Serentil (Mesoridazine Besylate) - Indications and Dosage

INDICATIONS

Serentil^® (mesoridazine besylate) is indicated for the management of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Due to the risk of significant, potentially life-threatening, proarrhythmic effects with Serentil treatment, Serentil should be used only in patients who have failed to respond adequately to treatment with appropriate courses of 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 (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.

DOSAGE AND ADMINISTRATION

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.

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.

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.

HOW SUPPLIED

Tablets mesoridazine (as the besylate).

Bottles of 100.

      10 mg………………………………………………………………NDC 0597-0020-01

      25 mg………………………………………………………………NDC 0597-0021-01

      50 mg………………………………………………………………NDC 0597-0022-01

      100 mg……………………………………………………………..NDC 0597-0023-01

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

STORAGE

Tablets: Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF).

[See USP Controlled Room Temperature]

Dispense in a tight container (USP).

Injection: Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF).

[See USP Controlled Room Temperature]

Dispense in a tight container (USP); protect from light.

Oral Solution: Store below 77ºF (25ºC); protect from light; dispense in amber glass bottles only.

      The concentrate may be diluted with distilled 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.

PHARMACOLOGY

Pharmacological studies in laboratory animals have established that Serentil^® (mesoridazine besylate) has a spectrum of pharmacodynamic actions typical of an antipsychotic. In common with other antipsychotics 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 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 (emetogenic defecation) or tests in which “emotional mydriasis” is elicited in the mouse by an electric shock. In both of these tests Serentil is effective in reducing emotive reactions. Its ED₅₀ in inhibiting emetogenic defecation in the rat is 0.053 mg/kg (subcutaneous administration). Serentil has a potent antiemetic action. The intravenous ED₅₀ against apomorphine-induced emesis in the dog is 0.64 mg/kg. Serentil, 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 in these studies appears to be somewhere between 24 to 48 hours. Although significant urinary excretion was observed following the administration of Serentil, these studies also suggest that biliary excretion is an important excretion route for mesoridazine and/or its metabolites.

Toxicity Studies

      Acute LD ₅₀ (mg/kg):

Route	Mouse	Rat	Rabbit	Dog
Oral	560±62.5	644±48	MLD=800	MLD=800
I.M.	-	509M	405	-
		584F
I.V.	26±0.08	-	-	-

Chronic toxicity studies were conducted in rats and dogs. Rats were administered Serentil orally seven days per week for a period of seventeen months in doses up to 160 mg/kg per day. Dogs were administered Serentil 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 which occurred upon chronic administration of high dose-levels included: