Serentil

Before taking mesoridazine,

• tell your doctor and pharmacist if you are allergic to mesoridazine or any other drugs.
• tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially antacids, antihistamines, appetite reducers (amphetamines), benztropine (Cogentin), bromocriptine (Parlodel), carbamazepine (Tegretol), dicyclomine (Bentyl), fluoxetine (Prozac), guanethidine (Ismelin), lithium, medications for colds, medications for depression, meperidine (Demerol), methyldopa (Aldomet), phenytoin (Dilantin), propranolol (Inderal), quinidine, sedatives, trihexyphenidyl (Artane), valproic acid (Depakane), and vitamins.
• tell your doctor if you have or have ever had depression; seizures; shock therapy; asthma; emphysema; chronic bronchitis; problems with your urinary system or prostate; glaucoma; history of alcohol abuse; thyroid problems; angina; irregular heartbeat; problems with your blood pressure; blood disorders; or blood vessel, heart, kidney, liver, or lung disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking mesoridazine, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking mesoridazine.
• you should know that this drug may make you drowsy. Do not drive a car or operate machinery until you know how this drug affects you.
• remember that alcohol can add to the drowsiness caused by this drug.
• plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Mesoridazine may make your skin sensitive to sunlight.

While ocular changes have not to date been related to Serentil® (mesoridazine besylate), one should be aware that such changes have been seen with other drugs of this class.

      Because of possible hypotensive effects, reserve parenteral administration for bedfast patients or for acute ambulatory cases, and keep patient lying down for at least one-half hour after injection.

      Leukopenia and/or agranulocytosis have been attributed to phenothiazine therapy. A single case of transient granulocytopenia has been associated with Serentil. Since convulsive seizures have been reported, patients receiving anticonvulsant medication should be maintained on that regimen while receiving Serentil.

      Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.

Drug Interactions

There are no studies of the coadministration of mesoridazine and other drugs which prolong the QTc interval. However, it is expected that such coadministration would produce additive prolongation of the QTc interval and, thus, such use is contraindicated (see WARNINGS and CONTRAINDICATIONS).

Information for Patients

Patients should be informed that Serentil has been associated with potentially fatal heart rhythm disturbances. The risk of such events may be increased when certain drugs are given together with Serentil. Therefore, patients should inform the prescriber that they are receiving Serentil treatment before taking any new medication.

      Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk.

Usage In Pregnancy

The safety of this drug in pregnancy has not been established; hence, it should be given only when the anticipated benefits to be derived from treatment exceed the possible risks to mother and fetus.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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.

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.

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 α-adrenergic blocking properties of the phenothiazines makes the use of vasopressors with mixed α and β adrenergic agonist properties inappropriate, including epinephrine and dopamine. Paradoxical vasodilation may result. In addition, it is reasonable to expect that the α-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®*.

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.

LactMed Record Number

171

Last Revision Date

20150310

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