Consensus of GLOBAL ALLIANCE: Oral isotretinoin is the mainstay of therapy for severe acne Targets all pathophysiologic factors in acne May achieve dramatic results even in severe disease Now used more frequently in moderate, non-responsive acne Side effects are common, but usually manageable Education is vital (side effects, teratogenicity, adverse psychiatric events, monitoring) Leads to prolonged remission. Variable rate of recurrence; retreatment may be necessary
Oral Isotretinoin
Clinically used in :
severe nodular and cystic acne moderate or severe acne unresponsive to topical therapy moderate to severe acne with scarring inflammatory acne resistant to conventional therapy late onset in the mid-20s or 30s (acne at this age is often resistant to oral antibiotics). chronic acne prone to relapse
Isotretinoin
Dramatic reduction in sebaceous gland activity and sebum production that leads to a significant decrease in the P acnes population. Patients suitable for isotretinoin treatment are those with severe nodular or cystic acne; (acne conglobata) moderate acne that is resistant to conventional treatment (that is, the patient having received two courses of oral antibiotics at the correct dose for the correct length of time); late onset in the mid-20s or 30s (acne at this age is often resistant to oral antibiotics). Delays in starting isotretinoin treatment for patients with severe acne can result in substantial scarring, so it is important that such patients are referred urgently to dermatology departments.
Acne relapse
Low rates usually seen as compared to other therapies 40% usually relapse in 3 yrs. Relapses can increase due to following reasons severe seborrhoea and a high score of inflammatory lesions at the end of the treatment, an early age, a family history of acne, prepubertal acne and acne extended to the trunk are the factors increasing significantly the risk of relapse.
Therapeutic Class: Anti acne Introduced in 1982. Chemical Class: Synthetic analogue of vitamin A (13-cis retinoic acid ) Structure
13-cis
retinoic acid is produced by rotating the terminal carboxyl group of neutrally occurring all trans-retinoic acid across the double bond in the 13 position
Mechanism of action
Keratolytic effect
Retinoids affect the keratinization process (effective in many hyperkeratotic conditions ) Decrease keratinocyte adhesion The number of keratin precursors (tonofilaments and tonofibrils) are reduced, desmosomes become smaller and less well-developed, and microvilli appear on the cell surface The stratum corneum becomes less well organized, losing its superficial layers and becoming thinner . Comedones are shed and formation of microcomedones is prevented. Improves the differentiation of keratinocytes and follicular cells in the pilosabaeceous unit.
Mechanism of action
Anti- seborrheic effect Decreases the production of sebum in a doserelated manner (Efficacy noted with doses as low as
0.05 mg/kg/day)
decreases the size and secretion of the sebaceous glands ( shrinkage) 30% to 80% reduction in sebaceous gland activity was still present 80 weeks after discontinuing isotretinoin therapy indirectly inhibits P acnes growth via changes of the follicular milieu & by substantial decrease in sebum.
Mechanism of action
Profound inhibition of both neutrophil and monocyte chemotaxis across intact biologic barriers - anti inflammatory effect.
Prolonged remissions (38 months) have also been observed following 3 to 4 month treatment
Thus, oral isotretinoin is unique among current acne treatments in that it affects all of the pathogenic factors involved in this disease.
Immunoadjuvant action
stimulation of the immune system: Increase in levels of immunoglobulins and helper T cells at 8 weeks and increased levels of B cells at 16 weeks contributory factor to their marked clinical improvement
Indications
Severe Nodular and/or Inflammatory Acne Nodulocystic acne & Acne Conglobata Recalcitrant Acne (failure of conventional treatment. eg, a combination of topical retinoids, benzoyl peroxide and topical or systemic antibiotics and, when appropriate, hormonal therapies) Maintainence treatment to prevent relapse
Cunliffe WJ, van DeKerkhof PC, Caputo R, Cavicchini S, Cooper A, Fyrand OL et al. Dermatology 1997; 194:3517.
