LEPONEX

Clozapine, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5 H -dibenzo [ b,e ] diazepine.

The structural formula is

Clozapine Orally Disintegrating Tablets (referred to as Clozapine ODT) are available as peach, orally disintegrating tablets of 25 mg, 100 mg, 150 mg or 200 mg for oral administration without water.

Clozapine orally disintegrating tablets may be chewed.

Each orally disintegrating tablet contains clozapine, USP equivalent to 25 mg, 100 mg, 150 mg or 200 mg. The active component of clozapine orally disintegrating tablets is clozapine.

The remaining components are aspartame, crospovidone, FD&C Yellow No.

Lake, magnesium stearate, mannitol, microcrystalline cellulose, peppermint flavor, silicon dioxide and sodium stearyl fumarate.

ODT contains aspartame.

Phenylalanine is a component of aspartame.

Each 25 mg, orally disintegrating tablet contains 3.38 mg aspartame, thus, 1.90 mg phenylalanine.

Each 100 mg, orally disintegrating tablet contains 13.52 mg aspartame, thus, 7.59 mg phenylalanine.

Each 150 mg, orally disintegrating tablet contains 20.28 mg aspartame, thus, 11.38 mg phenylalanine.

Each 200 mg, orally disintegrating tablet contains 27.04 mg aspartame, thus, 15.18 mg phenylalanine. structural formula.

He uses clozapine mainly to treat schizophrenia.

He reduces hallucination, and reduces negative thoughts associated with schizophrenia and suicidal behavior among schizophrenics.

The anti-disease agent has to be treated as a pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulse of the pulp of the pulp of the pulp of the pulse of the pulse of the pulse of the pulse of the pulp of the pulp of the pulp of the pulp of the pulp of the pulp of the pulp.

The mechanism of action of clozapine is unknown.

However, it has been proposed that the therapeutic efficacy of Clozapine ODT in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors.

Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors. 12.2 Pharmacodynamics Clozapine demonstrated binding affinity to the following receptors: histamine H 1 (K i 1.1 nM), adrenergic α 1A (K i 1.6 nM), serotonin 5-HT 6 (K i 4 nM ) , serotonin 5-HT 2A (K i 5.4 nM), muscarinic M 1 (K i 6.2 nM), serotonin 5-HT 7 (K i 6.3 nM), serotonin 5-HT 2C (K i 9.4 nM), dopamine D 4 (K i 24 nM), adrenergic α 2A (K i 90 nM), serotonin 5-HT 3 (K i 95 nM), serotonin 5-HT 1A (K i 120 nM), dopamine D 2 (K i 160 nM), dopamine D 1 (K i 270 nM), dopamine D 5 (K i 454 nM), and dopamine D 3 (K i 555 nM).

Clozapine causes little or no prolactin elevation.

Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies.

Enhanced synchronization occurs.

Sharp wave activity and spike and wave complexes may also develop.

Patients have reported an intensification of dream activity during clozapine therapy.

REM sleep was found to be increased to 85% of the total sleep time.

In these patients, the onset of REM sleep occurred almost immediately after falling asleep. 12.3 Pharmacokinetics Absorption In humans, Clozapine ODT (25 mg and 100 mg) is equally bioavailable relative to a clozapine oral solution.

Clozapine ODT is bioequivalent to

Clozaril ® (clozapine) tablets.

Following a dosage of 100 mg twice daily, the average steady-state peak plasma concentration was 413 ng/mL (range: 132 to 854 ng/mL), occurring at the average of 2.3 hours (range: 1 to 6 hours) after dosing.

The average minimum concentration at steady-state was 168 ng/mL (range: 45 to 574 ng/mL), after 100 mg b.i.d. dosing.

A comparative bioequivalence/bioavailability study was conducted in 32 patients (with schizophrenia or schizoaffective disorder) comparing Clozapine ODT 200 mg to 2 × Clozapine ODT 100 mg (the approved reference product) under fasted conditions.

The study also evaluated the effect of food and chewing on the pharmacokinetics of the 200 mg tablet.

