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FazaClo® General Information Of the two million Americans who suffer from schizophrenia, approximately 20%1 are termed treatment-refractory because they derive little or no benefit from conventional antipsychotic medications. Due to its demonstrated superior efficacy2,3, clozapine is the only atypical antipsychotic medication indicated in the treatment of this sub-population of patients with schizophrenia. Because treatment-refractory patients are typically more disabled as compared to other patients with schizophrenia and suffer from poor adherence which can contribute to relapse, treatment can be a challenge. Recognizing the need for an antipsychotic with improved adherence and enhanced control of schizophrenic symptoms, FazaClo®(clozapine, USP) Orally Disintegrating Tablets was acquired. FazaClo is an innovative tablet that uses the proprietary DuraSolv® technology licensed from CIMA LABS INC. FazaClo is designed to disintegrate in the mouth in about 15 to 30 seconds with a pleasant mint flavor and is then swallowed reflexively in saliva. It also offers considerable convenience, as no water is required for administration. These clear advantages may be important in treating a disease such as schizophrenia since any barrier may present significant impedance for the patient. FazaClo is also indicated for reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder who are at chronic risk of reexperiencing suicidal behavior. The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was explored over a 2-year period in the InterSePT™ study4. More detailed information about the InterSePT study is available in the Package Insert. Click here to view the Package Insert. On a milligram for milligram basis FazaClo Orally Disintegrating Tablets have been shown to be bioequivalent to Clozaril® tablets. Click here to read more about Bioequivalence to Clozaril. Because of the risk of agranulocytosis and granulocytopenia associated with the use of clozapine, the FazaClo®Patient Registry is maintained. Prescribing health care practitioners, dispensing pharmacists and FazaClo patients must be registered in the FazaClo Patient Registry, which will compare patient information against the National Non-Rechallenge Masterfile and maintain a continuing record of total white blood cell (WBC) counts and absolute neutrophil count (ANC) values and related information for all patients who receive the FazaClo brand of clozapine. Click here to read more About the Registry. Click here to read more about Dispensing FazaClo. In May 2005, the FDA approved monthly WBC count and ANC monitoring for patients who have 12 months of acceptable blood test results while on clozapine. Please see full Prescribing Information including BOXED WARNINGS regarding agranulocytosis, seizures, myocarditis, dementia-related psychosis in elderly patients, and other adverse cardiovascular and respiratory effects. Click here to view the Package Insert. Phenylketonurics: FazaClo Orally Disintegrating Tablets contain phenylalanine. Agranulocytosis Agranulocytosis, a severe reduction in white blood cells, is a rare side effect of this medicine. If this condition is not recognized early, infections may develop, followed by severe symptoms of illness. This reaction could prove fatal if not detected early and therapy interrupted. Persons taking this medicine should report immediately to a health care professional if they become weak or tired, or develop fever, sore throat, mouth sores, or any other possible signs of infection. Because of the risk of developing agranulocytosis in association with FazaClo use, patients, physicians and pharmacists must monitor total WBC counts and ANC according to this program:
There are no established risk factors for the development of agranulocytosis in association with clozapine use. Most cases occur within 4–10 weeks of exposure, but neither dose nor duration is a reliable predictor of the development of this problem. No patient characteristics have been clearly linked to agranulocytosis in association with clozapine use, but agranulocytosis associated with other antipsychotic drugs has been reported to occur with greater frequency in women, the elderly, and in patients who have serious underlying medical illness; such patients may also be at particular risk with FazaClo. Hyperglycemia and Diabetes Hyperglycemia and diabetes mellitus are medical conditions in which the levels of sugar (glucose) in the blood become elevated, a condition that can lead to serious short-term and long-term consequences. These conditions can usually be treated medically at little risk to the patient, but if overlooked could lead to coma or death. Such outcomes have been reported in patients treated with atypical antipsychotics, including clozapine. The relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood for at least two reasons:
However, despite these complicating trends, available data confirm that there is an increased risk of developing hyperglycemia during the course of treatment with atypical antipsychotics, including FazaClo. This information is insufficient to provide reliable estimates of differences in hyperglycemia-related, adverse event risk among the marketed atypical antipsychotics. Patients with established diagnoses of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at baseline and periodically during treatment. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including increased thirst (polydipsia), frequent urination (polyuria), increased appetite (polyphagia), and weakness. Patients who develop such symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In patients who develop significant hyperglycemia, discontinuation of FazaClo should be considered. In some cases, hyperglycemia resolves when the atypical antipsychotic is discontinued; however, some patients require continuation of antidiabetic treatment, such as insulin, despite stopping the antipsychotic medicine. Fever During FazaClo therapy, patients may experience temporary body temperature elevations above 100.4 ºF (38 ºC). This usually occurs early in treatment, with peak incidence within the first three weeks of treatment. While this fever is generally self-limiting and not harmful in itself, it might be an indicator of a more serious condition that could require discontinuation of treatment. If fever develops, this should be called to the attention of a health care professional. Patients with fever should be carefully evaluated to rule out the possibility of an underlying infectious process or the development of agranulocytosis. In the presence of high fever, the possibility of neuroleptic malignant syndrome must be considered -- neuroleptic malignant syndrome is not a type of cancer. Hepatitis (Liver Inflammation) Hepatitis during clozapine treatment has been reported in both patients with normal and preexisting