Dosing recommendations
Importance of cumulative dosing Cumulative dosing more imp than daily dose in preventing relapse. Effective immediate and long term efficacy seen with mid to high dose regimens. Dose range, 0.51.0 mg/kg/day. In most patients, complete or near complete suppression of acne is achieved with a treatment course of 56 months Total cumulative dose: Should be 120 mg/kg treatment extended to 2 months after complete clearing of the acne to avoid recurrence of inflammatory lesions Under certain circumstances, higher cumulative doses (possibly up to 200 mg/kg) may be required (e.g. patients showing clear signs of ongoing resolution at the 150 mg/kg threshold)
Low-dose regimens
Acute flare
High-dose regimens: defined as >1.0
mg/kg/day young patients with acne of short duration male patients with truncal acne
Clinical experience
The effect in severe nodulocystic acne can be dramatic, most cases respond to a single 4- to 6 month therapeutic course . In general, pustules clear more rapidly than papules or nodules. Also, lesions on the face, upper arms and legs tend to respond more quickly than truncal lesions Results are not evident for 1 to 2 months after start of therapy; similarly, therapeutic benefits continue for several months after discontinuation of therapy. In a few cases, complete clearing may occur 1 to 2 months after oral isotretinoin is stopped, usually without additional treatment
Contraindications
hypersensitivity to isotretinoin hepatic and renal failure, hypervitaminosis A, and in patients with excessively elevated blood lipid values. Pregnant females contraindicated in females of childbearing potential unless all of the following conditions apply:
The patient has severe disfiguring nodular and/or inflammatory acne, acne conglobata or recalcitrant acne that has not responded to standard therapy, including systemic antibiotics. The patient is reliable in understanding and carrying out instructions.
1.
2.
3. The patient is able and willing to comply with the mandatory effective contraceptive measures. 4. The patient has received, and acknowledges understanding of oral and printed explanation of the hazards of fetal exposure to isotretinoin and the risk of possible contraception failure. 5. The patient uses effective contraception without any interruption for one month before beginning therapy, during therapy and for one month following discontinuation of isotretinoin therapy. It is recommended that two reliable forms of contraception be used simultaneously . 6. The patient has had two negative pregnancy tests before starting therapy with the second pregnancy test 11 days prior to initiating therapy. & two or three days of the normal menstrual period before therapy is initiated. 7. In the event of relapse treatment, the same uninterrupted and effective contraceptive measures must be usedone month prior to, during and for one month after isotretinoin therapy.
Pharmacokinetics
Due to its high lipophilicity, Absorption increases with food or milk . Bioavailability is doubled relative to fasting conditions
Pharmacokinetics
Isotretinoin and its metabolites are excreted almost equally in the urine and feces. Following an 80 mg dose 65% to 83% of the dose was recovered in urine and feces. Elimination half life of isotretinoin: 10-20 hours Metabolite: 4-oxo-isotretinoin: 17 to 50 hours mean minimum steady-state blood concentrations of isotretinoin were 160 ng/mL in 10 patients receiving 40 mg b.i.d. doses
No statistically significant differences in the pharmacokinetics of isotretinoin between pediatric(12- 15 yrs) and adult patients
Adverse effects
Cheilitis and hypertriglyceridemia are usually dose related. The common side effects are dermatologic. cheilitis (96%), Dry or chapped lips are seen in almost
all patients treated with isotretinoin.
facial erythema/dermatitis (55%), dry nose (51%), desquamation (50%),pruritus (30%), dry skin (22%), conjunctivitis (19%), alopecia (13%), irritation of the eyes (11%), rash (<10%). Dryness of the nasal mucosa and pharynx, hoarseness, Mild conjunctivitis and rarely loss of hair
Adverse effects
Secondary skin infection with S aureus is not uncommon and should be treated with topical antiseptics or oral antibiotics. Melasma can occur
ERYTHEMA NODOSUM, ERYTHEMA MULTIFORME
Some patients have muscle aches and backaches, and some have mild headaches at the start of therapy, but these often resolve during the course of treatment. Nosebleeds and skin fragility may also occur 13% of patients experience joint pain during treatment. Retinoid induced osteoporosis and osteophyte formation. Loss of bone density occurs.
