FazaClo (Tablet, Orally Disintegrating)

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FazaClo (Tablet, Orally Disintegrating)
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Treatment-Resistant Schizophrenia:<br/>Administration: FazaClo' (clozapine, USP) rapidly disintegrates after placement in the mouth. The FazaClo' (clozapine, USP) Orally Disintegrating Tablet dispensed in a blister should be left in the unopened blister until time of use. The orally disintegrating tablet should not be pushed through the blister foil. Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet. After removing the tablet from either the blister or the bottle, immediately place the tablet in the mouth and allow to disintegrate and swallow with saliva. No water is needed to take FazaClo' (clozapine, USP). Upon initiation of FazaClo' (clozapine, USP) therapy, up to a 1-week supply of additional FazaClo' (clozapine, USP) orally disintegrating tablets may be provided to the patient to be held for emergencies (eg, weather, holidays).<br/>Initial Treatment: It is recommended that treatment with FazaClo' (clozapine, USP) begin with a 12.5-mg dose once or twice daily. The dosing should be continued with daily dosage increments of 25-50 mg/day, if well-tolerated, to achieve a target dose of 300-450 mg/day by the end of 2 weeks. Subsequent dosage increments should be made no more than once or twice weekly, in increments not to exceed 100 mg. Cautious titration and a divided dosage schedule are necessary to minimize the risks of hypotension, seizure, and sedation. In the multicenter study that provides primary support for the effectiveness of clozapine in patients resistant to standard drug treatment for schizophrenia, patients' doses were titrated during the first 2 weeks up to a maximum dose of 500 mg/day on a t.i.d. basis. Subsequent dosage increments were then dosed in a total daily dose range of 100-900 mg/day on a t.i.d. basis, with clinical response and adverse effects as guides to correct dosing.<br/>Therapeutic Dose Adjustment: Daily dosing should continue on a divided basis as an effective and tolerable dose level is sought. While many patients may respond adequately at doses between 300-600 mg/day, it may be necessary to raise the dose to the 600-900 mg/day range to obtain an acceptable response. (Note: In the multicenter study providing the primary support for the superiority of clozapine in treatment-resistant patients, the mean and median clozapine doses were both approximately 600 mg/day.) Because of the possibility of increased adverse reactions at higher doses, particularly seizures, patients should ordinarily be given adequate time to respond to a given dose level before escalation to a higher dose is contemplated. Clozapine can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizures threshold in a dose-dependent manner and may induce myoclonic jerks or generalized seizures. These symptoms may be likely to occur with rapid-dose increase and in patients with preexisting epilepsy. In this case, the dose should be reduced and, if necessary, anticonvulsant treatment initiated. Dosing should not exceed 900 mg/day. Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided.<br/>Maintenance Treatment: While the maintenance effectiveness of clozapine in schizophrenia is still under study, the effectiveness of maintenance treatment is well established for many other drugs used to treat schizophrenia. It is recommended that responding patients be continued on FazaClo' (clozapine, USP), but at the lowest level needed to maintain remission. Because of the significant risk associated with the use of FazaClo' (clozapine, USP), patients should be periodically reassessed to determine the need for maintenance treatment.<br/>Discontinuation of Treatment: In the event of planned termination of FazaClo' (clozapine, USP) therapy, gradual reduction in dose is recommended over a 1-2 week period. However, should a patient's medical condition require abrupt discontinuation (eg, leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as headache, nausea, vomiting, and diarrhea.