Picloza

1 INDICATIONS AND USAGE Clozapine orally disintegrating tablets (Clozapine ODT) is an atypical antipsychotic indicated for: 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 ODT should be used only in patients who have failed to respond adequately to standard antipsychotic treatment ( 1.1 ) 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 ( 1.2 ) 1.1 Treatment-resistant Schizophrenia Clozapine Orally Disintegrating Tablets (Clozapine ODT) are 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 their use, Clozapine ODT should be used only in patients who have failed to respond adequately to standard antipsychotic treatment [see Warnings and Precautions (5.1 , 5.4) ]. The effectiveness of Clozapine ODT in treatment-resistant schizophrenia was demonstrated in a 6-week, randomized, double-blind, active-controlled study comparing Clozapine ODT and chlorpromazine in patients who had failed other antipsychotics [see Clinical Studies (14.1) ]. 1.2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder Clozapine ODT is 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. The effectiveness of Clozapine ODT in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period…

2 DOSAGE AND ADMINISTRATION Recommended starting oral dosage is 12.5 mg once daily or twice daily. ( 2.2 ) 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. ( 2.2 ) Subsequently may increase the doage in increments up to 100 mg, once or twice weekly. ( 2.2 ) Maximum daily dosage is 450 mg twice daily. ( 2.2 ) Administer with or without food. Clozapine 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. ( 2.2 ) See dosage modification based on ANC results. ( 2.3 , 2.4 ) See recommendations for discontinuing Clozapine ODT treatment ( 2.5 ), restarting Clozapine ODT after interrupting dosing (2.6), dosage modifications for drug interactions ( 2.7 ), dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers ( 2.8 ) in the full prescribing information. Tablets rapidly disintegrate after placement in the mouth and may be chewed if desired. No water is needed. ( 2.2 ) 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 [see Warnings and Precautions (5.1) ] . 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 [see Warnings and Precautions (5.1) ] . For dosage modifications based on ANC results, see Dosage and Administration (2.3 , 2.4) . 2.2 Recommended Dosage and Administration Recommended Dosage To reduce the risk of orthostatic hypotension, bradycardia, and syncope, the recommended starting dosage is much…

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.

6 ADVERSE REACTIONS 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) ] Patients with Phenylketonuria [see Warnings and Precautions (5.18) ] Cerebrovascular Adverse Reactions [see Warnings and Precautions (5.19) ] Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see Warnings and Precautions (5.20) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact…

4 CONTRAINDICATIONS Clozapine 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 [see Adverse Reactions (6.2) ] . Known hypersensitivity to clozapine or any other component of Clozapine ODT ( 4 )

5 WARNINGS AND PRECAUTIONS Severe neutropenia: See ( 5.1 ) Gastrointestinal Hypomotility with Severe Complications: Severe gastrointestinal adverse reactions have occurred with the use of clozapine. If constipation is identified, close monitoring and prompt treatment is advised. ( 5.7 ) Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. ( 5.8 ) QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs). ( 5.9 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include ( 5.10 ): Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. Dyslipidemia: Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics. Weight Gain: Significant weight gain has occurred. Monitor weight gain. Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Assess for co-morbid conditions. ( 5.11 ) Hepatotoxicity: Can be fatal. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur. ( 5.12 ) Fever: Evaluate for infection and for neutropenia, NMS. ( 5.13 ) Pulmonary Embolism (PE): Consider PE if respiratory distress, chest pain, or deep vein thrombosis occurs. ( 5.14 ) Anticholinergic Toxicity: When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. ( 5.15 , 7.1 ) Interference with Cognitive and…

7 DRUG INTERACTIONS Concomitant use of Strong CYP1A2 Inhibitors : Reduce Clozapine ODT 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 Clozapine ODT dose when CYP1A2 (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 Clozapine ODT Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering Clozapine ODT concomitantly with drugs that are inducers or inhibitors of these enzymes. CYP1A2 Inhibitors Concomitant use of Clozapine ODT and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Reduce the Clozapine ODT dose to one-third of the original dose when Clozapine ODT is coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin). The Clozapine ODT 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 Clozapine ODT is coadministered with these inhibitors. Consider reducing the Clozapine ODT dosage if necessary [see Dosage and Administration (2.7) ] . CYP2D6 and CYP3A4 Inhibitors Concomitant treatment with Clozapine ODT 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) ]…