Clozapine: uses, dosing, side effects & brands

The following adverse reactions are discussed in more detail in other sections of the labeling: • Severe Neutropenia [see Warnings and Precautions ( 5.1 )] • Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions ( 5.2 )] • Falls [see Warnings and Precautions ( 5.3 )] • Seizures [see Warnings and Precautions ( 5.4 )] • Myocarditis, Pericarditis, Cardiomyopathy, and Mitral Valve Incompetence [see Warnings and Precautions ( 5.5 )] • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.6 )] • Gastrointestinal Hypomotility with Severe Complications [See Warnings and Precautions ( 5.7) ] • Eosinophilia [see Warnings and Precautions ( 5.8 )] • QT Interval Prolongation [see Warnings and Precautions ( 5.9 )] • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions ( 5.10 )] • Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.11 )] • Hepatotoxicity [see Warnings and Precautions ( 5.12 )] • Fever [see Warnings and Precautions ( 5.13 )] • Pulmonary Embolism [see Warnings and Precautions ( 5.14 )] • Anticholinergic Toxicity [see Warnings and Precautions ( 5.15 )] • Interference with Cognitive and Motor Performance [see Warnings and Precautions ( 5.16 )] • Tardive Dyskinesia [see Warnings and Precautions ( 5.17 )] • Cerebrovascular…

CLOZARIL is contraindicated in patients with a history of hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson syndrome) or any other component of CLOZARIL [see Adverse Reactions ( 6.2 )]. Known hypersensitivity to clozapine or any other component of CLOZARIL. ( 4 )

Concomitant use of Strong CYP1A2 Inhibitors: Reduce CLOZARIL dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin). ( 2.7 , 7.1 ) • Concomitant use of Strong CYP3A4 Inducers is not recommended. ( 2.7 , 7.1 ) • Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing CLOZARIL dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued. ( 2.7 , 7.1 ) • Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity. ( 5.7 , 5.15 , 7.1 ) 7.1 Potential for Other Drugs to Affect CLOZARIL Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering CLOZARIL concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of CLOZARIL and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the CLOZARIL dose to one-third of the original dose when CLOZARIL is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The CLOZARIL dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration ( 2.7 ), Clinical Pharmacology ( 12.3 )] . Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when CLOZARIL is coadministered with these inhibitors. Consider reducing the CLOZARIL dosage if necessary [see Dosage and Administration ( 2.7 )] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with CLOZARIL and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology ( 12.3 )] . Use caution and monitor patients closely when using such inhibitors. Consider reducing the CLOZARIL dose [see Dosage and Administration ( 2.7 )] . CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of CLOZARIL. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the CLOZARIL dose if used concomitantly with inducers of these enzymes. However, concomitant use of CLOZARIL and strong CYP3A4 inducers is not recommended [see Dosage and Administration ( 2.7 )] . Consider reducing the CLOZARIL dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration ( 2.7 )] . Anticholinergic Drugs Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of CLOZARIL with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7 , 5.15 )] . Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions ( 5.9 )] . 7.2 Potential for CLOZARIL to Affect Other Drugs Concomitant use of CLOZARIL with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering CLOZARIL with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide). 7.1 Potential for Other Drugs to Affect CLOZARIL Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering CLOZARIL concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of CLOZARIL and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the CLOZARIL dose to one-third of the original dose when CLOZARIL is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The CLOZARIL dose should be increased to the original dose when coadministration of strong CYP1A2 inhibitors is discontinued [see Dosage and Administration ( 2.7 ), Clinical Pharmacology ( 12.3 )] . Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when CLOZARIL is coadministered with these inhibitors. Consider reducing the CLOZARIL dosage if necessary [see Dosage and Administration ( 2.7 )] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with CLOZARIL and CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline) can increase clozapine levels and lead to adverse reactions [see Clinical Pharmacology ( 12.3 )] . Use caution and monitor patients closely when using such inhibitors. Consider reducing the CLOZARIL dose [see Dosage and Administration ( 2.7 )] . CYP1A2 and CYP3A4 Inducers Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness of CLOZARIL. Tobacco smoke is a moderate inducer of CYP1A2. Strong CYP3A4 inducers include carbamazepine, phenytoin, St. John’s wort, and rifampin. It may be necessary to increase the CLOZARIL dose if used concomitantly with inducers of these enzymes. However, concomitant use of CLOZARIL and strong CYP3A4 inducers is not recommended [see Dosage and Administration ( 2.7 )] . Consider reducing the CLOZARIL dosage when discontinuing coadministered enzyme inducers; because discontinuation of inducers can result in increased clozapine plasma levels and an increased risk of adverse reactions [see Dosage and Administration ( 2.7 )] . Anticholinergic Drugs Concomitant treatment with clozapine and other drugs with anticholinergic activity (e.g., benztropine, cyclobenzaprine, diphenhydramine) can increase the risk for anticholinergic toxicity and severe gastrointestinal adverse reactions related to hypomotility. Avoid concomitant use of CLOZARIL with anticholinergic drugs when possible [see Warnings and Precautions ( 5.7 , 5.15 )] . Drugs that Cause QT Interval Prolongation Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, and pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Warnings and Precautions ( 5.9 )] . 7.2 Potential for CLOZARIL to Affect Other Drugs Concomitant use of CLOZARIL with other drugs metabolized by CYP2D6 can increase levels of these CYP2D6 substrates. Use caution when coadministering CLOZARIL with other drugs that are metabolized by CYP2D6. It may be necessary to use lower doses of such drugs than usually prescribed. Such drugs include specific antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide).