol Depend 1981 8: 51-60

60. Tsujimoto A, Nakashima T, Tanino S: Tissue distribution of [3H]nicotine in dogs and rhesus monkeys, Toxicol Appl Pharmacol 1975 32: 21-31

61. Griffiths MC (The United States Pharmacopeial Convention, Inc., Rockville, MD): Personal communication; 1984 Jun 29.

62. The United States pharmacopeia, 21st rev, and The national formulary, 16th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1984:1587-9.

63. Benowitz NL, Jacob P III, Jones RT: Interindividual variability in the metabolism and cardiovascular effects of nicotine in man, J Pharmacol Exp Ther 1980 221: 368-72

64. Russell MAH, Wilson C, Taylor C: Effect of general practitioners' advice against smoking, Br Med J 1979 2: 231-5

65. Hall SM, Tunstall C, Rugg D et al. Nicotine gum and behavioral treatment in smoking cessation. J Consult Clin Psychol. (in press)

66. Vocci FJ Jr (US Public Health Service, Rockville, MD): Personal communication; 1984 Jun 29.

67. Blum A: Nicotine chewing gum and the medicalization of smoking, Ann Intern Med 1984 101: 121-3

68. Christen AG, McDonald JL, Olson BL: Efficacy of nicotine chewing gum in facilitating smoking cessation, J Am Dent Assoc 1984 108: 594-7

69. Anon: Smoking and cancer, MMWR Morb Mortal Wkly Rep 1982 31: 77-80

70. Luck W, Nau H: Exposure of the fetus, neonate, and nursed infant to nicotine and cotinine from maternal smoking, N Engl J Med 1984 311: 672

71. Lees AJ: Hemidystonia relieved by nicotine, Lancet 1984 2: 871

72. Anon: Dental effects of nicotine gum, Med Lett Drugs Ther 1984 26: 98

73. Luck W, Nau H: Nicotine and cotinine concentrations in serum and urine of infants exposed via passive smoking or milk from smoking mothers, J Pediatr 1985 107: 816-20

74. Fielding JE. Smoking: health effects and control. (Second of two parts.) N Engl J Med. 1985; 313:55561.

75. Eraker SA, Becker MH, Strecher VJ: Smoking behavior, cessation techniques, and the health decision model, Am J Med 1985 78: 817-25

76. Raw M. Does nicotine chewing gum work? Br Med J. 1985; 290:1231-2.

77. Anon: Nicotine chewing gum, Lancet 1985 1: 320-1

78. Hughes JR, Hatsukami DK, Pickens RW: Effect of nicotine on the tobacco withdrawal syndrome, Psychopharmacology (Berl) 1984 83: 82-7

79. West RJ, Jarvis MJ, Russell MAH: Effect of nicotine replacement on the cigarette withdrawal syndrome, Br J Addict 1984 79: 215-9

80. Schneider NG, Jarvik ME, Forsythe AB: Nicotine vs. placebo gum in the alleviation of withdrawal during smoking cessation, Addict Behav 1984 9: 149-56

81. Shapiro J: Nicotine chewing gum in general practice, BMJ 1984 289: 1308

82. Clavel F, Benhamou S. Desintoxication tabagique. Comparaison de l'efficacite de differentes methodes. Resultats intermediaires d'une etude comparative. (French; with English abstract.) Presse Med. 1984; 13:975-7.

83. Clavel F, Benhamou S: Nicotine chewing gum in general practice, BMJ 1984 289: 1308

84. Marshall A, Raw M: Nicotine chewing gum in general practice: effect of follow up appointments, BMJ 1985 290: 1397-8

85. Jamrozik K, Fowler G, Vessey M: Placebo controlled trial of nicotine chewing gum in general practice, BMJ 1984 289: 794-7

86. American College of Physicians Health and Public Policy Committee: Methods for stopping cigarette smoking, Ann Intern Med 1986 105: 281-91

