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Prescribing Information
Federal law prohibits dispensing without prescription.
Serentil® (mesoridazine besylate), the besylate salt of a metabolite of thioridazine, is a phenothiazine tranquilizer which is effective in the treatment of schizophrenia, organic brain disorders, alcoholism and psychoneuroses. Serentil® (mesoridazine besylate) is l0-[2(1-methyl-2-piperidyl) ethyl]-2-(methyl-sulfinyl)-phenothiazine [as the besylate].
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Tablet, 10 mg, for oral administration
ACTIVE INGREDIENT : mesoridazine (as the besylate), 10 mg. INACTIVE INGREDIENTS : acacia, carnauba wax, colloidal silicon dioxide, FD&C Red No. 40 aluminum lake, lactose, microcrystalline cellulose, povidone, sodium benzoate, starch, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide and other ingredients.
Tablet, 25 mg, for oral administration
ACTIVE INGREDIENT : mesoridazine (as the besylate), 25 mg. INACTIVE INGREDIENTS : acacia, carnauba wax, colloidal silicon dioxide, FD&C Red No. 40 aluminum lake, lactose, microcrystalline cellulose, povidone, sodium benzoate, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide and other ingredients.
Tablet, 50 mg, for oral administration
ACTIVE INGREDIENT : mesoridazine (as the besylate), 50 mg. INACTIVE INGREDIENTS : acacia, carnauba wax, colloidal silicon dioxide, FD&C Red No. 40 aluminum lake, gelatin, lactose, microcrystalline cellulose, povidone, sodium benzoate, starch, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide and other ingredients.
Tablet, 100 mg, for oral administration
ACTIVE INGREDIENT : mesoridazine (as the besylate), 100 mg. INACTIVE INGREDIENTS : acacia, carnauba wax, colloidal silicon dioxide, FD&C Red No. 40 aluminum lake, gelatin, lactose, microcrystalline cellulose, povidone, sodium benzoate, starch, stearic acid, sucrose, synthetic black iron oxide, talc, titanium dioxide and other ingredients.
Ampuls, 1 mL, for intramuscular administration
ACTIVE INGREDIENT : mesoridazine (as the besylate), 25 mg. INACTIVE INGREDIENTS : edetate disodium USP, 0.5 mg; sodium chloride USP, 7.2 mg; carbon dioxide gas (bone dry) q.s., water for injection USP, q.s. to 1 ml.
Concentrate, for oral administration
ACTIVE INGREDIENT : mesoridazine (as the besylate), 25 mg per mL. INACTIVE INGREDIENTS : alcohol, 0.61% by volume; citric acid; FD&C Red No. 40; flavors; methylparaben; propylparaben; purified water; sodium citrate, sorbitol.
Based upon animal studies, Serentil® (mesoridazine besylate), as with other phenothiazines, acts indirectly on reticular formation, whereby neuronal activity into reticular formation is reduced without affecting its intrinsic ability to activate the cerebral cortex. In addition, the phenothiazines exhibit at least part of their activities through depression of hypothalamic centers. Neurochemically, the phenothiazines are thought to exert their effects by a central adrenergic blocking action.
In clinical studies Serentil® (mesoridazine besylate) has been found useful in the following disease states:
Schizophrenia Serentil® (mesoridazine besylate) is effective in the treatment of schizophrenia. It substantially reduces the severity of emotional withdrawal, conceptual disorganization, anxiety, tension, hallucinatory behavior, suspiciousness and blunted affect in schizophrenic patients. As with other phenothiazines, patients refractory to previous medication may respond to Serentil® (mesoridazine besylate).
Behavioral Problems in Mental Deficiency and Chronic Brain Syndrome The effect of Serentil® (mesoridazine besylate) was found to be excellent or good in the management of hyperactivity and uncooperativeness associated with mental deficiency and chronic brain syndrome.
Alcoholism--Acute and Chronic Serentil® (mesoridazine besylate) ameliorates anxiety, tension, depression, nausea and vomiting in both acute and chronic alcoholics without producing hepatic dysfunction or hindering the functional recovery of the impaired liver.
Psychoneurotic Manifestations Serentil® (mesoridazine besylate) reduces the symptoms of anxiety and tension, prevalent symptoms often associated with neurotic components of many disorders, and benefits personality disorders in general.