<br/>Reinitiation of Treatment in Patients Previously Discontinued: When restarting patients who have had even a brief interval off FazaClo' (clozapine, USP) (ie, 2 days or more since the last dose), it is recommended that treatment be reinitiated with a 12.5-mg dose once or twice daily. If that dose is well tolerated, it may be feasible to titrate patients back to a therapeutic dose more quickly than is recommended for initial treatment. However, any patient who has previously experienced respiratory or cardiac arrest with initial dosing but was then able to be successfully titrated to a therapeutic dose should be retitrated with extreme caution after even 24 hours of discontinuation. Certain additional precautions seem prudent when reinitiating treatment. The mechanisms underlying clozapine-induced adverse reactions are unknown. It is conceivable, however, that reexposure of a patient might enhance the risk of an untoward event's occurrence and increase its severity. Such phenomena, for example, occur when immune-mediated mechanisms are responsible. Consequently, during the reinitiation of treatment, additional caution is advised. Patients discontinued for WBC counts below 2000/mmor an ANC below 1000/mmmust not be restarted on FazaClo' (clozapine, USP). (See WARNINGS.) Reducing The Risk Of Recurrent Suicidal Behavior In Patients With Schizophrenia Or Schizoaffective Disorder The dosage and administration recommendations outlined above regarding the use of FazaClo' (clozapine, USP) in patients with treatment-resistant schizophrenia should also be followed when treating patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior. The InterSePT study demonstrated the efficacy of clozapine in the treatment of patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior where the mean daily dose was about 300 mg (range 12.5 to 900 mg). Patients previously treated with other antipsychotics were cross-titrated to clozapine over a one-month interval; the dose of the previous antipsychotic was gradually decreased simultaneously with a gradual increase in clozapine dose over the first month of the study. Patients on depot antipsychotic medication began clozapine after one full dosing interval since the last injection.<br/>Recommendations to Reduce the Risk of Recurrent Suicidal Behavior in Patients Who Otherwise Previously Responded to Treatment of Schizophrenia or Schizoaffective Disorder with Another Antipsychotic Medication: The results of the InterSePT study demonstrated that, for a two-year treatment period, the probability of a suicide attempt or a hospitalization due to imminent suicide risk is stable at approximately 24% after one year of treatment with clozapine (Figure 1, Clinical Trial Data Section). A course of treatment with FazaClo' (clozapine, USP) of at least two years is recommended in order to maintain the reduction of risk for suicidal behavior. After two years, it is recommendedthat the patient's risk of suicidal behavior be assessed. If the physician's assessment indicates that a significant risk for suicidal behavior is still present, treatment with FazaClo' (clozapine, USP) should be continued. Thereafter, the decision to continue treatment with FazaClo' (clozapine, USP) should be revisited at regular intervals, based on thorough assessments of the patient's risk for suicidal behavior during treatment. If the physician determines that the patient is no longer at risk for suicidal behavior, treatment with FazaClo' (clozapine, USP) may be discontinued (see recommendations above regarding discontinuation of treatment), and treatment of the underlying disorder with an antipsychotic medication to which the patient has previously responded may be resumed.
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FazaClo' (clozapine, USP), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine. The structural formula is: FazaClo' (clozapine, USP) is available as yellow, orally disintegrating tablets of 12.5, 25, and 100 mg for oral administration without water. Each orally disintegrating tablet contains clozapine equivalent to 12.5, 25, or 100 mg. 12.5-, 25-, and 100-mg Orally Disintegrating Tablets Active Ingredient Clozapine is a yellow, crystalline powder, very slightly soluble in water. Inactive Ingredients Aminoalkyl methacrylate copolymer E, mannitol, aspartame, microcrystalline cellulose, crospovidone, natural and artificial mint flavor, sodium bicarbonate, citric acid, ferric oxide (yellow), and magnesium stearate THIS PRODUCT CONTAINS ASPARTAME AND IS NOT INTENDED FOR USE BY INFANTS. PHENYLKETONURICS: CONTAINS PHENYLALANINE. Phenylalanine is a component of aspartame. Each 12.5-mg, orally disintegrating tablet contains 1.6 mg aspartame, thus, 0.87 mg phenylalanine. Each 25-mg, orally disintegrating tablet contains 3.1 mg aspartame, thus, 1.74 mg phenylalanine. Each 100-mg, orally disintegrating tablet contains 12.4 mg aspartame, thus, 6.96 mg phenylalanine. The allowable daily intake of aspartame is 50 mg per kilogram of body weight per day. (See PRECAUTIONS, Phenylketonurics.)
