LEPONEX

Clozapine is a tricyclic dibenzodiazepine, classified as an atypical antipsychotic agent.

Clozapine displays affinity to various neuroreceptors with a particularly low affinity to the dopamine receptors, thus breaking the mold of first-generation antipsychotics and deeming it "atypical". 26.

This low affinity to dopamine receptors results in fewer extrapyramidal side effects, especially tardive dyskinesia.

However, its promiscuity toward the muscarinic and adrenergic receptors can result in other side effects, notably gastrointestinal hypomotility and orthostatic hypotension. 27, 8.

Despite its effectiveness in treating both positive and negative symptoms of schizophrenia, clozapine was briefly removed from the market in various jurisdictions in 1970 due to severe agranulocytosis. 24, 25 However, continued evidence of its effectiveness led to clozapine's eventual reintroduction, although with a reluctance to prescribe it.

Clozapine was approved by the

FDA in for treatment-resistant schizophrenia under the brand CLOZARIL.

Due to its severe adverse effects profile, clozapine is only available through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program.

Clozapine is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment.

Because of the risks of severe neutropenia and of seizure associated with its use, Clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment.

Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state.

Suicidal behavior refers to actions by a patient that put him/herself at risk for death.

Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives that is universally regarded as the treatment of choice for treatment-resistant schizophrenia.

Although it is thought to mediate its pharmacological effect through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors, research have shown that clozapine can act on various types of receptors.

Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use.

Clozapine-induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection. 8, 27 Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment.

The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils.

Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs.

Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range.

Monitoring parameters may change if there is any break in therapy.

In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program.

These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level.

Patients who enter the "Red" zone (WBC<2x109/L or ANC<1.5x109/L) should normally not be re-challenged.

Clozapine-induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients.

Monitor the patient's troponin, CRP, and ECG at baseline, and 28 days into treatment.

Follow guidelines for appropriate next steps according to the patient's lab results.

If myocarditis occurs, the patient should not be re-challenged with clozapine.

In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution.

Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102-771 ng/mL), occurring at the average of 2.5 hours (range: 1-6 hours) after dosing.

The average minimum concentration at steady state was 122 ng/mL (range: 41-343 ng/mL), after 100 mg twice daily dosing.

The median volume of distribution of clozapine was calculated to be 508 L (272–1290 L). 9, 10, 11, 13, 12.

Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces.

Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.The unmethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces.

Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive.

Hover over products below to view reaction partners Clozapine N-desmethylclozapine Desmethylclozapine glucuronide Clozapine N-oxide Clozapine 5-N-glucuronide.

Approximately 50% of the administered dose is excreted in the urine and 30% in the feces.

The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4-12 hours), compared to a mean elimination half-life of 12 hours (range: 4-66 hours), after achieving a steady state with 100 mg twice daily dosing.

A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics.

The median clearance of clozapine is calculated to be 30.3 L/h (14.4–45.2 L/h). 10, 12, 14, 15, 16, 17.

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There are no adequate or well-controlled studies of clozapine in pregnant women.

Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis.

The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine.

Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed.

Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum.

Consider early screening for gestational diabetes for patients treated with antipsychotic medications.

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization.

The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma tachycardia, hypotension, respiratory depression or failure; and hypersalivation. pneumonia, cardiac arrhythmias, and seizure.

Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.

There is no available specific antidote to an overdose of CLOZARIL.

Establish and maintain an airway; ensure adequate oxygenation and ventilation.

Monitor cardiac status and vital signs.

Use general symptomatic and supportive measures.

Consider the possibility of multiple-drug involvement.

No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times respectively, the maximum recommended human dose (MRHD) of 900 mg/day on an mg/m2 body surface area basis.

Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice.

Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered Oral to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on an mg/m2 body surface area basis.

ODT 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 Clozapine ODT.

Known hypersensitivity to clozapine or any other component of Clozapine ODT.

Recommended starting oral dosage is 12.5 mg once daily or twice daily.

If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day at target dosage of 150 mg to 225 mg twice per day by the end of two weeks.

Subsequently may increase the doage in increments up to 100 mg, once or twice weekly.

Maximum daily dosage is 450 mg twice daily.

Administer with or without food.

ODT may be allowed to disintegrate or chewed, and may be taken with or without water.

See additional administration instructions in the full prescribing information.

See dosage modification based on

ANC results.

See recommendations for discontinuing Clozapine

ODT treatment, restarting Clozapine ODT after interrupting dosing, dosage modifications for drug interactions, dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers in the full prescribing information.

