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Cheng YF, Lundberg T, Bondesson U et al. Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Clin Pharmacol. Banki CM. Alterations of cerebrospinal fluid 5-hydroxyindoleacetic acid, and total blood serotonin content during clozapine treatment. Psychopharmacology. Management of treatment-resistant schizophrenia in severely ill patients who fail to respond adequately to standard antipsychotic therapy. 1 2 10 14 21 33 34 61 63 64 87 121 156 347 395 406 Because of the risk of severe neutropenia and seizures, use only in patients who have failed to respond adequately to standard antipsychotic treatment. 1 395 406 See Boxed Warning and also see Severe Neutropenia under Cautions. buy online rhinocort store

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Use Clozaril as directed by your doctor. Check the label on the medicine for exact dosing instructions. Risk of potentially fatal myocarditis and cardiomyopathy. Efficacy thought to be principally mediated through antagonist activity at dopamine type 2 D 2 and serotonin type 2A 5-HT 2A receptors.

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Gerbino L, Shopsin B, Collora M. Clozapine in the treatment of tardive dyskinesia: an interim report. In: Fann WE, Smith RC, Davis JM et al, eds. Schuster P, Gabriel E, Kufferle B et al. Reversal by physostigmine of clozapine-induced delirium. Clin Tox. Guirguis E, Voiseskos G, Gray J et al. Clozapine Leponex vs chlorpromazine Largactil in acute schizophrenia a double-blind controlled study. Curr Ther Res.

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Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry. Etminan M, Streiner DL, Rochon PA. Exploring the association between atypical neuroleptic agents and diabetes mellitus in older adults. Pharmacotherapy. Bess AL, Cunningham SR. Dear health care provider letter regarding revised prescribing information for Clozaril tablets. East Hanover, NJ: Novartis; 2005 Dec.

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Pearlman CA. Neuroleptic malignant syndrome: a review of the literature. J Clin Psychopharmacol. See Withdrawal of Therapy under Cautions. We have GMP and DMF. Contact: magi. Effects of renal or hepatic impairment not specifically studied, but higher plasma clozapine concentrations expected in patients with substantial renal or hepatic impairment when administered in usual dosages. May cause side effects to become worse. Seizures: Inform patients and caregivers about the significant risk of seizure during Clozapine Orally Disintegrating Tablets treatment. Stock B, Spiteller G, Heipertz R. Austausch aromatisch gebundenen Halogens gegen OH- und SCH 3- bei der Metabolisierung des Clozapins im menschlichen Körper. Arzneimittelforschung. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. Ereshefsky L, Richards A. Psychoses. In: Young LY, Koda-Kimble MA, eds. Applied therapeutics: the clinical use of drugs. PE and DVT reported in clozapine-treated patients; causal relationship not established. 1 Consider possibility of PE in patients presenting with DVT, chest pain, acute dyspnea, or other respiratory symptoms. Check with your doctor right away if you are having convulsions seizures difficulty with breathing, fast heartbeat, high fever, high or low blood pressure, increased sweating, loss of bladder control, severe muscle stiffness, unusually pale skin, or tiredness. These could be symptoms of a serious condition called neuroleptic malignant syndrome NMS. ANC measurement within 24 hours. Coward DM, Imperato A, Urwyler S et al. Biochemical and behavioural properties of clozapine. Psychopharmacology. Rodova A, Svestka J, Nahunek K et al. A blind comparison of clozapine and perphenazine in schizophrenics. Act Nerv Super. This medicine will add to the effects of alcohol and other central nervous system CNS depressants, which are medicines that slow down the nervous system and possibly cause drowsiness. Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds, sedatives, tranquilizers, or sleeping medicine, prescription pain medicine or narcotics, medicine for seizures or barbiturates, muscle relaxants, or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using this medicine.

Important information

Keep out of the reach of children. Ellis PM, Harrison-Woolrych M 2008. Monitor ANC if fever occurs during the 2 weeks after discontinuance. Schyve PM, Smithline F, Meltzer HY. Neuroleptic-induced prolactin level elevation and breast cancer: an emerging clinical issue. Arch Gen Psychiatry. Use only if clearly needed and only if the anticipated benefit to the mother outweighs the risk to the fetus. Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for clinical management. J Clin Psychiatry. Approximately 88% of patients from the clozapine and chlorpromazine groups completed the 6-week trial. At the end of 6 weeks, 30% of the clozapine group responded to treatment, and 4% of the chlorpromazine group responded to treatment. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP3A4, and CYP2D6. Use caution when administering Clozapine Orally Disintegrating Tablets concomitantly with drugs that are inducers or inhibitors of these enzymes. Sandoz Pharmaceuticals. Formulary information on Clozaril clozapine. East Hanover, NJ; 1989. 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. WBC counts and differential should be monitored closely during therapy and for 4 weeks after end of therapy according to product labeling. Also, patients should be advised to immediately report signs of infection such as fever, sore throat, malaise, lethargy, and flu-like symptoms. Jazz Pharmaceuticals, Inc. FazaClo clozapine orally disintegrating tablets prescribing information. Palo Alto, CA; 2015 Sep. Continue to take Clozaril even if you feel well. Do not miss any doses. Melkersson K, Dahl ML. Adverse metabolic effects associated with atypical antipsychotics. Drugs. Halperin R, Guerin JJ, Davis KL. Regional differences in the induction of behavioral supersensitivity by prolonged treatment with atypical neuroleptics. Psychopharmacology. Gianutsos G, Moore KE. Dopaminergic supersensitivity in striatum and olfactory tubercle following chronic administration of haloperidol or clozapine. Life Sci. ivermectin

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The most serious adverse reactions include agranulocytosis, seizure, cardiovascular effects, and fever. Doepp S, Buddeberg C. Extrapyramidale Symptome unter Clozapin. Nervenarzt. Clozapine Orally Disintegrating Tablets are 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. Clozapine and Ascorbate by Myeloperoxidase. Jeste DV, Wyatt RJ. Therapeutic strategies against tardive dyskinesia. Two decades of experience. Arch Gen Psychiatry. Inform patients and caregivers about substantial risk of seizures during clozapine therapy. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther. The use of the Truven Health products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Truven Health and Drugs. Clozapine-associated eosinophilia without organ involvement also may occur and can resolve without intervention. 1 In such cases, may continue clozapine therapy with careful monitoring. 1 If total eosinophil count continues to increase over several weeks in the absence of systemic disease, base decision whether to interrupt clozapine therapy and rechallenge after the eosinophil count decreases on the overall clinical assessment, in consultation with an internist or hematologist. 1 Successful rechallenge after discontinuance of clozapine, without recurrence of eosinophilia, reported. Oro Valley, AZ 85755. November 17, 2015. For diabetic patients: This medicine may increase the amount of sugar in your blood. Check with your doctor right away if you have increased thirst or urination. Diabetic patients should check their blood and urine sugar levels more often than normal while taking this medicine. Dose reduction may be necessary in patients who are CYP2D6 poor metabolizers. Usually occurs during first month of therapy. slimex

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Chouinard G, Annable L. Clozapine in the treatment of newly admitted schizophrenic patients: a pilot study. J Clin Pharmacol. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristics of the patients is not clear. Novartis Pharmaceuticals Corporation, East Hanover, NJ: Personal communication. Honigfeld G, Patin J. Predictors of response to clozapine therapy. Psychopharmacology. Ayd FJ Jr. Neuroleptic malignant syndrome: new therapies. Int Drug Therapy Newsl. Eli Lilly and Company, Indianapolis, IN: Personal communication. Chiodo LA, Bunney BS. Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons. J Neoroscience. Please refer to the for information on shortages of one or more of these preparations. Clozaril has potent anticholinergic effects. Treatment with Clozaril can result in CNS and peripheral anticholinergic toxicity. Use with caution in the presence of narrow-angle glaucoma, concomitant anticholinergic medications, prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions. Use with caution. May make these conditions worse. Reportedly present in low concentrations in placenta and may distribute into milk in animals; 2 not known whether crosses placenta in humans. 292 Distributed into milk in humans. In man, clozapine tablets 25 mg and 100 mg are equally bioavailable relative to a clozapine solution. sertraline and minerals