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Pharmacodynamics: FazaClo' (clozapine, USP) is classified as an���atypical���antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine mediated behaviors differ from those exhibited by more typical antipsychotic drug products. In particular, although FazaClo' (clozapine, USP) does interfere with the binding of dopamine at D, D, D, and Dreceptors, and has a high affinity for the Dreceptor, it does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that FazaClo' (clozapine, USP) is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of FazaClo' (clozapine, USP) from extrapyramidal side effects. FazaClo' (clozapine, USP) also acts as an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors.<br/>Absorption, Distribution, Metabolism, and Excretion: In man, clozapine tablets (25 and 100 mg) are equally bioavailable relative to a clozapine solution. FazaClo' (clozapine, USP) orally disintegrating tablets are bioequivalent to Clozaril' (clozapine) tablets, a registered trademark of Novartis Pharmaceuticals Corporation. Following a dosage of 100 mg b.i.d.,the average steady-state peak plasma concentration was 413 ng/mL (range: 132-854 ng/mL), occurring at the average of 2.3 hours (range: 1-6 hours) after dosing. The average minimum concentration at steady state was 168 ng/mL (range: 45-574 ng/mL), after 100-mg b.i.d. dosing. Food does not appear to affect the systemic bioavailability of clozapine. Thus, FazaClo' (clozapine, USP) may be administered with or without food. 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. (See PRECAUTIONS.) Clozapine is almost completely metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. 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: 4-12 hours), compared to a mean elimination half-life, after achieving steady state with 100-mg b.i.d. dosing, of 12 hours (range: 4-66 hours). A comparison of single-dose and multiple-dose administration of clozapine showed 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, linearly 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 b.i.d.<br/>Human Pharmacology: In contrast to more typical antipsychotic drugs, clozapine therapy produces little or no prolactin elevation. As is true of more typical antipsychotic drugs, clinical electroencephalogram (EEG) studies have shown 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, on rare occasions, may report 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. Clinical Trial Data (Reducing The Risk Of Recurrent Suicidal Behavior In Patients With Schizophrenia Or Schizoaffective Disorder Who Are Judged To Be At Risk Of Reexperiencing Suicidal Behavior) The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT���, a trademark of Novartis Pharmaceuticals Corporation), which was a prospective, randomized, international, parallel-group comparison of clozapine (Clozaril') versus olanzapine (Zyprexa', a registered trademark of Eli Lilly and Company) in patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for reexperiencing suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment and the remainder were not. Patients met one of the following criteria: Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200���900 mg/day for clozapine and 5���20 mg/day for olanzapine. For the 956 patients who received clozapine or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics, 65% with anxiolytics, 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group. The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide; (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized; or (3) worsening of suicidality severity as demonstrated by���much worsening���or���very much worsening���from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB), a group of experts blinded to patient data. A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as���treatment-resistant���at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years of age (range 18���69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of���other���races. Data from this study indicate that clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior and not a demonstration of the superior efficacy of clozapine over olanzapine. The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization due to imminent suicide risk, including increased level of surveillance for suicidality for patients already hospitalized, was lower for clozapine patients than for olanzapine patients at Week 104: clozapine 24% versus olanzapine 32%; 95% CI of the difference: 2%, 14% (Figure 1). Figure 1. Kaplan-Meier Estimates of Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide
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FazaClo' (clozapine, USP) is contraindicated in patients with a previous hypersensitivity to clozapine or any other component of this drug, in patients with myeloproliferative disorders, uncontrolled epilepsy, paralytic ileus, or a history of clozapine-induced agranulocytosis or severe granulocytopenia. As with more typical antipsychotic drugs, FazaClo' (clozapine, USP) is contraindicated in severe central nervous system (CNS) depression or comatose states from any cause. FazaClo' (clozapine, USP) should not be used simultaneously with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function. The mechanism of clozapine-induced agranulocytosis is unknown; nonetheless, it is possible that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression.