Tablets rapidly disintegrate after placement in the mouth and may be chewed if desired.

No water is needed. 2.1 Absolute Neutrophil Count Testing Prior to Clozapine ODT Initiation Prior to initiating Clozapine ODT treatment, obtain a baseline absolute neutrophil count (ANC).

Clozapine ODT initiation is not recommended in patients with an ANC less than 1500/µL.

For patients with documented Benign Ethnic

Neutropenia (BEN) (also known as Duffy-null associated neutrophil count)), obtain at least two baseline ANC levels.

Clozapine ODT initiation is not recommended in patients with BEN with an ANC less than 1000/µL.

For dosage modifications based on

ANC results, see Dosage and Administration. 2.2 Recommended Dosage and Administration Recommended Dosage To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much lower than the target dosage.

The recommended starting oral dosage of Clozapine ODT is 12.5 mg once or twice daily.

If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks.

Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly.

The maximum recommended Clozapine

ODT oral dosage is 450 mg twice daily.

ODT can be taken with or without food, may be allowed to disintegrate or chewed, and may be taken with or without water.

After removing Clozapine

ODT from the bottle, immediately place in the mouth. 2.3 Dosage Modifications Based on ANC Results Table 1 provides recommended Clozapine ODT dosage modifications based on ANC results.

For dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count), see Table 2.

Table 1: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine ODT Treatment ANC Within Normal Range (≥ 1500/µL) No dosage modification; continue treatment Day to Month 6: Weekly Month to Month 12: Every 2 weeks Month and thereafter: Every month If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment Mild Neutropenia (ANC between to 1499/µL) Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours No dosage modification; continue treatment Three times weekly Once ANC ≥ 1500/µL, recommend returning to the patient’s last Normal Range ANC testing frequency Moderate Neutropenia (ANC between to 999/µL) Interrupt treatment and recommend hematology consultation Resume treatment once ANC ≥ 1000/µL Daily Once ANC ≥ 1000/µL, three times weekly Once ANC ≥ 1500/µL, test weekly for 4 weeks.

If ANC ≥ 1500/µL after monitoring weekly for 4 weeks, return to the patient’s last Normal Range ANC testing frequency Severe Neutropenia (ANC less than 500/µL) Discontinue treatment and recommend hematology consultation Daily Once ANC ≥ 1000/µL, three times weekly Once ANC ≥ 1500/µL, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients who initiate treatment 2.4 Dosage Modifications Based on ANC Results for Patients with Benign Ethnic Neutropenia Table 2 provides recommended Clozapine ODT dosage modifications based on ANC results for patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) .

For dosage modifications based on ANC results for patients without BEN, see Table 1.

Table 2: Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count.

Recommended Dosage Modification Recommended Frequency of ANC Testing During Clozapine ODT Treatment in Patients with BEN ANC Within the Normal Range for Patients with BEN (≥ 1000/µL ) No dosage modification; continue treatment Day to Month 6: Weekly Month to Month 12: Every 2 weeks Month and thereafter: Monthly If Clozapine ODT treatment is reinitiated after a dosage interruption (e.g., patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/µL and ≥ the patient’s ANC baseline prior to treatment) for: < 30 days, continue previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between to 999/µL) Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours Recommend hematology consultation No dosage modification; continue treatment Three times weekly Once ANC ≥ 1000/µL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks If ANC ≥ 1000/µL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN.

Severe Neutropenia in Patients with

BEN (ANC level less than 500/µL) Discontinue treatment and recommend hematology consultation Daily Once ANC ≥ 500/µL, obtain ANC three times weekly Once ANC ≥ 1000/µL and ≥ the patient’s baseline, if the benefits outweigh the risks of restarting treatment, resume treatment and obtain ANC tests according to the frequency for patients with BEN who initiate treatment 2.5 Discontinuation of Clozapine ODT Treatment If discontinuing Clozapine ODT in patients with: Moderate or severe neutropenia, see Table 1.

Normal or mild neutropenia, reduce the dosage gradually over a period of to 2 weeks, and continue monitoring ANC levels until their ANC is ≥ 1500/µL. If discontinuing Clozapine ODT in patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) with: Neutropenia, see Table 2.

ANC within their normal range of

ANC reduce the dosage gradually over a period of to 2 weeks.

When discontinuing Clozapine

ODT, monitor patients for the symptoms related to psychotic recurrence and cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, diarrhea). 2.6 Restarting Clozapine ODT Treatment After Interrupting Clozapine ODT When restarting Clozapine ODT in patients who have interrupted Clozapine ODT treatment, use a lower dosage to minimize the risk of hypotension, bradycardia, and syncope.

