Versacloz (clozapine)

Cautious dosage titration and administration of clozapine in divided doses are necessary to minimize the risk of certain adverse effects such as orthostatic hypotension, bradycardia, syncope, seizures, and sedation.

Concomitant use of strong cytochrome P-450 (CYP) 1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine), moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, caffeine), CYP2D6 or CYP3A4 inhibitors (e.g., bupropion, cimetidine, duloxetine, erythromycin, escitalopram, fluoxetine, paroxetine, quinidine, sertraline, terbinafine), CYP1A2 inducers (e.g., tobacco smoke), or CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort (Hypericum perforatum)) may warrant dosage adjustment of clozapine or monitoring for adverse effects. When used concomitantly with strong CYP1A2 inhibitors, clozapine dosage should be reduced to one-third of the original dosage. The dosage should be increased back to the original dosage when the strong CYP1A2 inhibitor is discontinued.

When used concomitantly with moderate or weak CYP1A2 inhibitors, or with CYP2D6 or CYP3A4 inhibitors, patients should be monitored for adverse effects and dosage reduction of clozapine should be considered, if necessary. If a moderate or weak CYP1A2 inhibitor or a CYP2D6 or CYP3A4 inhibitor is discontinued during clozapine therapy, patients should be monitored for decreased efficacy of clozapine; an increase in clozapine dosage may be necessary.

Conversely, concomitant use of clozapine with drugs or substances that induce CYP1A2 or CYP3A4 may result in decreased plasma concentrations of clozapine. The manufacturers state that concomitant use of a strong CYP3A4 inducer with clozapine is not recommended; however, if concomitant use cannot be avoided, patients should be monitored for decreased efficacy of clozapine, and consideration should be given to increasing the dosage of clozapine, if necessary. If clozapine is used concomitantly with a moderate or weak CYP1A2 inducer (e.g., tobacco smoke), patients should be monitored for decreased efficacy of clozapine; an increase in clozapine dosage may be necessary. If a CYP1A2 or CYP3A4 inducer is discontinued during clozapine therapy, patients should be monitored for possible adverse effects and dosage reduction of clozapine should be considered, if necessary.

Clozapine is administered orally as conventional tablets, disintegrating tablets, or as a suspension without regard to meals; administration in divided doses may help minimize the risk of certain adverse effects.

The orally disintegrating tablets and conventional tablets of clozapine are bioequivalent; the oral suspension and conventional tablets of the drug also are bioequivalent.

Commercially available conventional clozapine tablets should be stored in tight containers at a controlled room temperature of 20-25degreesC and not exceeding 30degreesC.

Patients receiving clozapine orally disintegrating tablets should be instructed not to remove a tablet from the blister until just prior to dosing. The tablet should not be pushed through the foil; instead, the foil blister backing should be peeled from the blister. The tablet should then be gently removed and immediately placed on the tongue, where it rapidly disintegrates in saliva, and then subsequently swallowed with or without liquid, or the tablet can be chewed as desired.

Clozapine orally disintegrating tablets should be stored in their original package at a controlled room temperature of 20-25degreesC, but may be exposed to temperatures ranging from 15-30degreesC. The orally disintegrating tablets should be protected from moisture.

Clozapine oral suspension should be shaken for 10 seconds prior to each use. The bottle adapter and calibrated oral dosing syringe supplied by the manufacturer should be used to administer the suspension. After withdrawing the appropriate dose into the calibrated oral dosing syringe, the dose should be administered directly into the patient's mouth; clozapine oral suspension should not be stored in the syringe for later use.

Clozapine oral suspension should be stored at a controlled room temperature of 20-25degreesC, but may be exposed to temperatures ranging from 15-30degreesC; the oral suspension should be protected from light and should not be refrigerated or frozen. The oral suspension is stable for 100 days after initial bottle opening.

No dosing information is available for this tab.

No dosing information is available for this tab.