Benign Ethnic Neutropenia BEN

They had been hospitalized to prevent a suicide attempt within the 3 years prior to their baseline evaluation. This container provides light-resistance. Engraved with “Clozaril” once on the periphery of one side. Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury hepatic, cholestatic, and mixed and liver failure. Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit. The efficacy of clozapine in treatment-resistant schizophrenia was established in a multicenter, randomized, double-blind, active-controlled chlorpromazine study in patients with a DSM-III diagnosis of schizophrenia who had inadequate responses to at least three different antipsychotics from at least two different chemical classes during the preceding 5 years. The antipsychotic trials must have been judged adequate; the antipsychotic dosages must have been equivalent to or greater than 1000 mg per day of chlorpromazine for a period of at least 6 weeks, each without significant reduction of symptoms. There must have been no period of good functioning within the preceding 5 years. Patients must have had a baseline score of at least 45 on the investigator-rated Brief Psychiatric Rating Scale BPRS. On the 18-item BPRS, 1 indicates the absence of symptoms, and 7 indicates severe symptoms; the maximum potential total BPRS score is 126. At baseline, the mean BPRS score was 61. In addition, patients must have had a score of at least 4 on at least two of the following four individual BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. Patients must have had a Clinical Global Impressions - Severity Scale score of at least 4 moderately ill. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Gilman AG, Rall TW, Nies AS et al, eds. Lipsitz L. Orthostatic hypotension in the elderly. N Engl J Med. This unit dose package is not child resistant. Flood JG. Serum levels of clozapine and norclozapine in patients treated with selective serotonin reuptake inhibitors. If you have been using this medicine regularly, do not stop taking it without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping it completely. This is to help prevent the illness from suddenly returning and to decrease the chance of having symptoms such as headache, nausea, vomiting or diarrhea. Watling KJ, Beer MS, Stanton JA et al. Interaction of the atypical neuroleptic clozapine with 5-HT 3 receptors in the cerebral cortex and superior cervical ganglion of the rat. Eur J Pharmacol. Co-administration of citalopram and clozapine: effect on plasma clozapine levels. Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. erythromycin online mail order

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If you experience these problems, contact your doctor. The dose of your medicines may be need to be adjusted. Your doctor may want to monitor a test called an electrocardiogram ECG on you to see if your medicines are affecting your heart's rhythm. Let your doctor know right away if you notice an irregular heartbeat or have any dizziness, fainting episodes, or seizures. Friedman JH. Clozapine and the mandatory monitoring system. N Engl J Med. Use of clozapine requires blood monitoring. Interaction not evaluated but may be important, since clozapine binds extensively to plasma proteins. Hypokalemia and hypomagnesemia also increase risk of QT-interval prolongation. Gerson SL, Lieberman JA, Friedenberg WR et al. Polypharmacy in fatal clozapine-associated agranulocytosis. Lancet. Kane JM, Cooper TB, Sachar EJ et al. Clozapine: plasma levels and prolactin response. Psychopharmacology. Importance of informing patients of other important precautionary information. 1 395 406 See Cautions. Clozaril is an atypical antipsychotic. It may work by affecting certain chemicals in the brain, which has an effect on thinking and behavior.