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FazaClo' (clozapine, USP) is available as 12.5-, 25-, and 100-mg round, yellow, orally disintegrating tablets packaged in bottles. FazaClo' (clozapine, USP) is also available as 25- and 100-mg tablets packaged in blisters.<br/>FazaClo' (clozapine, USP) Orally Disintegrating Tablets: 12.5 mg 1/4-inch diameter tablet debossed with���A05���on one side. Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap ................ NDC No. 18860-101-10 25 mg 5/16-inch diameter tablet debossed with���A06���on one side. Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap ................. NDC No. 18860-102-10 Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistantblisters per card ............................................................................................................ NDC No. 18860-102-01 100 mg 1/2-inch diameter tablet debossed with���A08���on one side. Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap ................... NDC No. 18860-104-10 Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistantblisters per card .............................................................................................................. NDC No. 18860-104-01<br/>Store and Dispense: Store FazaClo' (clozapine, USP) at 25��C (77��F); excursions permitted to 15-30��C (59-86��F). (See USP Controlled Room Temperature.) Protect from moisture. KEEP OUT OF REACH OF CHILDREN. FazaClo' (clozapine, USP) tablets must remain in the original package until used by the patient. Drug dispensing should not ordinarily exceed a weekly supply. If a patient is eligible for WBC count and ANC testing every 2 weeks, then a two-week supply of FazaClo' (clozapine, USP) can be dispensed. If a patient is eligible for WBC count and ANC testing every 4 weeks, then a 4-week supply of FazaClo' (clozapine, USP) can be dispensed. Dispensing should be contingent upon the WBC count and ANC testing results. Manufactured forAzur Pharma, Inc.420 Lexington Avenue, Suite 2400New York, NY 10170 USAbyCIMA LABS INC.Eden Prairie, Minnesota 55344 CIMA LABS INC.; U.S. Patent Nos. 5,178,878; 6,024,981; 6,221,392 FazaClo' is a registered trademark of Azur Pharma International III Limited. All rights reserved. July 2008 Printed in USA Rev. 10 Medical Affairs 877-FAZACLO (877-329-2256)
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WARNING: 1. AGRANULOCYTOSIS BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT, CLOZAPINE SHOULD BE RESERVED FOR USE IN (1) THE TREATMENT OF SEVERELY ILL PATIENTS WITH SCHIZOPHRENIA WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF STANDARD ANTIPSYCHOTIC DRUG TREATMENT, OR (2) FOR REDUCING THE RISK OF RECURRENT SUICIDAL BEHAVIOR IN PATIENTS WITH SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER WHO ARE JUDGED TO BE AT RISK OF REEXPERIENCING SUICIDAL BEHAVIOR. PATIENTS BEING TREATED WITH CLOZAPINE MUST HAVE A BASELINE WHITE BLOOD CELL (WBC) COUNT AND ABSOLUTE NEUTROPHIL COUNT (ANC) BEFORE INITIATION OF TREATMENT AS WELL AS REGULAR WBC COUNTS AND ANCs DURING TREATMENT AND FOR AT LEAST 4 WEEKS AFTER DISCONTINUATION OF TREATMENT. (SEE WARNINGS.) CLOZAPINE IS AVAILABLE ONLY THROUGH A DISTRIBUTION SYSTEM THAT ENSURES MONITORING OF WBC COUNTS AND ANCs ACCORDING TO THE SCHEDULE DESCRIBED BELOW PRIOR TO DELIVERY OF THE NEXT SUPPLY OF MEDICATION. (SEE WARNINGS.) 