Under fasted conditions, the mean AUC ss and C min,ss of clozapine for the 200 mg oral disintegrating tablets were equivalent to those of the 2 x 100 mg tablets.

The mean

C max,ss of clozapine for Clozapine ODT 200 mg was 85% that for 2 x 100 mg Clozapine ODT.

This decrease in

C max,ss for Clozapine ODT 200 mg is not clinically significant.

ODT 200 mg, food significantly increased the C min,ss of clozapine by 21%.

However, this increase is not clinically significant.

The mean AUC ss and

C max,ss of clozapine under fed conditions were equivalent to those under fasted conditions.

Food delayed clozapine absorption by 1.5 hours, from a median T max of 2.5 hours under fasted conditions to 4 hours under fed conditions.

C max,ss of clozapine under chewed conditions for Clozapine ODT 200 mg was about 86% that for 2 x 100 mg Clozapine ODT under non-chewed conditions, while the AUC ss and C min,ss values were similar between the chewed and non-chewed conditions.

In a food-effect study, a single dose of Clozapine ODT 12.5 mg was administered to healthy volunteers under fasting conditions and after a high-fat meal.

ODT was administered after a high-fat meal, the C max of both clozapine and its active metabolite, desmethylclozapine, were decreased by approximately 20%, compared to administration under fasting conditions, while the AUC values were unchanged.

C max is not clinically significant.

Therefore, Clozapine ODT can be taken without regard to meals.

Clozapine is approximately 97% bound to serum proteins.

The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important.

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.

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

The demethylated, 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.

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

A comparison of single-dose and multiple-dose administration of Clozapine ODT 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.

However, at steady-state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily.

A pharmacokinetic study was conducted in 16 patients with schizophrenia who received clozapine under steady-state conditions.

After coadministration of fluvoxamine for 14 days, mean trough concentrations of clozapine and its metabolites, N -desmethylclozapine and clozapine N -oxide, were elevated about three-fold compared to baseline steady-state concentrations.

Paroxetine, Fluoxetine, and Sertraline: In a study of patients with schizophrenia (n = 14) who received clozapine under steady-state conditions, coadministration of paroxetine produced only minor changes in the levels of clozapine and its metabolites.

However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline.

Specific Population Studies Renal or Hepatic Impairment: No specific pharmacokinetic studies were conducted to investigate the effects of renal or hepatic impairment on the pharmacokinetics of clozapine.

Higher clozapine plasma concentrations are likely in patients with significant renal or hepatic impairment when given usual doses.

CYP2D6 Poor Metabolizers: A subset (3% to 10%) of the population has reduced activity of CYP2D6 (CYP2D6 poor metabolizers).

These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses.

Patients with Pneumonia and Other Inflammatory Conditions: Published case reports describe examples where pneumonia or other inflammatory conditions may increase clozapine concentrations.

The clinical significance, the impact of treatments to modulate this inflammation, and mechanism of this potential increase in clozapine concentrations have not been fully characterized but may involve reduced cytochrome P450 1A2 activity.

Lebonex is given to psychosis only to treat serious schizophrenia cases that have failed to treat them with other antipsychotics or in case the patient does not tolerate the side effects of other antipsychotic drugs.

As a result of the high risk of causing LIBONEX to injure women with pulses and seizures, the patient must undergo adequate treatment and at least two different types of anti-psychotic drugs before beginning treatment with lebonex.

Lebonex and epilepsy.

Lebonex use of lebonics in patients with seizures or epilepsy may increase the risk of seizures.

Lebonex and the white cell count test must be conducted before taking the lebonics.

The following adverse reactions are discussed in more detail in other sections of the labeling: Severe Neutropenia Orthostatic Hypotension, Bradycardia, and Syncope Falls Seizures Myocarditis, Pericarditis, Cardiomyopathy, and Mitral Valve Incompetence Increased Mortality in Elderly Patients with Dementia-Related Psychosis Gastrointestinal Hypomotility with Severe Complications Eosinophilia QT Interval Prolongation Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) Neuroleptic Malignant Syndrome Hepatotoxicity Fever Pulmonary Embolism Anticholinergic Toxicity Interference with Cognitive and Motor Performance Tardive Dyskinesia Patients with Phenylketonuria Cerebrovascular Adverse Reactions Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation Most common adverse reactions (≥ 5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most commonly reported adverse reactions (≥ 5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever.

