Following is some information about Clozaril, taken from the Physicians's Drug Reference book. You must remember that this medication was originally developed to treat people with Schizophrenia, hence the references to it. Also there is some information regarding known drug interactions. Brian Symonds <[log in to unmask]> ADVERSE REACTIONS Associated with Discontinuation of Treatment. Sixteen percent of 1080 patients who received Clozaril (clozapine) in premarketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to Clozaril (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. Commonly Observed Adverse events observed in association with the use of Clozaril (clozapine) in clinical trials at an incidence of greater than 5% were: central nervous system 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; and 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. Incidence in Clinical Trials The following table (TABLE 1) enumerates adverse events that occurred at a frequency of 1% or greater among Clozaril (clozapine) patients who participated in clinical trials. These rates are not adjusted for duration of exposure. TABLE 1 - Clozapine, Adverse Reactions Treatment-Emergent Adverse Experience Incidence Among Patients Taking Clozaril (clozapine) in Clinical Trials (N = 842) (Percentage of Patients Reporting) ---------------------------------------------------------------------- Body System Adverse Event a Percent ---------------------------------------------------------------------- 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) 3b Rigidity 3 Akathisia 3 Confusion 3 Fatigue 2 Insomnia 2 Hyperkinesia 1 Weakness 1 Lethargy 1 Ataxia 1 Slurred speech 1 Depression 1 Epileptiform movements/Myoclonic jerks 1 Anxiety 1 Cardiovascular Tachycardia 25b Hypotension 9 Hypertension 4 Chest pain/Angina 1 ECG change/Cardiac abnormality 1 Gastrointestinal Constipation 14 Nausea 5 Abdominal discomfort/Heartburn 4 Nausea/Vomiting 3 Vomiting 3 Diarrhea 2 Liver test abnormality 1 Anorexia 1 Urogenital Urinary abnormalities 2 Incontinence 1 Abnormal ejaculation 1 Urinary urgency/frequency 1 Urinary retention 1 Autonomic Nervous System Salivation 31 Sweating 6 Dry mouth 6 Visual disturbances 5 Integumentary (Skin) Rash 2 Musculoskeletal Muscle weakness 1 Pain (back, neck, legs) 1 Muscle spasm 1 Muscle pain, ache 1 Respiratory Throat discomfort 1 Dyspnea, shortness of breath 1 Nasal congestion 1 Hemic/Lymphatic Leukopenia/Decreased WBC/Neutropenia 3 Agranulocytosis 1b Eosinophilia 1 Miscellaneous Fever 5 Weight gain 4 Tongue numb/sore 1 ---------------------------------------------------------------------- aEvents reported by at least 1% of Clozaril (clozapine) patients are included. bRate based on population of approximately 1700 exposed during premarket clinical evaluation of Clozaril (clozapine). Other Events Observed During the Premarketing Evaluation of Clozaril (clozapine) This section reports additional, less frequent adverse events which occurred among the patients taking Clozaril (clozapine) in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to Clozaril (clozapine) treatment cannot be determined in the absence of appropriate controls in some of the studies. The table (TABLE 1) above enumerates adverse events that occurred at a frequency of at least 1% of patients treated with Clozaril (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. 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. Cardiovascular System: edema, palpitations, phlebitis/thrombophlebitis, cyanosis, premature ventricular contraction, bradycardia, and nose bleed. Gastrointestinal System: abdominal distention, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer, bitter taste, and eructation. Urogenital System: dysmenorrhea, impotence, breast pain/discomfort, and vaginal itch/infection. Autonomic Nervous System: numbness, polydipsia, hot flashes, dry throat, and mydriasis. Integumentary (Skin): pruritus, pallor, eczema, erythema, bruise, dermatitis, petechiae, and urticaria. Musculoskeletal System: twitching and joint pain. Respiratory System: coughing, pneumonia/pneumonia-like symptoms, rhinorrhea, hyperventilation, wheezing, bronchitis, laryngitis, and sneezing. Hemic and Lymphatic System: anemia and leukocytosis. Miscellaneous: chills/chills with fever, malaise, appetite increase, ear disorder, hypothermia, eyelid disorder, bloodshot eyes, and nystagmus. Postmarketing Clinical Experience Postmarketing experience has shown an adverse experience profile similar to that presented above. Voluntary reports of adverse events temporally associated with Clozaril (clozapine) not mentioned above that have been received since market introduction and that may have no causal relationship with