Adverse effects
Ophthalmic S/E: Decreased Night Vision, Cataracts and corneal opacities , visual disturbances have also been reported. optic neuritis, photophobia, eye lid inflammation, keratitis, and colour vision disturbances . Dry eyes and/or decreased tolerance to contact lenses. Gastrointestinal: nausea, mild gastrointestinal bleeding, rectal bleeding. Severe pancreatitis has been reported (especially those with high triglyceride levels) Cardiovascular: edema, transient pain in the chest, palpitations, tachycardia. RIGHT BRANCH BUNDLE BLOCK (RBBB) associated with SINUS
TACHYCARDIA
Respiratory: respiratory infections, Bronchospasm in pts with history of asthma. Psychiatric Disorders: Depression, psychotic symptoms and, rarely, suicide attempts, suicide and aggressive and/or violent behaviours. Emotional instability CNS: seizures, dizziness, nervousness, drowsiness, malaise, weakness, insomnia, lethargy, paresthesia.
Adverse effects
Reproductive system: abnormal menses. Urinary system: glomerulonephritis Hematological: hematuria/proteinuria Body as a whole: weight loss, anemia, lymphadenopathy, vasculitis including allergic vasculitis, allergic responses, and systemic hypersensitivity. Musculoskeletal: arthritis, muscle pain (myalgia; elevations of serum CPK values), arthralgia, calcification of ligaments and tendon and tendinitis. Hearing: impaired hearing at certain frequencies.
Adverse effects
Potent teratogen:
women of child-bearing age must not start therapy until a negative pregnancy test result has been obtained. Adequate contraception is essential before and during oral isotretinoin therapy, as well as for 6 weeks post-therapy. Therapy should start on the first, second, or third day of the menstrual period once the results of the pregnancy test have been obtained. CNS (hydrocephalus, hydranecephaly, microcephaly, posterior fossa abnormalities, cranial nerve dysfunction, cerebellar malformation); Craniofacial (microtia, low set ears, small or absent external auditory canals, microphthalmia, facial dysmorphia, cleft palate); Cardiac (septal defects, aortic arch abnormalities, tetralogy of Fallot); Thymus gland abnormalities; and parathyroid hormone
Adverse effects
If pregnancy does occur during treatment of a female patient who is taking isotretinoin, isotretinoin must be discontinued immediately. she should be referred to an ObstetricianGynecologist
In rats :
adrenal medullary hyperplasia was also increased at the higher dosage No human reportsof increase in carcinogenecity.
Ames test was positive in one and negative in other centre. Other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative. In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed
Impairment of Fertility
In dogs, testicular atrophy : at 20 to 30 times doses for 30 weeks. microscopic evidence for depression of spermatogenesis
In human studies of 66 men: no significant changes in spermatozoa count or motility In study of 50 men (17 to 32 years) no significant effects on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
Lab abnormalities
Elevation of serum triglycerides (25% of patients), mild to moderate decrease in serum high density lipoprotein (HDL) (16% of patients), and minimal elevations of serum cholesterol (7% of patients). Elevated blood glucose have been reported, and new cases of diabetes A rise in serum levels of liver enzymes may occur, especially with higher dosages elevated CPK, and hyperuricemia.
White blood cells and red blood cells in the urine and proteinuria.
Precautions
Acute pancreatitis and fatal hemorrhagic pancreatitis (rare) Caution in h/0 depression , psychiatric disorder
Hepatotoxicity- hepatitis and elevated liver enzymes have been; monitor LFT at before Rx and 1, 3, 6 mnths.
