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 and therefore is exposed to 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 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-(s) that alter clozapine

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 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 (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 metabolized by these enzymes. • Clozapine is metabolized to 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 (Wellbutrin®)  (Tegretol®)  (Thorazine®)  (Anafranil®)  Despiramine (Norpramin®)  Duloxetine (Cymbalta®)  Escitalopram (Lexapro®)  (Prozac®)  (Luvox®)  (Haldol®)  (Tofranil®)  (Serzone®)  (Paxil®)  Phenobarbital  (Dilantin®)  (Risperdal®)  (Zoloft®)  (Mellaril®)  Tranylcypromine (Parnate®)  Valproic acid,  (Depakote®, Depakene®)

Effects of selected non-psychotropic medications on clozapine levels Medication Increases clozapine levels Decreases clozapine levels Abiraterone acetate  (Zytiga®) (Cordarone®)  (Norvasc®)  (Emend®)  (Nuvigil®)  Atazanavir (Reyataz®)  Bosentan (Tracleer®)  Chloroquine (Aralen®)  (Tagamet)  Cinacalcet (Sensipar®) 

Clarithromycin (Biaxin®)  Clotrimazole  Cobicistat (Tybost®)  Cyproterone (Androcur®)  (Enablex®)  Defiraserox (Exjade®)  (Rescriptor®)   (Precedex®) Diclofenac (Voltaren®)   (Benadryl® Enoxacin (Penetrex®)  Erythromycin (Ery-Tab®)  Fluoroquinolone antibiotics  (, levofloxacin, norfloxacin, ofloxacin) Fosphenytoin (Cerebyx®,  Prodilantin®) Fospropofol (Lusedra®)  Gemfibrozil (Lopid®)  (Gleevec®)  Isoniazid (Nydrazid®)  Ketoconozole (Nizoral®)  (Xylocaine®)   Methoxsalen (Oxsoralen®)  (Mexitil®)  Miconazole (Oravig®)  (Cardene®)  (Procardia®)  Omeprazole (Prilosec®)  Oral Contraceptives  (Quinidex®)  Quinine (Qualaquin®)  (Ranexa®)  Rifampin (Rifadin®)  Ritonivir (Norvir®)  Terbinafine  Ticlopidine (Ticlid®)  Other substances:  Caffeine (high levels) 

Echinacea  Grapefruit, grapefruit juice  St. John’s Wort  Tobacco smoking 