the drug include the following: Central Nervous System: delirium; EEG abnormal; exacerbation of psychosis; myoclonus; overdose; paresthesia; and status epilepticus. Cardiovascular System: atrial or ventricular fibrillation and periorbital edema. Gastrointestinal System: acute pancreatitis; dysphagia; fecal impaction; hepatitis; intestinal obstruction/paralytic ileus; jaundice; and salivary gland swelling. Urogenital System: priapism. Integumentary (Skin): hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome. Respiratory System: aspiration and pleural effusion. Hemic and Lymphatic System: deep vein thrombosis; elevated hemoglobin/hematocrit; ESR increased; pulmonary embolism; sepsis; thrombocytosis; and thrombocytopenia. Miscellaneous: CPK elevation; hyperglycemia; hyperuricemia; hyponatremia; and weight loss. DRUG ABUSE AND DEPENDENCE Physical and psychological dependence have not been reported or observed in patients taking Clozaril (clozapine). OVERDOSAGE Human Experience The most commonly reported signs and symptoms associated with Clozaril (clozapine) overdose are: altered states of consciousness, including drowsiness, delirium and coma; tachycardia; hypotension; respiratory depression or failure; 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 Clozaril (clozapine), generally at doses above 2500 mgs. There have also been reports of patients recovering from overdoses well in excess of 4 gms. 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 is recommended along with general symptomatic and 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 Clozaril (clozapine). 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 Poison Control Centers are listed in the Physicians GenRx. DOSAGE AND ADMINISTRATION In order to minimize the risk of agranulocytosis, Clozaril (clozapine) is available only through a distribution system that ensures weekly WBC testing prior to delivery of the next week's supply of medication. Upon initiation of Clozaril (clozapine) therapy, up to a 1 week supply of additional Clozaril (clozapine) tablets may be provided to the patient to be held for emergencies (e.g., weather, holidays). Initial Treatment It is recommended that treatment with Clozaril (clozapine) begin with one-half of a 25 mg (12.5 mg) once or twice daily and then 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 Clozaril (clozapine) in patients resistant to standard antipsychotic drug treatment, patients were titrated during the first 2 weeks up to a maximum dose of 500 mg/day, on a t.i.d. basis, and were then dosed in a total daily dose range of 100-900 mg/day, on a t.i.d. basis thereafter, with clinical response and adverse effects as guides to correct dosing. 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 Clozaril (clozapine) in treatment resistant patients, the mean and median Clozaril (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. 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. Maintenance Treatment While the maintenance effectiveness of Clozaril (clozapine) in schizophrenia is still under study, the effectiveness of maintenance treatment is well established for many other antipsychotic drugs. It is recommended that responding patients be continued on Clozaril (clozapine), but at the lowest level needed to maintain remission. Because of the significant risk associated with the use of Clozaril (clozapine), patients should be periodically reassessed to determine the need for maintenance treatment. Discontinuation of Treatment In the event of planned termination of Clozaril (clozapine) therapy, gradual reduction in dose is recommended over a 1-2 week period. However, should a patient's medical condition require abrupt discontinuation (e.g., leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms. Re-initiation of Treatment in Patients Previously Discontinued When restarting patients who have had even a brief interval off Clozaril (clozapine), i.e., 2 days or more since the last dose, it is recommended that treatment be reinitiated with one-half of a 25 mg tablet (12.5 mg) once or twice daily (see Warnings). 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 re-titrated with extreme caution after even 24 hours of discontinuation. Certain additional precautions seem prudent when re-initiating treatment. The mechanisms underlying Clozaril (clozapine)-induced adverse reactions are unknown. It is conceivable, however, that re-exposure 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 re-initiation of treatment, additional caution is advised. Patients discontinued for WBC counts below 2000/mm 3 or an ANC below 1000/mm 3 must not be restarted on Clozaril (clozapine). (See WARNINGS) Store and Dispense Storage temperature should not exceed 86F (30C). Drug dispensing should not ordinarily exceed a weekly supply. Dispensing should be contingent upon the results of a WBC count. HOW SUPPLIED Clozaril (clozapine) is available only through a distribution system that ensures weekly WBC testing prior to delivery of the next week's supply of medication. Clozaril (clozapine) Tablets 25 mg Round, pale yellow, scored, uncoated tablets, engraved with "CLOZARIL" (on the periphery) on one side, and "25" on the scored side. Bottle of 100 (NDC 0078-0126-05). SandoPak(R) unit-dose packages of 100: 2 x 5 strips, 10 blisters per strip (NDC 0078-0126-06). 