liver function abnormalities. Possible signs of hepatitis include nausea, vomiting, and loss of appetite. These problems should be reported to a health care professional, who may recommend blood tests to evaluate liver function. If the elevation of these values is high or if symptoms of jaundice occur (yellow appearance to skin and eyes), treatment with FazaClo should be discontinued. Caution is advised when prescribing FazaClo for patients who have liver disease. Pregnancy and Nursing Pregnancy. Studies in animals using high doses of clozapine have revealed no evidence of impaired fertility or harm to unborn infants. However, there have been no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and in view of the desirability of keeping the administration of all medicines to a minimum during pregnancy, FazaClo should be used only if clearly needed. Women who are pregnant, or who may become pregnant, should discuss this with a health care professional before considering treatment with FazaClo. Breast feeding. Animal studies suggest that clozapine may be excreted in breast milk and have an effect on the nursing infant. Therefore, women receiving FazaClo should not breast feed. Hypotension Orthostatic hypotension (loss of blood pressure when standing up) with or without syncope (fainting) can occur with FazaClo treatment and may represent a continuing risk in some patients. Orthostatic hypotension is more likely to occur during initial titration (dosage build-up) in association with rapid-dose escalation and may even occur on first dose. In one report, initial doses as low as 12.5 mg were associated with collapse and respiratory arrest. Rarely (approximately 1 case per 3000 patients), collapse can be profound and accompanied by respiratory and/or cardiac arrest (loss of heart and/or lung function). Dosage Interruption
When restarting FazaClo treatment, even after a brief interval of interrupted dosing (i.e., two days or more since the last dose), it is recommended that treatment be restarted with one-half of a 25-mg, orally-disintegrating tablet (12.5 mg) once or twice daily. Neuroleptic Malignant Syndrome (NMS) Description. A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, in general. Signs of NMS include hyperpyrexia (high fever), muscle rigidity, altered mental status, and evidence of autonomic nervous instability (irregular pulse or blood pressure, tachycardia, sweating, and cardiac rhythm abnormalities). Diagnosis. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. Management. The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other medicines not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. Restarting therapy. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Seizures (“Fits”) Overall risk of seizures. Seizures or ‘fits’
have been estimated to occur in association with clozapine use at a
cumulative incidence at one year of approximately 5%. That is, about one
person in every twenty treated with clozapine for one year or longer
developed a seizure. Dose-dependency. Dose appears to be an important predictor of seizure, with a greater likelihood of seizure at the higher clozapine doses used. Precautions. Caution should be used when FazaClo is used by patients having a history of seizures or other predisposing factors. Because of the substantial risk of seizure associated with clozapine use, patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., the operation of complex machinery, driving an automobile, swimming, climbing, etc.). Tachycardia (Rapid Heart Beat) Tachycardia has been observed in approximately 25%
of patients taking clozapine, with patients having an average increase
in pulse rate of 10–15 beats per minute. This reaction may be sustained
over time. Sustained tachycardia may be present in all positions monitored (i.e., whether standing up or lying down). Tachycardia may pose a serious risk for an individual with compromised (weakened) cardiovascular function. Tardive Dyskinesia General description. Tardive dyskinesia (TD), a syndrome consisting of potentially irreversible, involuntary, abnormal movements may develop in patients treated with antipsychotic drugs, in general. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict at the start of treatment which patients are likely to develop the syndrome. Clozapine may be different. There are several reasons for predicting that clozapine may be different from other antipsychotic drugs in its potential for inducing tardive dyskinesia, including the finding in animal studies that it has a relatively weak dopamine-blocking effect and the clinical finding of a virtual absence of certain acute extrapyramidal symptoms (e.g., dystonia). Prior treatment with other medicines. A few cases of tardive dyskinesia have been reported in patients on clozapine who had been previously treated with other antipsychotic agents, so that a causal relationship cannot be established. There have been no reports of tardive dyskinesia directly attributable to clozapine alone. Nevertheless, it cannot be concluded without more extended experience that FazaClo is incapable of inducing this syndrome. Cumulative effects are possible. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. No known treatment. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit partially or completely if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptom suppression has upon the long-term course of the syndrome is unknown. Clozapine treatment guidelines. Given these considerations, FazaClo should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. As with any antipsychotic drug, chronic FazaClo use should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on FazaClo, drug discontinuation should be considered. However, some patients may require treatment with FazaClo despite the presence of the syndrome. References 1. Kerwin RW, Bolonna A. Management of clozapine-resistant schizophrenia. Advances in Psychiatric Treatment. 2005 (11):101-106. 2. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988 Sep;45(9):789-96. 3. Fitton A, Heel RC. Clozapine. A review of its pharmacological properties, and therapeutic use in schizophrenia. Drugs. 1990 Nov;40(5):722-47. 4. Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam MZ, Kane J, Krishnan R, Lindenmayer JP, Potkin S; International Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003 Jan;60(1):82-91. * The ‘differential count’ provides separate counts for all the different subtypes of white blood cells. † ANC stands for ‘absolute neutrophil count’; the neutrophil is the subtype of white blood cell that is most important for fighting infection, and is the most likely to be affected by clozapine-induced agranulocytosis. Clozaril® is a registered trademark of Novartis Pharmaceuticals Corporation. OraSolv® is a registered trademark of CIMA LABS INC. InterSePT™ is a trademark of Novartis Pharmaceuticals Corporation. |