87. Hughes JR, Hatsukami DK, Skoog KP: Physical dependence on nicotine in gum: a placebo substitution trial, JAMA 1986 255: 3277-9

88. West RJ, Russell MAH: Effects of withdrawal from long-term nicotine gum use, Psychol Med 1985 15: 891-3

89. Hjalmarson AIM: Effect of nicotine chewing gum in smoking cessation: a randomized, placebocontrolled, double-blind study, JAMA 1984 252: 2835-8

90. Hughes JR, Miller SA: Nicotine gum to help stop smoking, JAMA 1984 252: 2855-8

91. McNabb ME, McClellan JL. Nicotine gum addiction? JAMA. 1984; 252:2890. Letter.

92. Goodman RP, Douglas CR: Rash from nicotine gum, South Med J 1987 80: 539

93. Lee BL, Benowitz NL, Jacob P III: Cigarette abstinence, nicotine gum, and theophylline disposition, Ann Intern Med 1987 106: 553-5

94. Benowitz NL, Jacob P III, Savanapridi C: Determinants of nicotine intake while chewing nicotine polacrilex gum, Clin Pharmacol Ther 1987 41: 467-73

95. Krivokapich J, Schneider NG, Child JS et al. Cardiovascular effects of nicotine gum and cigarettes assessed by ECG and echocardiography. In: Grabowski J, Hall SM, eds. Pharmacological adjuncts in smoking cessation. NIDA Research Monograph 53. DHHS Pub No. [ADM] 85-1333. Washington, DC: US Government Printing Office; 1985:42-55.

96. Tonnesen P, Fryd V, Hansen M: Effect of nicotine chewing gum in combination with group counseling on the cessation of smoking, N Engl J Med 1988 318: 15-8

97. US Department of Health and Human Services. The health consequences of smoking: nicotine addiction. A report of the Surgeon General. Washington, DC: US Government Printing Office; 1988.

98. Hajek P, Jackson P, Belcher M: Long-term use of nicotine chewing gum: occurrence, determinants, and effect on weight gain, JAMA 1988 260: 1593-6

99. Anon: The Surgeon General's 1990 report on the health benefits of smoking cessation: executive summary, MMWR Morb Mortal Wkly Rep 1990 39: 1-12

100. Henningfield JE, Radzius A, Cooper TM: Drinking coffee and carbonated beverages blocks absorption of nicotine from nicotine polacrilex gum, JAMA 1990 264: 1560-4

101. Basel Pharmaceuticals. Habitrol (nicotine transdermal therapeutic system) prescribing information. Summit, NJ; 1991 Nov.

102. Marion Merrell Dow. Nicoderm (nicotine transdermal system) prescribing information. Kansas City, MO; 1991 Nov.

103. Lederle Laboratories Division. Prostep (nicotine transdermal system) prescribing information. Pearl River, NY; 1992 Jun.

104. Parke-Davis. Nicotrol (nicotine transdermal system) prescribing information. Morris Plains, NJ; 1992 March 5.

105. Dubois JP, Sioufi A, Muller P: Pharmacokinetics and bioavailability of nicotine in healthy volunteers following single and repeated administration of different doses of transdermal nicotine systems, Methods Find Exp Clin Pharmacol 1989 11: 187-95

106. Ross HD, Chan KKH, Piraino AJ: Pharmacokinetics of multiple daily transdermal doses of nicotine in healthy smokers, Pharmaceut Res 1991 8: 385-8

107. Caspary S, Keller-Stanislawski B, Huber T: Pharmacokinetics of nicotine after application of a 30 cm2 nicotine patch under steady-state conditions, Int J Clin Pharmacol Ther Toxicol 1991 29: 92-5

108. Bannon YB, Corish J, Corrigan OI: Transdermal delivery of nicotine in normal human volunteers: a single dose and multiple dose study, Eur J Clin Pharmacol 1989 37: 285-90

109. Mulligan SC, Masterson JG, Devane JG: Clinical and pharmacokinetic properties of a transdermal nicotine patch, Clin Pharmacol Ther 1990 47: 331-7

