FDA label 0f2c6eb5-7426-89c6-b28d-bb693af1c1b2

WARNING SERENTIL ® (MESORIDAZINE BESYLATE) HAS BEEN SHOWN TO PROLONG THE QTc INTERVAL IN A DOSE RELATED MANNER, AND DRUGS WITH THIS POTENTIAL, INCLUDING SERENTIL, HAVE BEEN ASSOCIATED WITH TORSADE DE POINTES-TYPE ARRHYTHMIAS AND SUDDEN DEATH. DUE TO ITS POTENTIAL FOR SIGNIFICANT, POSSIBLY LIFE-THREATENING, PROARRHYTHMIC EFFECTS, SERENTIL SHOULD BE RESERVED FOR USE IN THE TREATMENT OF SCHIZOPHRENIC PATIENTS WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF TREATMENT WITH OTHER ANTIPSYCHOTIC DRUGS, EITHER BECAUSE OF INSUFFICIENT EFFECTIVENESS OR THE INABILITY TO ACHIEVE AN EFFECTIVE DOSE DUE TO INTOLERABLE ADVERSE EFFECTS FROM THOSE DRUGS. (SEE WARNINGS, CONTRAINDICATIONS, AND INDICATIONS.)

WARNINGS Potential for Proarrhythmic Effects DUE TO THE POTENTIAL FOR SIGNIFICANT, POSSIBLY LIFE-THREATENING, PROARRHYTHMIC EFFECTS WITH SERENTIL ® (MESORIDAZINE BESYLATE) TREATMENT, SERENTIL SHOULD BE RESERVED FOR USE IN THE TREATMENT OF SCHIZOPHRENIC PATIENTS WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF TREATMENT WITH OTHER ANTIPSYCHOTIC DRUGS, EITHER BECAUSE OF INSUFFICIENT EFFECTIVENESS OR THE INABILITY TO ACHIEVE AN EFFECTIVE DOSE DUE TO INTOLERABLE ADVERSE EFFECTS FROM THOSE DRUGS. CONSEQUENTLY, BEFORE INITIATING TREATMENT WITH SERENTIL, IT IS STRONGLY RECOMMENDED THAT A PATIENT BE GIVEN AT LEAST TWO TRIALS, EACH WITH A DIFFERENT ANTIPSYCHOTIC DRUG PRODUCT, AT AN ADEQUATE DOSE, AND FOR AN ADEQUATE DURATION. SERENTIL HAS NOT BEEN SYSTEMATICALLY EVALUATED IN CONTROLLED TRIALS IN THE TREATMENT OF REFRACTORY SCHIZOPHRENIC PATIENTS AND ITS EFFICACY IN SUCH PATIENTS IS UNKNOWN. A study in nine chronic schizophrenic patients who were treated with mesoridazine 75 mg/day for the first week, 200 mg/day during week 2, and 300 mg/day during weeks 3 and 4, revealed evidence of a dose-related prolongation of the QT interval. All patients had a normal ECG at baseline and eight of the nine had normal ECG’s two weeks after drug discontinuation. Prolongation of the QTc interval has been associated with the ability to cause torsade de pointes-type arrhythmias, a potentially fatal polymorphic ventricular tachycardia, and sudden death. There are published case reports of ventricular tachycardia, in one case with a fatal outcome, in association with mesoridazine overdosage. A causal relationship between these events and Serentil therapy has not been established but, given the ability of Serentil to prolong the QTc interval, such a relationship is possible. Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including 1) bradycardia, 2) hypokalemia, 3) concomitant use of other drugs that prolong the QTc interval, and 4) presence of congenital prolongation of the QT interval (see CONTRAINDICATIONS and PRECAUTIONS). It is recommended that patients being considered for Serentil treatment have a baseline ECG performed and serum potassium levels measured. Serum potassium should be normalized before initiating treatment and patients with a QTc interval greater than 450 msec should not receive Serentil treatment. It may also be useful to periodically monitor ECG’s and serum potassium during Serentil treatment especially during a period of dose adjustment. Serentil should be discontinued in patients who are found to have a QTc interval over 500 msec. Patients taking Serentil who experience symptoms that may be associated with the occurrence of torsade de pointes (e.g., dizziness, palpitations, or syncope) may warrant further cardiac evaluation; in particular, Holter monitoring should be considered. Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. 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. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness 1) that is known to respond to antipsychotic drugs, and 2) for which alternative, equally effective but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to the sections on Information for Patients and Adverse Reactions.) Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). 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 (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs 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. 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. Where patients are participating in activities requiring complete mental alertness, (e.g., driving) it is advisable to administer the phenothiazines cautiously and to increase the dosage gradually. Central Nervous System Depressants As in the case of other phenothiazines, Serentil is capable of potentiating central nervous system depressants (e.g., alcohol, anesthetics, barbiturates, narcotics, opiates, other psychoactive drugs, etc.) as well as atropine and phosphorus insecticides. Severe respiratory depression and respiratory arrest have been reported when a patient was given Serentil and a concomitant high dose of a barbiturate.