2. SEIZURES SEIZURES HAVE BEEN ASSOCIATED WITH THE USE OF CLOZAPINE. DOSE APPEARS TO BE AN IMPORTANT PREDICTOR OF SEIZURE, WITH A GREATER LIKELIHOOD AT HIGHER CLOZAPINE DOSES. CAUTION SHOULD BE USED WHEN ADMINISTERING CLOZAPINE TO PATIENTS HAVING A HISTORY OF SEIZURES OR OTHER PREDISPOSING FACTORS. PATIENTS SHOULD BE ADVISED NOT TO ENGAGE IN ANY ACTIVITY WHERE SUDDEN LOSS OF CONSCIOUSNESS COULD CAUSE SERIOUS RISK TO THEMSELVES OR OTHERS. (SEE WARNINGS.) 3. MYOCARDITIS ANALYSES OF POSTMARKETING SAFETY DATABASES SUGGEST THAT CLOZAPINE IS ASSOCIATED WITH AN INCREASED RISK OF FATAL MYOCARDITIS, ESPECIALLY DURING, BUT NOT LIMITED TO, THE FIRST MONTH OF THERAPY. IN PATIENTS IN WHOM MYOCARDITIS IS SUSPECTED, CLOZAPINE TREATMENT SHOULD BE PROMPTLY DISCONTINUED. (SEE WARNINGS.) 4. OTHER ADVERSE CARDIOVASCULAR AND RESPIRATORY EFFECTS ORTHOSTATIC HYPOTENSION, WITH OR WITHOUT SYNCOPE, CAN OCCUR WITH CLOZAPINE TREATMENT. RARELY, COLLAPSE CAN BE PROFOUND AND BE ACCOMPANIED BY RESPIRATORY AND/OR CARDIAC ARREST. ORTHOSTATIC HYPOTENSION IS MORE LIKELY TO OCCUR DURING INITIAL TITRATION IN ASSOCIATION WITH RAPID DOSE ESCALATION. IN PATIENTS WHO HAVE HAD EVEN A BRIEF INTERVAL OFF CLOZAPINE (ie, 2 OR MORE DAYS SINCE THE LAST DOSE) TREATMENT SHOULD BE STARTED WITH 12.5 MG ONCE OR TWICE DAILY. SINCE COLLAPSE, RESPIRATORY ARREST, AND CARDIAC ARREST DURING INITIAL TREATMENT HAS OCCURRED IN PATIENTS WHO WERE BEING ADMINISTERED BENZODIAZEPINES OR OTHER PSYCHOTROPIC DRUGS, CAUTION IS ADVISED WHEN CLOZAPINE IS INITIATED IN PATIENTS TAKING A BENZODIAZEPINE OR ANY OTHER PSYCHOTROPIC DRUG. (SEE WARNINGS.) 5. INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS TREATED WITH ATYPICAL ANTIPSYCHOTIC DRUGS ARE AT AN INCREASED RISK OF DEATH COMPARED TO PLACEBO. ANALYSES OF 17 PLACEBO-CONTROLLED TRIALS (MODAL DURATION OF 10 WEEKS) IN THESE PATIENTS REVEALED A RISK OF DEATH IN THE DRUG-TREATED PATIENTS OF BETWEEN 1.6 TO 1.7 TIMES THAT SEEN IN PLACEBO-TREATED PATIENTS. OVER THE COURSE OF A TYPICAL 10-WEEK CONTROLLED TRIAL, THE RATE OF DEATH IN DRUG-TREATED PATIENTS WAS ABOUT 4.5%, COMPARED TO A RATE OF ABOUT 2.6% IN THE PLACEBO GROUP. ALTHOUGH THE CAUSES OF DEATH WERE VARIED, MOST OF THE DEATHS APPEARED TO BE EITHER CARDIOVASCULAR (eg, HEART FAILURE, SUDDEN DEATH) OR INFECTIOUS (eg, PNEUMONIA) IN NATURE. FAZACLO' (clozapine, USP) IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.
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Human Experience: The most commonly reported signs and symptoms associated with clozapine overdose are: altered states of consciousness, including drowsiness, delirium, and coma; tachycardia; hypotension; respiratory depression or failure; and hypersalivation. Aspiration pneumonia and cardiac arrhythmias have also been reported. Seizures have occurred in a minority of reported cases. 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.<br/>Management of Overdose: Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage and should be considered in treating overdosage. Cardiac and vital signs monitoring are recommended along with general symptomaticand supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine and derivatives when treating hypotension and quinidine and procainamide when treating cardiac arrhythmia. There are no specific antidotes for FazaClo' (clozapine, USP). Forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. In managing overdosage, the physician should consider the possibility of multiple-drug involvement. Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians' Desk Reference', a registered trademark of Thomson PDR.