If one day’s dosage is missed, resume Clozapine ODT treatment at 40% to 50% of the previous dosage.

If two days of dosing is missed, resume Clozapine ODT treatment at approximately 25% of the previous dosage.

For longer interruptions, restart Clozapine ODT treatment with a dosage of 12.5 mg once or twice daily.

If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial Clozapine ODT treatment. 2.7 Dosage Modifications for Drug Interactions See Table for recommended dosage modifications to reduce the risk of Clozapine ODT-associated adverse reactions or reduce the risk of lower effectiveness.

Table 3: Clozapine ODT Dosage Modifications for Drug Interactions Strong CYP1A2 Inhibitors Administer one third of the Clozapine ODT dosage.

CYP1A2 Inhibitors Consider reducing the Clozapine ODT dosage if necessary.

CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended.

However, if concomitant use is necessary, it may be necessary to increase the Clozapine ODT dosage.

Monitor for decreased effectiveness.

Moderate or weak

CYP1A2 or CYP3A4 Inducers Consider increasing the Clozapine ODT dosage if necessary. 2.8 Dosage Recommendations in Patients with Renal or Hepatic Impairment, or CYP2D6 Poor Metabolizers It may be necessary to reduce the Clozapine ODT dosage in patients with significant renal impairment or hepatic impairment, or in CYP2D6 poor metabolizers.

Tablets are available containing 100 mg of clozapine, USP.

The 100 mg tablets are peach, round, unscored tablets debossed with C over on one side of the tablet and blank on the other side.

They are available as follows

NDC 48433-022-04 – Unit dose blister packages of 40 (5 cards of 8 tablets each). 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F).

Protect from moisture.

Keep out of reach of children.

ODT in the original package until used by the patient.

Dispense a Medication Guide with each prescription.

The quantity of Clozapine ODT depends on the ANC testing results.

If a patient is eligible for ANC testing: Every week, then a 1-week supply of Clozapine ODT can be dispensed.

Every 2 weeks, then a 2-week supply of Clozapine ODT can be dispensed.

Every 4 weeks, then a 4-week supply of Clozapine ODT can be dispensed.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including Clozapine ODT, during pregnancy.

Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Atypical Antipsychotics at1-866-961-2388 or visiting Risk Summary Neonates exposed to antipsychotic drugs, including Clozapine ODT, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

Available data from published epidemiologic studies over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including Clozapine ODT, during pregnancy.

In animal reproduction studies, no adverse developmental effects were observed when clozapine was administered orally to pregnant rats or rabbits during the period of organogenesis, or to pregnant rats during pregnancy and lactation, at doses up to approximately 0.4 and 0.9 times the maximum recommended human dose (MRHD) of 900 mg/day, for rats and rabbits respectively, based on mg/m2 body surface area.

The background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide.

Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth.

It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal adverse reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who have been exposed to antipsychotic drugs, including Clozapine ODT, during the third trimester of pregnancy.

These symptoms have varied in severity.

Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

In embryofetal developmental studies, clozapine had no effects on maternal parameters, litter sizes, or fetal parameters when administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 0.4 and 0.9 times, respectively, the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

In peri/postnatal developmental studies, pregnant female rats were administered clozapine over the last third of pregnancy and until day 21 postpartum.

Observations were made on fetuses at birth and during the postnatal period; the offspring were allowed to reach sexual maturity and mated.

Clozapine caused a decrease in maternal body weight but had no effects on litter size or body weights of either F1 or F2 generations at doses up to 0.4 times the MRHD of 900 mg/day on a mg/m 2 body surface area basis.

Safety and effectiveness of clozapine in pediatric patients have not been established.

There have not been sufficient numbers of geriatric patients in clinical studies utilizing clozapine to determine whether those over 65 years of age differ from younger subjects in their response to clozapine.

Orthostatic hypotension and tachycardia can occur with Clozapine ODT treatment [seeand Warnings and Precautions.

Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.

Elderly patients may be particularly susceptible to the anticholinergic effects of Clozapine ODT, such as urinary retention and constipation.

Carefully select Clozapine

ODT doses in elderly patients, taking into consideration their greater frequency of decreased hepatic, renal, or cardiac function, as well as other concomitant disease and other drug therapy.

Clinical experience suggests that the prevalence of tardive dyskinesia appears to be highest among the elderly; especially elderly women.