Serentil (Tablet, Film Coated)

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Since Serentil (mesoridazine besylate) is associated with a dose-related prolongation of the QTc interval, which is a potentially life-threatening event, its use should be reserved for schizophrenia patients who fail to respond adequately to treatment with other antipsychotic drugs (see INDICATIONS and WARNINGS). The dosage of Serentil, as with most medications, should be adjusted to the needs of the individual. The lowest effective dosage should always be used. When maximum response is achieved, dosage may be reduced gradually to a maintenance dose.<br/>Tablets and Oral Solution: For most patients, regardless of severity, a starting dose of 50 mg three times a day is recommended. The usual optimum total daily dose range is 100-400 mg per day.<br/>Injectable Form: In those situations in which an intramuscular form of medication is indicated, Serentil injectable is available. For most patients, a starting dose of 25 mg is recommended. The dose may be repeated in 30 to 60 minutes, if necessary. The usual optimum total daily dose range is 25-200 mg per day.

The basic pharmacological activity of Serentil (mesoridazine besylate) is similar to that of other phenothiazines. However, mesoridazine has been shown to prolong the QTc interval in a dose-dependent fashion. This effect may increase the risk of serious, potentially fatal, ventricular arrhythmias, such as torsade de pointes-type arrhythmias. Due to this risk, Serentil is indicated only for schizophrenic patients who have not been responsive to or cannot tolerate other antipsychotic agents (see WARNINGS and CONTRAINDICATIONS). However, the prescriber should be aware that Serentil has not been systematically evaluated in controlled trials in treatment of refractory schizophrenic patients and its efficacy in such patients is unknown.

Serentil (mesoridazine besylate) use should be avoided in combination with other drugs that are known to prolong the QTc interval and in patients with congenital long QT syndrome or a history of cardiac arrhythmias (see WARNINGS and PRECAUTIONS). As with other phenothiazines, Serentil is contraindicated in severe central nervous system depression or comatose states from any cause including drug induced central nervous system depression (see WARNINGS). Serentil is contraindicated in individuals who have previously shown hypersensitivity to the drug.

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.)

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Symptoms of Acute Overdosage: Drowsiness, confusion, disorientation, agitation, coma, death. Dryness of mouth, edema of glottis, laryngeal spasms, nasal congestion, blurred vision, vomiting. Hyperpyrexia, dilated pupils, muscle rigidity, hyperactive reflexes, areflexia. Stupor, and CNS depression or stimulation with convulsions followed by respiratory depression. Cardiac abnormalities, including QRS changes, tachycardia, hypotension, bilateral bundle branch block, ventricular fibrillation, shock, cardiac arrest and congestive heart failure.<br/>Treatment of Acute Overdosage: An airway must be established and maintained. Adequate oxygenation and ventilation must be ensured. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Treatment may include one or more of the following therapeutic interventions: correction of electrolyte abnormalities and acid-base balance, lidocaine, phenytoin, isoproterenol, ventricular pacing, and defibrillation. Disopyramide, procainamide, and quinidine may produce additive QT-prolonging effects when administered to patients with acute overdosage of Serentil (mesoridazine besylate) and should be avoided (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS). Caution must be exercised when administering lidocaine, as it may increase the risk of developing seizures. Treatment of hypotension may require intravenous fluids and vasopressors. Phenylephrine, levarterenol, or metaraminol are the appropriate pressor agents for use in the management of refractory hypotension. The potent��-adrenergic blocking properties of the phenothiazines makes the use of vasopressors with mixed��and��adrenergic agonist properties inappropriate, including epinephrine and dopamine. Paradoxical vasodilation may result. In addition, it is reasonable to expect that the��-adrenergic blocking properties of bretylium might be additive to those of Serentil, resulting in problematic hypotension. In managing overdosage, the physician should always consider the possibility of multiple drug involvement. Gastric lavage and repeated doses of activated charcoal should be considered. Induction of emesis is less preferable to gastric lavage because of the risk of dystonia and the potential for aspiration of vomitus. Emesis should not be induced in patients expected to deteriorate rapidly or in those with impaired consciousness. No specific antidote is known. Acute extrapyramidal symptoms may be treated with diphenhydramine hydrochloride or benztropine mesylate. Avoid the use of barbiturates when treating seizures, as they may potentiate phenothiazine-induced respiratory depression. Forced diuresis, hemoperfusion, hemodialysis, and manipulation of urine pH are of unlikely benefit in the treatment of phenothiazine overdose due to their large volume of distribution and extensive plasma protein binding. 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*.

Serentil (Tablet, Film Coated)

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.<br/>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.)<br/>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 thedifferential 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 aboutspecific 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.<br/>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.

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