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The information contained in the Truven Health Micromedex products as delivered by Drugs. Pi EH, Simpson GM. Atypical neuroleptics: clozapine and the benzamides in the prevention and treatment of tardive dyskinesia. Mod Probl Pharmacopsychiat. Atypical antipsychotic drugs, including clozapine have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile. Carefully select Clozapine Orally Disintegrating Tablets 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. The cumulative incidence is estimated at 1% to 2% after one year of use. The onset is generally between 4 to 16 weeks following initiation of therapy, and it is usually reversible if detected early and the drug discontinued promptly. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Always consult your doctor or healthcare specialist for medical advice. procardia online no prior prescription usa

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Macfadden W. Dear health care professional letter regarding class labeling for atypical antipsychotics and risk of hyperglycemia and diabetes. Wilmington, DE: AstraZeneca Pharmaceuticals; 2004 Apr 22. From the FDA website. Zivkovic B, Guidotti A, Revuelta A et al. Effect of thioridazine, clozapine and other antipsychotics on the kinetic state of tyrosine hydroxylase and on the turnover rate of dopamine in striatum and nucleus accumbens. J Pharmacol Exp Ther. Hu XT, Wang RY. Haloperidol and clozapine: differential effects on the sensitivity of caudate-putamen neurons to dopamine agonists and cholecystokinin following one month continuous treatment. Brain Res. Sriwatanakul K. Minimizing the risk of antipsychotic-associated seizures. Drug Therapy. Sandoz Pharmaceuticals, East Hanover, NJ: Personal Communication. Maximum 900 mg daily. The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Do not take more than the recommended dose without checking with your doctor. Hepatobiliary System: Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury hepatic, cholestatic, and mixed and liver failure. Because of the risk of severe neutropenia, regular ANC monitoring is required during clozapine therapy. 1 408 Obtain baseline CBC count, including ANC, prior to initiation of clozapine, then monitor ANC at recommended intervals during therapy. buy cheapest tretinoin pharmacy europe

The cause of this interaction is not known

Contact your doctor as soon as possible if you have chest pain or discomfort, a fast or slow heartbeat, trouble breathing, or fever and chills. These can be symptoms of a very serious problem with your heart. Potential additive effect on QT-interval prolongation; use concomitantly with caution. 1 See Prolongation of QT Interval under Cautions and also see Specific Drugs under Interactions. Phenylketonuric patients should be informed that Clozapine Orally Disintegrating Tablets contain phenylalanine a component of aspartame. Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive. Kalow W. Ethnic differences in drug metabolism. Clin Pharmacokinet. Do not refrigerate or freeze the oral liquid. Throw away any unused medicine 100 days after opening the bottle for the first time. Weekly blood tests are required for the first 6 months. Antiarrhythmics eg, amiodarone, propafenone, flecainide, quinidine diuretics eg, furosemide, hydrochlorothiazide dolasetron, droperidol, iloperidone, macrolide antibiotics eg, erythromycin mefloquine, methadone, ondansetron, pentamidine, phenothiazines eg, chlorpromazine, thioridazine pimozide, quinolone antibiotics eg, ciprofloxacin tacrolimus, ziprasidone or any other medicine that may increase the risk of a certain type of irregular heartbeat prolonged QT interval. Clozaril may cause drowsiness, dizziness, or light-headedness. These effects may be worse if you take it with alcohol or certain medicines. Use Clozaril with caution. Do not drive or perform other possibly unsafe tasks while you take Clozaril. Clozaril is only available through a restricted program under a REMS called the Clozapine REMS Program because of the risk of severe neutropenia. See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia. See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia. Central Nervous System: Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions. eutirox

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C occurs in any patient, interrupt clozapine therapy and obtain an ANC; carefully evaluate for severe neutropenia or infection. 1 Monitor ANC in any patient who develops fever within 2 weeks after discontinuance of clozapine. 1 If high fever is present, also consider possibility of NMS. 1 See Neuroleptic Malignant Syndrome under Cautions. Food and Drug Administration. WebMD does not endorse any specific product, service, or treatment. Sassim N, Grohmann R. Adverse drug reactions with clozapine and simultaneous application of benzodiazepines. Pharmacopsychiatry. 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. Sangal R, Dimitrijevic R. Neuroleptic malignant syndrome: successful treatment with pancuronium. JAMA. 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. cytotec

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Advise patients to use caution when engaging in activities where sudden loss of consciousness could cause serious risk to patient or others. 1 See Seizures under Cautions. Severe neutropenia can lead to serious infection and death. Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. QTdrugs List, AZCERT, Inc. Leon CA. Therapeutic effects of clozapine. A 4-year follow-up of a controlled clinical trial. Acta Psychiatr Scand.