ADVERSE REACTIONS Drowsiness and hypotension were the most prevalent side effects encountered. Side effects tended to reach their maximum level of severity early with the exception of a few (rigidity and motoric effects) which occurred later in therapy. With the exceptions of tremor and rigidity, adverse reactions were generally found among those patients who received relatively high doses early in treatment. Clinical data showed no tendency for the investigators to terminate treatment because of side effects. Central Nervous System: Drowsiness, Parkinson’s syndrome, dizziness, weakness, tremor, restlessness, ataxia, dystonia, rigidity, slurring, akathisia, motoric reactions (opisthotonos) have been reported. Autonomic Nervous System: Dry mouth, nausea and vomiting, fainting, stuffy nose, photophobia, constipation and blurred vision have occurred in some instances. Genitourinary System: Inhibition of ejaculation, impotence, enuresis, incontinence, and priapism have been reported. Skin: Itching, rash, hypertrophic papillae of the tongue and angioneurotic edema have been reported. Cardiovascular System: Serentil ® (mesoridazine besylate) produces a dose related prolongation of the QTc interval, which is associated with the ability to cause torsade de pointes-type arrhythmias, a potentially fatal polymorphic ventricular tachycardia, and sudden death (see WARNINGS). Ventricular arrhythmias and death have been reported in association with Serentil overdosage. A causal relationship between these events and Serentil therapy has not been established but, given the ability of Serentil to prolong the QTc interval, such a relationship is possible. Other ECG changes have been reported (see Phenothiazine Derivatives: Cardiovascular Effects). Phenothiazine Derivatives It should be noted that efficacy, indications and untoward effects have varied with the different phenothiazines. The physician should be aware that the following have occurred with one or more phenothiazines and should be considered whenever one of these drugs is used. Autonomic Reactions: Miosis, obstipation, anorexia, paralytic ileus. Cutaneous Reactions: Erythema, exfoliative dermatitis, contact dermatitis. Blood Dyscrasias: Agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia, pancytopenia. Allergic Reactions: Fever, laryngeal edema, angioneurotic edema, asthma. Hepatotoxicity: Jaundice, biliary stasis. Cardiovascular Effects: Changes in the terminal portion of the electrocardiogram, to include prolongation of the QT interval, depression and inversion of the T wave, and the appearance of a wave tentatively identified as a bifid T wave or a U wave have been observed in patients receiving phenothiazines, including Serentil. To date, these appear to be due to altered repolarization, not related to myocardial damage, and appear to be reversible. Nonetheless, significant prolongation of the QT interval has been associated with serious ventricular arrhythmias and sudden death (see WARNINGS). Hypotension, rarely resulting in cardiac arrest, has been reported. Extrapyramidal Symptoms: Akathisia, agitation, motor restlessness, dystonic reactions, trismus, torticollis, opisthotonos, oculogyric crises, tremor, muscular rigidity, akinesia. Tardive Dyskinesia: Chronic use of antipsychotics may be associated with the development of tardive dyskinesia. The salient features of this syndrome are described in the WARNINGS section and below. The syndrome is characterized by involuntary choreoathetoid movements which variously involve the tongue, face, mouth, lips, or jaw (e.g., protrusion of the tongue, puffing of cheeks, puckering of the mouth, chewing movements), trunk and extremities. The severity of the syndrome and the degree of impairment produced vary widely. The syndrome may become clinically recognizable either during treatment upon dosage reduction, or upon withdrawal of treatment. Movements may decrease in intensity and may disappear altogether if further treatment with antipsychotics is withheld. It is generally believed that reversibility is more likely after short rather than long-term antipsychotic exposure. Consequently, early detection of tardive dyskinesia is important. To increase the likelihood of detecting the syndrome at the earliest possible time, the dosage of antipsychotic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. This maneuver is critical, for antipsychotic drugs may mask the signs of the syndrome. Endocrine Disturbances: Menstrual irregularities, altered libido, gynecomastia, lactation, weight gain, edema. False positive pregnancy tests have been reported. Urinary Disturbances: Retention, incontinence. Others: Hyperpyrexia. Behavioral effects suggestive of a paradoxical reaction have been reported. These include excitement, bizarre dreams, aggravation of psychoses and toxic confusional states. More recently a peculiar skin-eye syndrome has been recognized as a side effect following long-term treatment with phenothiazines. This reaction is marked by progressive pigmentation of areas of the skin or conjunctiva and/or accompanied by discoloration of the exposed sclera and cornea. Opacities of the anterior lens and cornea described as irregular or stellate in shape have also been reported. Systemic lupus erythematosus-like syndrome.