110. Gorsline J, Benowitz NL, Rolf CN: Comparison of plasma nicotine concentrations for nicotine transdermal system (NTS), cigarette smoking and nicotine polacrilex (nicotine gum), Clin Pharmacol Ther 1992 51: 129

111. Daughton DM, Heatlye SA, Prendergast JJ: Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy, Arch Intern Med 1991 151: 749-52

112. Rose JE, Levin ED, Behm FM: Transdermal nicotine facilitates smoking cessation, Clin Pharmacol Ther 1990 47: 323-30

113. Abelin T, Buehler A, Muller P: Controlled trial of transdermal nicotine patch in tobacco withdrawal, Lancet 1989 1: 7-9

114. Abelin T, Ehrsam R, Buhler-Reicher: Effectiveness of a transdermal nicotine system in smoking cessation studies, Methods Find Exp Clin Pharmacol 1989 11: 205-14

115. Hurt RD, Lauger GG, Offord KP: Nicotine-replacement therapy with use of a transdermal nicotine patcha randomized double-blind placebo-controlled trial, Mayo Clin Proc 1990 65: 1529-37

116. Peter JA: Nicotine-replacement therapy in cessation of smoking, Mayo Clin Proc 1990 65: 1619-23

117. Russell MAH: The future of nicotine replacement, Br J Addict 1991 86: 653-8

118. Tonnesen P, Norregaard J, Simonsen K: A double-blind trial of a 16-hour transdermal nicotine patch in smoking cessation, N Engl J Med 1991 325: 311-5

119. Morgan GD, Villagra VG: The nicotine transdermal patch: a cautionary note, Ann Intern Med 1992 116: 424

120. Benowitz NL, Chan K, Denaro CP: Stable isotope method for studying transdermal drug absorption: the nicotine patch, Clin Pharmacol Ther 1991 50: 286-93

121. Muller P, Abelin T, Ehrsam R: The use of transdermal nicotine in smoking cessation, Lung 1990 Suppl: 445-53

122. Lederle Laboratories. Prostep product information. Pearl River, NY; 1992 Jan.

123. Benowitz NL. Pharmacodynamics of nicotine: implications for rational treatment of nicotine addiction. Br J Addict. 1991; 495-9.

124. Rose JE, Herskovic JE, Trilling Y: Transdermal nicotine reduces cigarette craving and nicotine preference, Clin Pharmacol Ther 1985 38: 450-6

125. Srivastave ED, Russell MAH, Feyerabend C: Transdermal nicotine in active ulcerative colitis, Clin Exp Pharmacol 1991 78.2: 57

126. Buchkremer G, Minneker E, Block M: Smoking-cessation treatment combining transdermal nicotine substitution with behavioral therapy, Pharmacopsychiatry 1991 24: 96-102

127. Ranade VV: Drug delivery systems, 6, transdermal drug delivery, J Clin Pharmacol 1991 31: 401-18

128. Benowitz NL: Nicotine replacement therapy during pregnancy, JAMA 1991 266: 3174-7

129. Marion Merrell Dow. Nicoderm (nicotine transdermal system) patient instructions. Kansas City, MO; 1991 Nov.

130. Anon: Skin patches to prevent lung cancer, Eur J Cancer 1991 27: 223-4

131. Varma JR: Transdermal nicotine patch for smoking cessation, N Engl J Med 1992 326: 344

132. Tonnesen P, Norregaard J, Simonsen K: Transdermal nicotine patch for smoking cessation, N Engl J Med 1992 326: 345

133. Hughes JR, The Transdermal Nicotine Study Group: Transdermal nicotine for smoking cessation, Am Rev Respir Dis 1992 145: A685

134. Glover ED: Transdermal nicotine for smoking cessation, N Engl J Med 1992 326: 344

135. Hartman N, Leong GB, Glynn SM: Transdermal nicotine and smoking behavior in psychiatric patients, Am J Psychiatry 1991 148: 374-5

136. Transdermal Nicotine Study Group: Transdermal nicotine for smoking cessation: six-month results from two multicenter controlled clinical trials, JAMA 1991 266: 3133-8

137. Anon: Nicotine patches, Med Lett Drugs Ther 1992 34: 37-8

138. Lederle Laboratories. The Prostep patch and support services: important aids to a comprehensive stop-smoking program. Pearl River, NY; 1992 Feb.