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Clozapine concentrations may be increased; dosage reduction may be necessary in patients with clinically important renal impairment. 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. Nykiel S, Henderson D, Bhide G et al. Lithium to allow clozapine prescribing in benign ethnic neutropenia. Clin Schizophr Relat Psychoses. Meltzer HY. Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology Berl. Monitor for adverse reactions. Consider reducing the Clozaril dose if necessary. Safferman AZ, Schwimmer JL, Schaaf JA 1993. Concomitant use of Clozaril and CYP1A2 inhibitors can increase plasma levels of clozapine, potentially resulting in adverse reactions. Marco LA, Joshi RS, Brigham TE et al. Effects of clozapine on ketamine-induced linguopharyngeal events in rats. Eur J Pharmacol. Nielsen H. Recombinant human granulocyte colony-stimulating factor rhG-CSF; filgrastim treatment of clozapine-induced agranulocytosis. J Intern Med. Faltus F, Hynek V, Dolezalova V et al. Experience in the treatment of schizophrenia with clozapine. Act Nerv Super. Consider reducing the dose if hypotension occurs. See Severe Neutropenia under Cautions. Moderate or weak CYP1A2 inhibitors include oral contraceptives and caffeine. Monitor patients closely when Clozapine Orally Disintegrating Tablets are coadministered with these inhibitors. is it legal dilantin online

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FDA approved a shared REMS for clozapine to ensure that the benefits outweigh the risks. The REMS consists of the following: elements to assure safe use and implementation system. See the FDA REMS page or the ASHP REMS Resource Center . Also see Restricted Distribution Program under Dosage and Administration. Jenkins M, Metzer WS. Avoidance of metoclopramide for the treatment of clozapine-induced nausea. J Clin Psychiatry. Although clozapine was not included in these studies, the consistent findings across all three relevant chemical classes support the opinion that these findings are likely to be applicable to all atypical antipsychotic agents. Clozapine is not indicated for use in the treatment of behavioral disorders in elderly patients with dementia.

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Neuroleptic malignant syndrome NMS a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including some cases with clozapine therapy alone or during concomitant therapy with carbamazepine, lithium, or other CNS-active agents. Information on Vitamins. It provides some general information about a particular vitamin and its image under the microscope. Symptoms may include coma; delirium; excessive salivation; fainting; fast or irregular heartbeat; seizures; severe or persistent dizziness or drowsiness; slow or shallow breathing.

Drug Safety 30: 47-57

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive. Sarafoff M, Davis L, Ruther E. Clozapine induced increase in human plasma norepinephrine. J Neural Transm.

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Smego RA Jr, Durack DT. The neuroleptic malignant syndrome. Arch Intern Med. Sandoz Pharmaceuticals. Treatment systems requirements: Clozaril clozapine. East Hanover, NJ; 1991 Mar. Clozapine Orally Disintegrating Tablets and is associated with an increase in the risk of serious and potentially fatal infections. Risk of neutropenia appears greatest during the first 18 weeks on treatment and then declines. The mechanism by which clozapine causes neutropenia is unknown and is not dose-dependent. Mattes J. Clozapine for refractory schizophrenia: an open study of 14 patients treated up to 2 years. J Clin Psychiatry.

Concomitant use is not recommended. Grohmann R, Ruther E, Sassim N et al. Adverse effects of clozapine. Psychopharmacology. Combination treatment with clozapine and paroxetine in schizophrenia: safety and tolerability data from a prospective open clinical trial. Myocarditis and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue Clozapine Orally Disintegrating Tablets and obtain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with Clozapine Orally Disintegrating Tablets. However, if the benefit of Clozapine Orally Disintegrating Tablets treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with Clozapine Orally Disintegrating Tablets in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.

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