Benign intracellular hypertension
Precautions
Hyperlipidemia Inflammatory bowel disease Psychiatric disorders- depression, psychosis Skeletal- age-related osteoporosis, osteomalacia, childhood osteoporosis, other bone metabolism disorders Visual problems- corneal opacities, decreased night vision Vitamin supplements containing vitamin A: additional toxicity
Precautions
Avoid resurfacing procedure (e.g., laser dermabrasion ) and wax epilation during therapy and till 6 months after therapy. Photosensitivity can occur - avoid uv light and sunlight for long time. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue high risk patients (with diabetes, obesity, alcoholism or lipid metabolism disorder) more frequent lipid and glucose levels .
Drug interactions
Microdosed progesterone preparations (minipills) are not a suitable method of contraception Vitamin A: Tetracyclines: Rare cases of benign intracranial hypertension pseudotumor cerebri Caution : phenytoin and steroids. Methotrexate : hepatotoxicity Alcohol : a disulfiram-like reaction
Dosage
Therapeutic response to isotretinoin is dose-related and varies between patients, necessitates individual adjustment of dosage weight and severity of the disease.
Maintenance Therapy: between 0.1 and 1 mg/kg body weight daily up to 2 mg/kg body weight daily (120 mg per day maximally)
Duration : 15 to 20 weeks.
Dosage
Complete or near-complete suppression of acne is achieved with a single 12 to 16 week course of therapy. total nodule count has been reduced by more than 70% - isotretinoin can be discontinued If a second course of therapy is needed, it can be initiated eight or more weeks after completion of the first course Long-term use (> 1yr) even in low doses, has not been studied, and is not recommended.
Clinical studies
Efficacy of isotretinoin was compared with minocycline in 24 men with severe cystic acne At the end of treatment isotretinoin was significantly more effective than minocycline and induced remission in all subjects.
For severe nodulocystic acne Double blind randomised clinical trial 2 groups : isotretinoin 1-2 mg/kg/day tetracycline 500- 1000 mg/kg/day 3 weeks wash up, 16 week therapy and 8 week follow up.
percentage
no of cysts
cyst size
During the 8-week post treatment period, patients who had been treated with isotretinoin continued to improve, while the acne condition of tetracycline-treated patients remained unchanged
Sixty-one per cent of the patients were nonrelapsers: 40% required no further therapy, and 21% required topical therapy alone. Thirty-nine per cent relapsed, and required systemic therapy in the form of oral antibiotics (16%) or further isotretinoin (23%)
Those patients who received 0. 5 mg/kg daily, or a cumulative dose of < 120 mg/kg, had a significantly higher relapse rate than patients receiving a larger dose. long-term remission in the majority of acne patients can be achieved , particularly if given in a dose regimen of 1 mg/kg/day. or a cumulative dose of > 120 mg/kg.
Factors may predict the need for more than one course
299 patients treated 5 years ago with isotretinoin followed for 5 years post treatment 22.7 % required repeat courses. Factors contributing to the need for further courses of treatment included lower dose regimens (0-1 and 0-5 mg/kg). the presence of severe acne, being a female over the age of 25 at the onset of therapy, and having a prolonged history of acne.
BJD (1993)129,297-301.
Two studies that show lack of correlation between isotretinoin and depression
Patients taking isotretinoin should let their physicians know about any depressive symptoms, self-destructive thoughts, or other mood changes, and maybe about headaches as well. Depressed persons need not avoid isotretinoin.
Aside from its teratogenic effect, isotretinoin is a safe for acne In authors opinion there is no need for a routine laboratory follow-up in young, healthy patients aside from a pregnancy test in females. considered as the DOC for moderate to severe acne.
Journal of Dermatological Treatment (2001) 12, 912
Infantile acne
Oral isotretinoin has been used with success to treat resistant occurrences of infantile acne causing severe scarring and cosmetic sequelae 0.2 mg/kg/day to 1.5 mg/kg/day for 5 to 14 months. Barnes et al: Pediatric Dermatology Vol.22 No. 2 166-169,2005