139. Seidman DS, Stevenson DK: Nicotine replacement therapy during pregnancy, JAMA 1992 267: 1922

140. Benowitz NL: Nicotine replacement therapy during pregnancy, JAMA 1992 267: 1922

141. Minneker-Hugel E, Unland H, Buchkremer G: Behavioral relapse prevention strategies in smoking cessation, Int J Addict 1992 27: 627-34

142. Gorsline J, Okerholm RA, Rolf CN: Comparison of plasma nicotine concentrations after application of nicoderm (nicotine transdermal system) to different skin sites, J Clin Pharmacol 1992 32: 576-81

143. Bronson DL. Transdermal nicotine system for smoking cessation. Therapeutics. 1992 May/June:80.

144. Palmer KJ, Buckley MM, Faulds D: Transdermal nicotine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an aid to smoking cessation, Drugs 1992 44: 498-529

145. Benowitz NL, Jacob P III, Olsson P: Intravenous nicotine retards transdermal absorption of nicotine: evidence of blood flowlimited percutaneous absorption, Clin Pharmacol Ther 1992 52: 223-30

146. Kochak GM, Sun JX, Choi RL: Pharmacokinetic disposition of multiple-dose transdermal nicotine in healthy adult smokers, Pharm Res 1992 9: 1451-5

147. Schneider NG: Nicotine therapy in smoking cessation. Pharmacokinetic considerations, Clin Pharmacokinet 1992 23: 169-72

148. Benowitz NL. Nicotine replacement therapy. What has been accomplishedcan we do better? Drugs. 1993; 45: 157-170.

149. Fiore MC, Jorenby DE, Baker TB: Tobacco dependence and the nicotine patch. Clinical guidelines for effective use, JAMA 1992 268: 2687-94

150. Gupta SK, Okerholm RA, Coen P: Single- and multiple-dose pharmacokinetics of Nicoderm (nicotine transdermal system), J Clin Pharmacol 1993 33: 169-74

151. Gorsline J, Gupta SK, Dye D: Steady-state pharmacokinetics and dose relationship of nicotine delivered from Nicoderm (nicotine transdermal system), J Clin Pharmacol 1993 33: 161-8

152. Sutherland G, Russell MA, Stapleton J: Nasal nicotine spray: a rapid nicotine delivery system, Psychopharmacology (Berl) 1992 108: 512-8

153. Pomerleau OF, Flessland KA, Pomerleau CS: Controlled dosing of nicotine via an Intranasal Nicotine Aerosol Delivery Device (INADD), Psychopharmacology (Berl) 1992 108: 519-26

154. Johansson CJ, Olsson P, Bende M: Absolute bioavailability of nicotine applied to different nasal regions, Eur J Clin Pharmacol 1991 41: 585-8

155. Lee EW, D'Alonzo GE: Cigarette smoking, nicotine addiction, and its pharmacologic treatment, Arch Intern Med 1993 153: 34-48

156. Rennard S, Daughton D, Fortmann S: Transdermal nicotine enhances smoking cessation in coronary artery disease patients, Chest 1991 100: 5S

157. Mueller P, Abelin T, Ehrsam R: The use of transdermal nicotine in smoking cessation, Lung 1990 168: Suppl 445-53

158. Foulds J, Stapleton J, Feyerabend C: Effect of transdermal nicotine patches on cigarette smoking: a double blind crossover study, Psychopharmacology (Berl) 1992 106: 421-7

159. Minneker E, Buchkremer G, Block M: The effect of different dosages of a transdermal nicotine substitution system on the success rate of smoking cessation therapy, Methods Find Exp Clin Pharmacol 1989 11: 219-22

160. Norregaard J, Tonnesen P, Simonsen K et al. Long-term nicotine substitution after application of a 16-hour nicotine patch in smoking cessation. Eur J Clin Pharm.

