Clozapine Plasma Levels

Clozapine plasma levels may be helpful in improving response rates and minimizing unnecessary side
effects.

Key facts about plasma levels:

• Inter-individual variation in blood level is high at constant dose (8-20 fold variation)
• Intra-individual variation in blood level is low on a clozapine constant dose (<20 percent)
• Clozapine is metabolized by the liver and therefore is exposed to drug interactions
• Clozapine side effects are often concentration/dose dependent
• Serum concentrations are age and gender dependent

Clozapine Plasma Level Monitoring is recommended under the Following Conditions:

• Any patient receiving more than 600 mg/day, given the increased risk of seizure above this
dosage
• When there is a question about compliance
• Patients showing excessive side effects at normal doses who may be metabolizing clozapine
less efficiently – e.g. the elderly
• When monitoring for drug-drug interaction(s) that alter clozapine metabolism

Clozapine plasma levels can also be used to examine response-dose patterns:

• The range of clozapine plasma levels associated with clinically meaningful response appears to
be wide, ranging from 200 ng/mL to 450 ng/mL.
• Some studies indicate a range of plasma levels between 350 ng/mL and 450 ng/mL associated
with clinically meaningful response, but many patients respond to lower plasma levels of
clozapine.
• Clinicians should use clinical judgment with plasma level data to find the best response while
minimizing side effects.
• The target plasma level for the vast majority of patients may be approximately 350 ng/mL.
Higher plasma levels may result in greater sedation and other unwanted side effects.
• However, patients who have not responded at a plasma level of 350 ng/mL after 6 weeks of
treatment should be raised to above 450 ng/mL. This strategy will result in increased rates of
response in some patients, but may also be associated with more side effects.
• There may be some ethnic differences in metabolism, which may dictate lower dosage levels,
such as low dose requirements in Chinese patients.

Clozapine metabolism:
• Clozapine is subject to considerable metabolism by the cytochrome P450 (CYP) enzyme
system. There are numerous variants of the genes encoding the CYP enzyme family within the
general population, resulting in complex individual genetic profiles and a variable response to
drugs metabolized by these enzymes.
• Clozapine is metabolized to desmethylclozapine by the CYP1A2 (also referred to as
norclozapine) and other compounds, but clozapine is the active CNS drug. Both CYP1A2 ultra-
rapid metabolizers tend to have low clozapine levels at high doses.
One of the most important interactions with clozapine is tobacco smoking, which tends to decrease
clozapine levels by inducing CYP1A2. The induction is by compounds in smoke and not by nicotine so
nicotine replacement medications do not affect clozapine levels. Patients whose clozapine dose was
optimized during a smoke-free inpatient admission will have lower clozapine levels if they resume
smoking as outpatients. Alternatively, stopping smoking is to be encouraged by all patients who smoke.
With successful smoking cessation, clozapine blood levels may increase necessitating gradual
clozapine dose decreases.

Effects of selected psychotropic medications on clozapine levels

Medication Increases clozapine level Decreases clozapine level
Bupropion (Wellbutrin®) 
Carbamazepine (Tegretol®) 
Chlorpromazine (Thorazine®) 
Clomipramine (Anafranil®) 
Despiramine (Norpramin®) 
Duloxetine (Cymbalta®) 
Escitalopram (Lexapro®) 
Fluoxetine (Prozac®) 
Fluvoxamine (Luvox®) 
Haloperidol (Haldol®) 
Imipramine (Tofranil®) 
Nefazodone (Serzone®) 
Paroxetine (Paxil®) 
Phenobarbital 
Phenytoin (Dilantin®) 
Risperidone (Risperdal®) 
Sertraline (Zoloft®) 
Thioridazine (Mellaril®) 
Tranylcypromine (Parnate®) 
Valproic acid, valproate 
(Depakote®, Depakene®)

Effects of selected non-psychotropic medications on clozapine levels

Medication Increases clozapine levels Decreases clozapine levels
Abiraterone acetate 
(Zytiga®)
Amiodarone (Cordarone®) 
Amlodipine (Norvasc®) 
Aprepitant (Emend®) 
Armodafinil (Nuvigil®) 
Atazanavir (Reyataz®) 
Bosentan (Tracleer®) 
Chloroquine (Aralen®) 
Cimetidine (Tagamet) 
Cinacalcet (Sensipar®) 
Clarithromycin (Biaxin®) 
Clotrimazole 
Cobicistat (Tybost®) 
Cyproterone (Androcur®) 
Darifenacin (Enablex®) 
Defiraserox (Exjade®) 
Delavirdine (Rescriptor®) 
Dexmedetomidine 
(Precedex®)
Diclofenac (Voltaren®) 
Diphenhydramine 
(Benadryl®
Enoxacin (Penetrex®) 
Erythromycin (Ery-Tab®) 
Fluoroquinolone antibiotics 
(ciprofloxacin, levofloxacin,
norfloxacin, ofloxacin)
Fosphenytoin (Cerebyx®, 
Prodilantin®)
Fospropofol (Lusedra®) 
Gemfibrozil (Lopid®) 
Imatinib (Gleevec®) 
Isoniazid (Nydrazid®) 
Ketoconozole (Nizoral®) 
Lidocaine (Xylocaine®) 
Methadone 
Methoxsalen (Oxsoralen®) 
Mexiletine (Mexitil®) 
Miconazole (Oravig®) 
Nicardipine (Cardene®) 
Nifedipine (Procardia®) 
Omeprazole (Prilosec®) 
Oral Contraceptives 
Quinidine (Quinidex®) 
Quinine (Qualaquin®) 
Ranolazine (Ranexa®) 
Rifampin (Rifadin®) 
Ritonivir (Norvir®) 
Terbinafine 
Ticlopidine (Ticlid®) 
Other substances:
Alcohol 
Caffeine (high levels) 
Echinacea 
Grapefruit, grapefruit juice 
St. John’s Wort 
Tobacco smoking 