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clozapine
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FazaClo (Tablet, Orally Disintegrating)
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Associated with Discontinuation of Treatment: Sixteen percent of 1080 patients who received clozapine in premarketing clinical trials discontinued treatment due to an adverse event, including both those that could reasonably be attributed to clozapine treatment and those that might more appropriately be considered intercurrent illness. The more common events considered to be causes of discontinuation included: CNS,primarily drowsiness/sedation, seizures, dizziness/syncope; cardiovascular, primarily tachycardia, hypotension, and ECG changes; gastrointestinal, primarily nausea/vomiting; hematologic, primarily leukopenia/granulocytopenia/agranulocytosis; and fever. None of the events enumerated accounts for more than 1.7% of all discontinuations attributed to adverse clinical events.<br/>Commonly Observed: Adverse events observed in association with the use of clozapine in clinical trials at an incidence of greater than 5% were: CNS complaints, including drowsiness/sedation, dizziness/vertigo, headache, and tremor; autonomic nervous system complaints, including salivation, sweating, dry mouth, and visual disturbances; cardiovascular findings, including tachycardia, hypotension, and syncope; gastrointestinal complaints, including constipation and nausea; and fever. Complaints of drowsiness/sedation tend to subside with continued therapy or dose reduction. Salivation may be profuse, especially during sleep, but may be diminished with dose reduction.<br/>Incidence in Clinical Trials: Table 2 enumerates adverse events that occurred at a frequency of 1% or greater among clozapine patients who participated in clinical trials. These rates are not adjusted for duration of exposure. Table 3 enumerates adverse events that occurred at a frequency of 10% for either treatment group in patients who took at least one dose of study medication during their participation in InterSePT, which was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. These rates are not adjusted for duration of exposure.<br/>Other Events Observed During the Premarketing Evaluation of Clozapine: This section reports additional, less frequent adverse events which occurred among the patients taking clozapine in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to clozapine treatment cannot be determined in the absence of appropriate controls in some of the studies. Table 2 enumerates adverse events that occurred at a frequency of at least 1% of patients treated with clozapine. The list below includes all additional adverse experiences reported as being temporally associated with the use of the drug which occurred at a frequency less than 1%, enumerated by organ system.<br/>Central Nervous System: Loss of speech, amentia, tics, poor coordination, delusions/hallucinations, involuntary movement, stuttering, dysarthria, amnesia/memory loss, histrionic movements, libido increase or decrease, paranoia, shakiness, Parkinsonism, and irritability<br/>Cardiovascular System: Edema, palpitations, phlebitis/thrombophlebitis, cyanosis, premature ventricular contraction, bradycardia, and nose bleed<br/>Gastrointestinal System: Abdominal distention, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer, bitter taste, and eructation<br/>Urogenital System: Dysmenorrhea, impotence, breast pain/discomfort, and vaginal itch/infection<br/>Autonomic Nervous System: Numbness, polydipsia, hot flashes, dry throat, and mydriasis<br/>Integumentary (skin): Pruritus, pallor, eczema, erythema, bruise, dermatitis, petechiae, and urticaria<br/>Musculoskeletal System: Twitching and joint pain<br/>Respiratory System: Coughing, pneumonia/pneumonia-like symptoms, rhinorrhea, hyperventilation, wheezing, bronchitis, laryngitis, and sneezing<br/>Hemic and Lymphatic System: Anemia and leukocytosis<br/>Miscellaneous: Chills/chills with fever, malaise, appetite increase, ear disorder, hypothermia, eyelid disorder, bloodshot eyes, and nystagmus<br/>Postmarketing Clinical Experience: Postmarketing experience has shown an adverse experience profile similar to that presented above. Voluntary reports of adverse events temporally associated with clozapine not mentioned above that have been received since market introduction and that may have no causal relationship with the drug include the following:<br/>Central Nervous System: Delirium, EEG abnormal, exacerbation of psychosis, myoclonus, overdose, paresthesia, possible mild cataplexy, and status epilepticus<br/>Cardiovascular System: Atrial or ventricular fibrillation and periorbital edema<br/>Gastrointestinal System: Acute pancreatitis, dysphagia, fecal impaction, intestinal obstruction/paralytic ileus, and salivary gland swelling<br/>Hepatobiliary System: Cholestasis, hepatitis, jaundice<br/>Hepatic System: Cholestasis<br/>Urogenital System: Acute interstitial nephritis and priapism<br/>Integumentary (skin): Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome<br/>Metabolic and Nutritional Disorders: Hypercholesterolemia (very rare) and hypertriglyceridemia (very rare)<br/>Musculoskeletal System: Myasthenic syndrome and rhabdomyolysis<br/>Respiratory System: Aspiration and pleural effusion<br/>Hemic and Lymphatic System: Deep-vein thrombosis, elevated hemoglobin/hematocrit, ESR increased, pulmonary embolism, sepsis, thrombocytosis, and thrombocytopenia<br/>Vision Disorders: Narrow-angle glaucoma<br/>Miscellaneous: Creatine phosphokinase elevation, hyperglycemia, hyperuricemia, hyponatremia, and weight loss<br/>Extrapyramidal Symptoms:<br/>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 frequentlyand 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. Clozapine, an atypical antipsychotic, is associated with a low incidence of dystonia.