161. Eichelberg D, Stolze P, Block M: Contact allergies induced by TTS-treatment, Methods Find Exp Clin Pharmacol 1989 11: 223-5

162. Tonnesen P, Norregaard J, Sawe U: Recycling with nicotine patches in smoking cessation, Addiction 1993 88: 533-9

163. Bircher AJ, Howald H, Rufli T: Adverse skin reactions to nicotine in a transdermal therapeutic system, Contact Dermatitis 1991 25: 230-6

164. Hwang SL, Waldholt M. Heart attacks reported in patch users still smoking. The Wall Street Journal: B1, June 19, 1992.

165. Ottervanger JP, Stricker BHC, Klomps HC: Transdermal nicotine: clarifications, side effects, and funding, JAMA 1993 269: 1940

166. Fagerstrom KO, Schneider NG, Lunnel E. Effectiveness of nicotine patch and nicotine gum as individual versus combined treatments for tobacco withdrawal symptoms. Psychopharmacology. (in press)

167. Lederle Laboratories, Pearl River, NY: Personal communication.

168. Hilleman DE, Mohiuddin SM, Delcore MG. Comparison of fixed-dose transdermal nicotine, tapereddose transdermal nicotine and buspirone in smoking cessation. J Allergy Clin Immunol. 1993:171. Abstract.

169. Grenhoff J, Svensson TH: Pharmacology of nicotine, Br J Addict 1989 84: 477-92

170. Abood LG, Banerjee S, Kanne DB: Sites, mechanisms, and structural characteristics of the brain's nicotine receptor, J Subst Abuse 1989 1: 259-71

171. Gora ML: Nicotine transdermal systems, Ann Pharmacother 1993 27: 742-50

172. Benowitz NL: Pharmacologic aspects of cigarette smoking and nicotine addiction, N Engl J Med 1988 319: 1318-30

173. Balfour DJ: The influence of stress on psychopharmacological responses to nicotine, Br J Addict 1991 86: 489-93

174. Corrigall WA: Understanding brain mechanisms in nicotine reinforcement, Br J Addict 1991 86: 50710

175. Stolerman IP: Behavioural pharmacology of nicotine: multiple mechanisms, Br J Addict 1991 86: 533-6

176. Prather RD, Tu TG, Rolf CN: Nicotine pharmacokinetics of Nicoderm (nicotine transdermal system) in women and obese men compared with normal-sized men, J Clin Pharmacol 1993 33: 644-9

177. Paoletti P, Tonnesen P, Rodriquez-Roisin R: CEASE (Collaborative European Anti-Smoking Evaluation). A challenging multicenter trial organized by the European Respiratory Society, Chest 1993 103: 1317-9

188. McNeil Consumer Products Company. Nicotrol (nicotine) transdermal system patient information & instructions. Fort Washington, PA. Undated.

189. SmithKline Beecham Consumer Healthcare. NicoDermCQ patient information. Philadelphia, PA. Undated.

190. SmithKline Beecham Consumer Healthcare. Nicorette (nicotine polacrilex) gum patient information (dated 1997). In: Physicians' desk reference for nonprescription drugs. 20th ed. Montvale, NJ: Medical Economics Company Inc; 1999:780-2.

191. McNeil Consumer Products Co. NicotrolNS (nicotine) nasal spray prescribing information. Fort Washington, PA; 1996 March 21.

192. Fiscella K, Franks P: Cost-effectiveness of the transdermal nicotine patch as an adjunct to physicians' smoking cessation counseling, JAMA 1996 275: 1247-51

193. Fiore MC, Smith SS, Jorenby DE: The effectiveness of the nicotine patch for smoking cessation: a meta-analysis, JAMA 1994 271: 1940-7

194. The Smoking Cessation Clinical Practice Guideline Panel and Staff: The Agency for Health Care Policy and Research Smoking Cessation Clinical Practice Guideline, JAMA 1996 275: 1270-80

195. Fiore MC, Bailey WC, Cohen SJ et al. Smoking cessation: clinical practice guideline. No. 18. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. AHCPR publication No. 96-0692.

196. American Psychiatric Association Work Group on Nicotine Dependence: Practice guideline for the treatment of patients with nicotine dependence, Am J Psychiatry 1996 153: Suppl Oct 1-31

197. Hughes JR. Treatment of nicotine Dependence: is more better? JAMA. 1995; 274:1390-1. Editorial. (IDIS 355388)

198. Sachs DPL: Effectiveness of the 4-mg dose of nicotine polacrilex for the initial treatment of highdependent smokers, Arch Intern Med 1995 155: 1973-80

199. Gourlay SG, Forbes A, Marriner T: Double blind trial of repeated treatment with transdermal nicotine for relapsed smokers, BMJ 1995 311: 363-6

200. Working Group for the Study of Transdermal Nicotine in Patients with Coronary Artery Disease: Nicotine replacement therapy for patients with coronary artery disease, Arch Intern Med 1994 154: 98995

201. Sutherland G, Stapleton JA, Russell MAH: Randomised controlled trial of nasal nicotine spray in smoking cessation, Lancet 1992 340: 324-9

202. Hjalmarson A, Franzon M, Westin A: Effect of nicotine nasal spray on smoking cessation, Arch Intern Med 1994 154: 2567-72

203. Schneider NG, Olmstead R, Mody FV: Efficacy of a nicotine nasal spray in smoking cessation: a placebo-controlled, double-blind trial, Addiction 1995 90: 1671-82

204. Sandborn WJ, Tremaine WJ, Offord KP: Transdermal nicotine for mildly to moderately active ulcerative colitis: a randomized, double-blind, placebo-controlled trial, Ann Intern Med 1997 126: 36471

205. Bonapace CR, Mays DA: The effect of mesalamine and nicotine in the treatment of inflammatory bowel disease, Ann Pharmacother 1997 31: 907-12

206. Pullan RD, Rhodes J, Ganesh S: Transdermal nicotine for active ulcerative colitis, N Engl J Med 1994 330: 811-5

207. Hanauer SB: Nicotine for colitisthe smoke has not yet cleared, N Engl J Med 1994 330: 856-7

208. Kennedy LD: Nicotine therapy for ulcerative colitis, Ann Pharmacother 1996 30: 1022-3

209. Rhodes J, Thomas G: Nicotine treatment in ulcerative colitis: current status, Drugs 1995 49: 157-60

210. Thomas GAO, Rhodes J, Mani V: Transdermal nicotine as maintenance therapy for ulcerative colitis, N Engl J Med 1995 332: 988-92

211. Benowitz NL, Gourlay SG: Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy, J Am Coll Cardiol 1997 29: 1422-31

212. Ottervanger JP, Festen JM, de Vries AG: Acute myocardial infarction while using the nicotine patch, Chest 1995 107: 1765-6

213. Warner JG Jr, Little WC: Myocardial infarction in a patient who smoked while wearing a nicotine patch, Ann Intern Med 1994 120: 695

214. Jackson M: Cerebral arterial narrowing with nicotine patch, Lancet 1993 342: 236-7

215. Pierce JR Jr: Stroke following application of a nicotine patch, Ann Pharmacother 1994 28: 402

216. Kafka HP: Heart attacks, smoking, and the nicotine patch, Ann intern Med 1994 121: 389

217. Mittleman MA: Smoking while wearing a nicotine patch, Ann Intern Med 1995 122: 476-7

218. Warner JG Jr, Little WC: Myocardial infarction in a patient who smoked while wearing a nicotine patch, Ann Intern Med 1994 120: 695