As with other phenothiazines, Serentil® (mesoridazine besylate) is contraindicated in severe central nervous system depression or comatose states from any cause including drug induced central nervous system depression (see ).
Serentil® (mesoridazine besylate) is contraindicated in individuals who have previously shown hypersensitivity to the drug.
Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with neuroleptic (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 neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic 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 neuroleptic 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 neuroleptic treatment is withdrawn. Neuroleptic 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, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness 1) that is known to respond to neuroleptic 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 neuroleptics, 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® (mesoridazine besylate) 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® (mesoridazine besylate) and a concomitant high dose of a barbiturate.
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.
Usage in Children The use of Serentil® (mesoridazinebesylate) in children under 12 years of age is not recommended, because safe conditions for its use have not been established.
While ocular changes have not to date been related toSerentil® (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® (mesoridazine besylate). Since convulsive seizures have been reported, patients receiving anticonvulsant medication should be maintained on that regimen while receiving Serentil® (mesoridazine besylate).
Neuroleptic 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 neuroleptic 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.
INFORMATION FOR PATIENTS Given the likelihood that some patients exposed chronically to neuroleptics 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.
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.
Serentil® (mesoridazine besylate) has demonstrated a remarkably low incidence of adverse reactions when compared with other phenothiazine compounds.
Central Nervous System Drowsiness, Parkinson' 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 Hypotension and tachycardia have been reported. EKG changes have occurred in some instances (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, including prolongation of the Q-T interval, lowering and inversion of the T wave and appearance of a wave tentatively identified as a bifid T or a U wave have been observed in some patients receiving the phenothiazine tranquilizers, including Serentil® (mesoridazine besylate). To date, these appear to be due to altered repolarization and not related to myocardial damage. They appear to be reversible. While there is no evidence at present that these changes are in any way precursors of any significant disturbance of cardiac rhythm, it should be noted that sudden and unexpected deaths apparently due to cardiac arrest have occurred in patients previously showing characteristic electrocardiographic changes while taking the drug. The use of periodic electrocardiograms has been proposed but would appear to be of questionable value as a predictive device. Hypotension, rarely resulting in cardiac arrest, has been noted.
Extrapyramidal Symptoms Akathisia, agitation, motor restlessness, dystonic reactions, trismus, torticollis, opisthotonos, oculogyric crises, tremor, muscular rigidity, akinesia.
Tardive Dyskinesia Chronic use of neuroleptics may be associated with the development of tardive dyskinesia. The salient features of this syndrome are described in the 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 neuroleptics is withheld. It is generally believed that reversibility is more likely after short rather than long-term neuroleptic 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 neuroleptic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. This maneuver is critical, for neuroleptic 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.
Treatment of Acute Overdosage No specific antidote is known. The drug is not dialyzable. Treatment should include:
Marrs-Simon P.A. et al. ("Cardiotoxic Manifestations of Mesoridazine Overdose", Ann Emerg Med. 1988;17:1074-1078) describes the management of a 20 year old female who experienced severe cardiotoxicity following an overdose of mesoridazine. The paper also describes similar cases from the published literature.
The serum mesoridazine level in a 115 lb. patient following ingestion of 4.5 to 6.0 grams of Serentil® (mesoridazine besylate) was 2.5 mcg/mL. She was comatose, hypotensive, convulsing, and had ECG changes. Twenty-four hours later, after hemoperfusion with activated charcoal, the mesoridazine blood levels fell to 1.3 mcg/mL and the patient was normotensive and responsive.
The dosage of Serentil® (mesoridazine besylate) as in 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 level.
Schizophrenia For most patients, regardless of severity, a starting dose of 50 mg t.i.d. is recommended. The usual optimum total daily dose range is 100-400 mg per day.
Behavioral Problems in Mental Deficiency and Chronic Brain Syndrome For most patients a starting dose of 25 mg t.i.d. is recommended. The usual optimum total daily dose range is 75-300 mg per day.
Alcoholism For most patients the usual starting dose is 25 mg b.i.d. The usual optimum total daily dose range is 50-200 mg per day.
Psychoneurotic Manifestations For most patients the usual starting dose is 10 mg t.i.d. The usual optimum total daily dose range is 30-150 mg per day.
Injectable Form In those situations in which an intramuscular form of medication is indicated, Serentil® (mesoridazine besylate) 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.