<br/>DRUG ABUSE AND DEPENDENCE: Physical and psychological dependence have not been reported or observed in patients taking clozapine.<br/>OVERDOSAGE:<br/>Human Experience: The most commonly reported signs and symptoms associated with clozapine overdose are: altered states of consciousness, including drowsiness, delirium, and coma; tachycardia; hypotension; respiratory depression or failure; and hypersalivation. Aspiration pneumonia and cardiac arrhythmias have also been reported. Seizures have occurred in a minority of reported cases. 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.<br/>Management of Overdose: Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage and should be considered in treating overdosage. Cardiac and vital signs monitoring are recommended along with general symptomaticand supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine and derivatives when treating hypotension and quinidine and procainamide when treating cardiac arrhythmia. There are no specific antidotes for FazaClo' (clozapine, USP). Forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. In managing overdosage, the physician should consider the possibility of multiple-drug involvement. Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians' Desk Reference', a registered trademark of Thomson PDR.<br/>DOSAGE AND ADMINISTRATION:<br/>Treatment-Resistant Schizophrenia:<br/>HOW SUPPLIED: FazaClo' (clozapine, USP) is available as 12.5-, 25-, and 100-mg round, yellow, orally disintegrating tablets packaged in bottles. FazaClo' (clozapine, USP) is also available as 25- and 100-mg tablets packaged in blisters.<br/>FazaClo' (clozapine, USP) Orally Disintegrating Tablets: 12.5 mg 1/4-inch diameter tablet debossed with���A05���on one side. Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap ................ NDC No. 18860-101-10 25 mg 5/16-inch diameter tablet debossed with���A06���on one side. Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap ................. NDC No. 18860-102-10 Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistantblisters per card ............................................................................................................ NDC No. 18860-102-01 100 mg 1/2-inch diameter tablet debossed with���A08���on one side. Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap ................... NDC No. 18860-104-10 Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistantblisters per card .............................................................................................................. NDC No. 18860-104-01<br/>Store and Dispense: Store FazaClo' (clozapine, USP) at 25��C (77��F); excursions permitted to 15-30��C (59-86��F). (See USP Controlled Room Temperature.) Protect from moisture. KEEP OUT OF REACH OF CHILDREN. FazaClo' (clozapine, USP) tablets must remain in the original package until used by the patient. Drug dispensing should not ordinarily exceed a weekly supply. If a patient is eligible for WBC count and ANC testing every 2 weeks, then a two-week supply of FazaClo' (clozapine, USP) can be dispensed. If a patient is eligible for WBC count and ANC testing every 4 weeks, then a 4-week supply of FazaClo' (clozapine, USP) can be dispensed. Dispensing should be contingent upon the WBC count and ANC testing results. Manufactured forAzur Pharma, Inc.420 Lexington Avenue, Suite 2400New York, NY 10170 USAbyCIMA LABS INC.Eden Prairie, Minnesota 55344 CIMA LABS INC.; U.S. Patent Nos. 5,178,878; 6,024,981; 6,221,392 FazaClo' is a registered trademark of Azur Pharma International III Limited. All rights reserved. July 2008 Printed in USA Rev. 10 Medical Affairs 877-FAZACLO (877-329-2256)
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Treatment-Resistant Schizophrenia: FazaClo' (clozapine, USP) is indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, FazaClo' (clozapine, USP) should be used only in patientswho have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. (See WARNINGS.) The effectiveness of clozapine in a treatment-resistant schizophrenic population was demonstrated in a 6-week study comparing clozapine and chlorpromazine. Patients meeting DSM-III criteria for schizophrenia and having a mean Brief Psychiatric Rating Scale (BPRS) total score of 61 were demonstrated to be treatment-resistant by history and by open, prospective treatment with haloperidol before entering into the double-blind phase of the study. The superiority of clozapine to chlorpromazine was documented in statistical analyses employing both categorical and continuous measures of treatment effect. Because of the significant risk of agranulocytosis and seizures, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically reevaluated. Reduction In The Risk Of Recurrent Suicidal Behavior In Schizophrenia Or Schizoaffective Disorders FazaClo' (clozapine, USP) 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 reexperiencing 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 in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT Trial . Therefore, FazaClo' (clozapine, USP) treatment to reduce the risk of suicidal behavior should be continued for at least two years (see DOSAGE AND ADMINISTRATION). The prescriber should be aware that a majority of patients in both treatment groups in InterSePT received other treatments as well to reduce suicide risk, such as antidepressants and other medications, hospitalization, and/or psychotherapy. The contributions of these additional measures are unknown.
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FazaClo