219. Lagrue G, Verra F, Lebargy F: Nicotine patches and vascular risks, Lancet 1993 342: 564

220. Jackson M: Nicotine patches and vascular risks, Lancet 1993 342: 564

221. Joseph AM, Norman SM, Ferry LH: The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease, N Engl J Med 1996 335: 1792-8

222. Mahmarian JJ, Moye LA, Nasser GA: Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia, J Am Coll Cardiol 1997 30: 125-30

223. Kottke TE: Managing nicotine dependence, J Am Coll Cardiol 1997 30: 131-2

224. Rigotti NA, Eagle KA: Atrial fibrillation while chewing nicotine gum, JAMA 1986 255: 1018

225. Murray RP, Bailey WC, Daniels K: Safety of nicotine polacrilex gum used by 3,094 participants in the Lung Health Study, Chest 1996 109: 438-45

226. Keeley EC, Pirwitz MJ, Landau C: Intranasal nicotine spray does not augment the adverse effects of cigarette smoking on myocardial oxygen demand or coronary arterial dimensions, Am J Med 1996 171: 357-63

227. Oncken CA, Hatsukami DK, Lupo VR: Effects of short-term use of nicotine gum in pregnant smokers, Clin Pharmacol Ther 1996 59: 654-61

228. Wright LN, Thorp JM Jr., Kuller JA: Transdermal nicotine replacement in pregnancy: maternal pharmacokinetics and fetal effects, Am J Obstet Gynecol 1997 176: 1090-4

229. Sanchez P, Ducasse JL, Lapeyre-Mestre M et al. Nicotine poisoning as a cause of cardiac arrest? Clin Toxicol. 1996; 34:475-6. Letter. (IDIS 372635)

230. Woolf A, Burkhart K, Caraccio T: Self-poisoning among adults using multiple transdermal nicotine patches, J Toxicol Clin Toxicol 1996 34: 691-8

231. van de Klauw MM, Hillo EV, van den Berg WHHW: Vasculitis attributed to the nicotine patch (Nicotinell), Br J Dermatol 1996 134: 361-4

232. Riche G, Nighoghossian N, Trouillas P: Intracerebral haematoma after application of nicotine patch, Lancet 1995 346: 777-8

233. Foulds J, Toone B. A case of nicotine psychosis? Addiction. 1995; 90:435-7.

234. Marston GM, Cormac ID: Nicotine patches and paranoid psychosis, Irish Journal of Psychological Medicine 1995 12: 70-1

235. Mogadam M: Transdermal nicotine for ulcerative colitis, Ann Intern Med 1997 127: 491-2

236. Guslandi M, Tittobello A: Transdermal nicotine for ulcerative colitis, Ann Intern Med 1997 127: 492

237. Sandborn WJ, Tremaine WJ, Hurt RD: Transdermal nicotine for ulcerative colitis, Ann Intern Med 1997 127: 492-3

238. Homsy W, Yan K, Houle JM: Plasma levels of nicotine and safety of smokers wearing transdermal delivery systems during multiple simultaneous intake of nicotine and during exercise, J Clin Pharmacol 1997 37: 728-36

239. Anonymous: Nicotine patches and exercise, Can Med Assoc J 1996 154: 61-2

240. Glaxo Wellcome Inc. Zyban (bupropion hydrochloride) sustained-release tablets prescribing information. Research Triangle Park, NC; 1997 May.

241. Cromwell J, Bartosch WJ, Fiore MC: Cost-effectiveness of the clinical practice recommendations in the AHCPR guideline for smoking cessation, JAMA 1997 278: 1759-66

242. Benowitz NL. Treating tobacco addiction-nicotine or no nicotine? N Engl J Med. 1997; 337:1230-1. Editorial.

243. Hurt RD, Sachs DPL, Glover ED: A comparison of sustained-release bupropion and placebo for smoking cessation, N Engl J Med 1997 337: 1195-202

244. McNeil Consumer Products Co. Nicotrol inhaler (nicotine inhalation system) prescribing information. Fort Washington, PA; 1998.