100 mg Round, pale yellow, compressed tablets, engraved with "CLOZARIL" (on the periphery) on one side, and "100" on the other side. Bottle of 100 (NDC 0078-0127-05). SandoPak unit-dose packages of 100: 2 x 5 strips, 10 blisters per strip (NDC 0078-0127-06). (Sandoz Pharmaceuticals Corporation, 3/94, 30518901) (94/03). HOW SUPPLIED - EQUIVALENTS NOT AVAILABLE Tablet, Uncoated - Oral - 25 mg 100's $132.00 CLOZARIL, Sandoz Pharm 00078-0126-05* 100's $132.00 CLOZARIL, U.D., Sandoz Pharm 00078-0126-06 Tablet, Uncoated - Oral - 100 mg 100's $342.00 CLOZARIL, Sandoz Pharm 00078-0127-05* 100's $342.00 CLOZARIL, U.D., Sandoz Pharm 00078-0127-06 From The Medical Letter ANTIDEPRESSANTS -- Depression commonly accompanies Parkinson's disease and must be treated, if present, for the patient to benefit adequately from antiparkinson drugs. A tricyclic antidepressant or trazodone (Desyrel) is usually the drug of choice. Experience with fluoxetine (Prozac), other selective serotonin reuptake inhibitors, or bupropion (Wellbutrin) is more limited; worsening of Parkinson's symptoms has been reported with fluoxetine (EN Steur, Neurology, 43:211, Jan 1993). MAO-A inhibitors should not be used because they can cause marked swings in blood pressure in patients taking levodopa. CLOZAPINE -- Several reports indicate that psychosis associated with levodopa or dopamine agonists responds to low doses of clozapine (Clozaril - Medical Letter, 35:16, 1993), an antipsychotic drug with hematological toxicity but few extrapyramidal effects (SI Wolk and CJ Douglas, J Clin Psychiatry, 53:373, 1992). Drug Interactions Clozapine: Clozaril with anti depressants Effect: Possible antidepressant toxicity with nortriptyline (possibly decreased metabolism) [1173] Comments: Single case report (1994); monitor clinical status and adjust antidepressat dosage if needed. Clozapine: Clozaril with H2 blockers Effect: Clozapine toxicity with cimetidine (possibly decreased metabolism)[913] Comments: Single case report (1991); did not occur with ranitidine. Clozapine: Clozaril with benzodiazepines Effect: Respiratory arrest (mechanism not established)[966] Comments: Has been reported more frequently with clozapine alone than with combination; monitor respiratory status. Clozapine: Clozaril with Carbamazepine Effect: 1)Neuroleptic malignant syndrome (mechanism not established)[797] 2)Agranulocytosis with pancytopenia (possibly synergism)[797] 3)Possibly decreased clozapine effect (possibly increased metabolism)[797] Comments: 1)Single case report (1988) in patient who received clozapine shortly after lithium was stopped; syndrome has been reported with clozapine or lithium alone 2)Single case report (1991); avoid concurrent use 3)Two case reports (1993). Clozapine: Clozarilwith Erythromycins Erythromycins: A/T/S, AK-Mycin, Akne-mycin, Dowmycin E, E-Base, E-Mycin, E.E.S., E.T.S., Ery-Sol, Ery-Tab, ERYC, Erycette, Eryderm, Erygel, Erymax, Erypar, Erythro, Erythrocin, Erythrocot, Ilosone, Ilotycin, My-E, PCE Dispertab, Pediamycin, Robimycin, RP-Mycin, Spectro-Erythromycin, Staticin, Wintrocin, Wyamycin Effect: Possible clozapine toxicity (decreased metabolism)[1182] Comments: Based on single case report of seizures (1994) and theoretical considerations (erythromycin inhibits enzyme that metabolizes clozapine, CYP1A2). Clozapine: Clozaril with Lithium Lithium: Cibalith-S, Eskalith, Lithane, Lithizine, Lithobid, Lithonate, Lithotabs Effect: CNS toxicity (mechanism not established)[1034] Comments: Monitor clinical status and maintain lithium concentration below 0.5 mEq/L. Clozapine: Clozaril with Phenytoin Phenytoin: Dihycon, Dilantin, Diphen, Diphentoin, Diphenylan, Dyatoin, Ekko, Phenytex Effect: Decreased clozapine effect (increased metabolism)[930] Comments: Two cases (1991). Clozapine: Clozaril with Selective serotonin reuptake inhibitors (SSRIs) Selective serotonin reuptake inhibitors (SSRIs): fluoxetine - Prozac fluvoxamine - Luvox paroxetine - Paxil sertraline - Zoloft Effect: Possible clozapine toxicity with fluoxetine or fluvoxamine (decreased metabollism)[1131] Comments: Monitor clozapine concentration.