Table 9 summarizes the most commonly reported adverse reactions (≥ 5%) in clozapine-treated patients (compared to chlorpromazine-treated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia.

Table 9: Common Adverse Reactions (≥ 5%) in the 6-Week, Randomized, Chlorpromazine-Controlled Trial in Treatment-Resistant Schizophrenia Adverse Reaction Clozapine (N = 126) (%) Chlorpromazine (N = 142) (%) Sedation 21 13 Tachycardia 17 11 Constipation 16 12 Dizziness 14 16 Hypotension 13 38 Fever (hyperthermia) 13 4 Hypersalivation 13 1 Hypertension 12 5 Headache 10 10 Nausea/vomiting 10 12 Dry mouth 5 20 Table 10 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2 year InterSePT™ Study).

These rates are not adjusted for duration of exposure.

Table 10: Adverse Reactions (≥ 2%) Reported in Clozapine-treated Patients (N = 842) Across all Clozapine Studies (excluding the 2 year InterSePT™ Study) Body System Adverse Reaction Clozapine N = 842 Percentage of Patients Central Nervous System Drowsiness/Sedation 39 Dizziness/Vertigo 19 Headache 7 Tremor 6 Syncope 6 Disturbed Sleep/Nightmares 4 Restlessness 4 Hypokinesia/Akinesia 4 Agitation 4 Seizures (convulsions) 3 † Rigidity 3 Akathisia 3 Confusion 3 Fatigue 2 Insomnia 2 Cardiovascular Tachycardia 25 † Hypotension 9 Hypertension 4 Gastrointestinal Constipation 14 Nausea 5 Abdominal Discomfort/Heartburn 4 Nausea/Vomiting 3 Vomiting 3 Diarrhea 2 Urogenital Urinary abnormalities 2 Autonomic Nervous System Salivation 31 Sweating 6 Dry mouth 6 Visual disturbances 5 Skin Rash 2 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Miscellaneous Fever 5 Weight Gain 4 † Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine.

Table 11 summarizes the most commonly reported adverse reactions (≥ 10% of the clozapine or olanzapine group) in the InterSePT™ Study.

This was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder.

The rates are not adjusted for duration of exposure.

Table 11: Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT™ Study (≥ 10% in the clozapine or olanzapine group) Adverse Reactions Clozapine N = 479 % Reporting Olanzapine N = 477 % Reporting Salivary hypersecretion 48% 6% Somnolence 46% 25% Weight increased 31% 56% Dizziness (excluding vertigo) 27% 12% Constipation 25% 10% Insomnia 20% 33% Nausea 17% 10% Vomiting 17% 9% Dyspepsia 14% 8% Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.

Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue.

While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs.

An elevated risk of acute dystonia is observed in males and younger age groups. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clozapine.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions.

Atrial or ventricular fibrillation, ventricular tachycardia, QT interval prolongation, Torsades de Pointes, myocardial infarction, cardiac arrest, pericarditis, and periorbital edema.

Acute pancreatitis, dysphagia, salivary gland swelling, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis.

Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.

Disorders Angioedema, leukocytoclastic vasculitis.

Acute interstitial nephritis, nocturnal enuresis, priapism, and renal failure.

Disorders Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome.

Disorders Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus.

Aspiration, pleural effusion, pneumonia, lower respiratory tract infection.

Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.

Disorders Narrow-angle glaucoma.

Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.

The most commonly reported signs and symptoms associated with Clozapine ODT overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation.

There are reports of aspiration 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. 10.2 Management of Overdosage There are no specific antidotes for Clozapine ODT overdose.

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.

Center for the most up to date information on the management of overdosage.

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.