245. Hjalmarson A, Nilsson F, Sjostrom L: The nicotine inhaler in smoking cessation, Arch Intern Med 1997 157: 1721-8

246. Tonnesen P, Norregaard J, Mikkelsen K: A double-blind trial of a nicotine inhaler for smoking cessation, JAMA 1993 269: 1268-71

247. Molander L, Lunell E, Andersson SB: Dose released and absolute bioavailability of nicoyine from a nicotine vapor inhaler, Clin Pharmacol Ther 1996 59: 394-400

248. Bergstrom M, Nordberg A, Lunell E: Regional deposition of inhaled 11-nicotine vapor in the human airway as visulaized by positron emission tomography, Clin Pharmacol Ther 1995 57: 309-17

249. Lunell E, Bergstrom M, Antoni B et al. Nicotine deposition and body distribution from a nicotine inhaler and a cigarette studies with positron emission tomography, Clin Pharmacol Ther. 1996; 59:593-4. Letter.

250. McNeil Consumer Products Co. Nicotrol inhaler (nicotine inhalation system) patient information. Fort Washington, PA; 1998.

251. Russell MAH, Jarvis MJ, Sutherland G: Nicotine replacement in smoking cessation: pharmacokinetic considerations, JAMA 1992 23: 169-72

252. Schneider NG, Lunell E, Olmstead RE: Clinical pharmacokinetics of nasal nicotine delivery: a review and comparison with other nicotine systems, Clin Pharmacokinet 1996 31: 65-80

253. Curry SJ, Grothaus LC, McAfee T: Use and cost effectiveness of smoking-cessation services under four insurance plans in a health maintenance organization, N Engl J Med 1998 339: 673-9

254. Eliasson B, Taskinen MR, Smith U: Long-term use of nicotine gum is associated with hyperinsulinemia and insulin resistance, Circulation 1996 94: 878-81

255. Schuh KJ, Schuh LM, Henningfield JE: Nicotine nasal spray and vapor inhaler: abuse liability assessment, Psycopharmacology (Berl) 1997 130: 352-61

256. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). From http://www.acc.org/clinical/guidelines and http://www.americanheart.org.

257. Fiore MC, Bailey WC, Cohen SJ et al. Treating tobacco use and dependence: clinical practice guideline. Rockville, MD: US Department of Health and Human Services, Public Health Service. 2000 Jun.

258. The Tobacco Use and Dependence Clinical Practice Guideline Panel, Staff, and Consortium Representatives: A clinical practice guideline for treating tobacco use and dependence: a US Public Health Service report, JAMA 2000 283: 3244-54

259. Anon. FDA warns sellers of nicotine lollipops & lip balm that their products are illegal. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2002 Apr 10. From the FDA website: ( http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01144.html)

260. GlaxoSmithKline. Facts about: Commit lozenge. From website http://www.commitlozenge.com. Accessed 2002 Dec.

261. Ganley C, Rappaport B, US Department of Health and Human Services. Letter to David Schifkovitz, Director, Regulatory Affairs, GlaxoSmithKline regarding NDA 21-330 (NDA submission for Commit [nicotine polacrilex lozenge]). Posted on US Food and Drug Administration website 2002 Nov 18.

262. Pharmacia. Nicotrol helps beat cigarettesone craving at a time! From Pharmacia website. 2002.

263. Shiffman S, Dresler CM, Hajek P: Efficacy of nicotine lozenge for smoking cessation, Arch Intern Med 2002 162: 1267-76

264. GlaxoSmithKline Consumer Healthcare. Commit (nicotine polacrilex lozenges) patient information. Pittsburgh, PA; 2002.

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AHFS DRUG INFORMATION (2004) 12:00 Autonomic Drugs 12:92 Miscellaneous Autonomic Drugs