Tablets 10 mg (NDC 0597-0020-01), 25 mg (NDC 0597-0021-01), 50 mg (NDC 0597-0022-01), and 100 mg (NDC 0597-0023-01) mesoridazine (as the besylate). Bottles of 100.
Ampuls 1 mL [25 mg mesoridazine (as the besylate)]. Boxes of 20 (NDC 0597-0027-02).
Concentrate Contains 25 mg mesoridazine (as the besylate) per mL, alcohol, USP, 0.61% by volume. Immediate containers: Amber glass bottles of 4 fl oz (118 mL) packaged in cartons of 12 bottles, with an accompanying dropper graduated to deliver 10 mg, 25 mg, and 50 mg of mesoridazine (as the besylate) (NDC 0597-0025-04).
Tablets: Below 86°F (30°C). Injection: Below 86°F (30°C); protect from light. Oral solution: Below 77°F (25°C); protect from light; dispense in amber glass bottles only.
The concentrate may be diluted with distilled water, acidified tap water, orange juice or grape juice.
Each dose should be diluted just prior to administration. Preparation and storage of bulk dilutions is not recommended.
Additional information available to physicians.
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Pharmacological studies in laboratory animals have established that Serentil® (mesoridazine besylate) has a spectrum of pharmacodynamic actions typical of a major tranquilizer. In common with other tranquilizers it inhibits spontaneous motor activity in mice, prolongs thiopental and hexobarbital sleeping time in mice and produces spindles and block of arousal reaction in the EEG of rabbits. It is effective in blocking spinal reflexes in the cat and antagonizes d-amphetamine excitation and toxicity in grouped mice. It shows a moderate adrenergic blocking activity in vitro and in vivo and antagonizes 5-hydroxytryptamine in vivo. Intravenously administered, it lowers the blood pressure of anesthetized dogs. It has a weak antiacetylcholine effect in vitro.
The most outstanding activity of Serentil® (mesoridazine besylate) is seen in tests developed to investigate antiemotive activity of drugs. Such tests are those in which the rat reacts to acute or chronic stress by increased defecation (emotogenic defecation) or tests in which "emotional mydriasis" is elicited in the mouse by an electric shock. In both of these tests Serentil® (mesoridazine besylate) is effective in reducing emotive reactions. Its ED 50 in inhibiting emotogenic defecation in the rat is 0.053 mg/kg (subcutaneous administration). Serentil® (mesoridazine besylate) has a potent antiemetic action. The intravenous ED 50 against apomorphine-induced emesis in the dog is 0.64 mg/kg. Serentil® (mesoridazine besylate), in common with other phenothiazines, demonstrates antiarrhythmic activity in anesthetized dogs.
Metabolic studies in the dog and rabbit with tritium labeled mesoridazine demonstrate that the compound is well absorbed from the gastrointestinal tract. The biological half-life of Serentil® (mesoridazine besylate) in these studies appears to be somewhere between 24 and 48 hours. Although significant urinary excretion was observed following the administration of Serentil® (mesoridazine besylate), these studies also suggest that biliary excretion is an important excretion route for mesoridazine and/or its metabolites.
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Chronic toxicity studies were conducted in rats and dogs. Rats were administered Serentil® (mesoridazine besylate) orally seven days per week for a period of seventeen months in doses up to 160 mg/kg per day. Dogs were administered Serentil® (mesoridazine besylate) orally seven days per week for a period of thirteen months. The daily dosage of the drug was increased during the period of this test such that the "top-dose" group received a daily dose of 120 mg/kg of mesoridazine for the last month of the study.
Untoward effects that occurred upon chronic administration of high dose levels included:
Rats Reduction of food intake, slowed weight gain, morphological changes in pituitary-supported endocrine organs, and melanin-like pigment deposition in renal tissues.
Dogs Emesis, muscle tremors, decreased food intake and death associated with aspiration of oral-gastric contents into the respiratory system.
Increased intrauterine resorptions were seen with Serentil® (mesoridazine besylate) in rats at 70 mg/kg and in rabbits at 125 mg/kg but not at 60 and 100 mg/kg, respectively. No drug related teratology was suggested by these reproductive studies.
Local irritation from the intramuscular injection of Serentil® (mesoridazine besylate) was of the same order of magnitude as with other phenothiazines.
SE-PI-7/96 Rev
Manufactured by:
Sandoz Pharmaceuticals Corporation,
East Hanover, NJ 07936
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877