Clozapine is a substrate for many cytochrome P-450 (CYP) isoenzymes, in particular 1A2, 2D6, and 3A4; it is also an inhibitor of CYP2D6.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*History of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, Stevens-Johnson syndrome) or any ingredient in the formulation.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Adverse effects reported in at least 5% of patients receiving clozapine include CNS reactions (e.g., sedation, dizziness/vertigo, headache, tremor), cardiovascular reactions (e.g., tachycardia, hypotension, syncope), autonomic nervous system reactions (e.g., hypersalivation, sweating, dry mouth, visual disturbances), GI reactions (e.g., constipation, nausea), and fever.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

The manufacturers state that the safety and efficacy of clozapine in pediatric patients have not been established. However, clozapine has been used in a limited number of children and adolescents with treatment-refractory schizophrenia+ and results of at least one randomized, double-blind clinical study indicate that adverse hematologic effects were a major concern for children and adolescents receiving clozapine. Although no cases of agranulocytosis occurred in this study, 24% of these children and adolescents experienced mild to moderate neutropenia during 2 years of follow-up compared with an estimated cumulative risk of 1.5-2% of developing neutropenia in adults. When children metabolize clozapine, higher concentrations of the metabolite norclozapine, which has been associated with hematopoietic toxicity, have been suggested as a possible reason for the increased risk in this age group.

In addition to adverse hematologic effects, clinically important seizure activity (e.g., epileptiform spikes, myoclonus, tonic-clonic seizures) also has been reported in children and adolescents with no previous history of epilepsy who received clozapine. In some cases, EEG abnormalities were associated with clinical deterioration (i.e., increased aggression, psychosis, irritability). Because some children and adolescents responded behaviorally to reduced dosages of clozapine and the addition of an anticonvulsant (e.g., valproate), it has been suggested that the EEG may be a sensitive indicator of clozapine toxicity in children as well as in adults.

A pregnancy registry is available that monitors pregnancy outcomes of women exposed to antipsychotics, including clozapine, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or by visiting https://womensmentalhealth.org/research/pregnancyregistry/.

There are risks to the mother from untreated schizophrenia, including an increased risk of relapse, hospitalization, and suicide, and from exposure to antipsychotic therapy during pregnancy. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth, but it is not known if this is a direct impact of the illness or from other comorbid factors. Reproduction studies in rats and rabbits using clozapine dosages up to 0.4 and 0.9 times the maximum recommended human dosage on a mg/m2 basis, respectively, have not revealed evidence of harm to the fetus.

Neonates exposed to antipsychotic agents, including clozapine, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored and symptoms managed appropriately. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization.

The manufacturers state that there are no adequate and well-controlled studies to date using clozapine in pregnant women, and the drug should be used during pregnancy only when clearly needed. Women should be advised to notify their clinician if they become pregnant or plan to become pregnant during therapy with the drug.

Clozapine is distributed into milk in humans. There is one reported case of sedation and one of agranulocytosis in an infant exposed to clozapine through breast milk. It is not known how clozapine affects milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from clozapine or from the underlying maternal condition.

Infants that are exposed to clozapine through breast milk should be monitored for excessive sedation and neutropenia.

In general, dosage should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range; the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.

Clinical studies of clozapine did not include sufficient numbers of patients >=65 years of age to determine whether geriatric patients respond differently than younger patients. Because geriatric patients may be at increased risk for certain cardiovascular (e.g., orthostatic hypotension, tachycardia) and anticholinergic effects of the drug (e.g., constipation, urinary retention), clozapine should be used cautiously in this age group. Data from clinical studies indicate that the incidence of tardive dyskinesia appears to be highest among geriatric patients, especially women. In general, dosage should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range; the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death compared with patients receiving placebo.

The manufacturer states that clozapine is not labeled for the treatment of patients with dementia-related psychosis.

An increased risk of adverse cerebrovascular events (e.g., stroke, transient ischemic attack), including fatalities, has been observed in patients with dementia treated with some atypical antipsychotic agents. The mechanism for this increased risk is not known. The manufacturers state that an increased risk cannot be excluded for other antipsychotics, including clozapine, or other patient populations. Clozapine should therefore be used with caution in patients with risk factors for stroke.