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The mode of action of Sandomigran in the prophylactic management of vascular headaches has not yet been elucidated. Sandomigran is a serotonin and histamine antagonist, with sedative and weak anticholinergic effects. In man, some radioactivity was noted in blood at two hours, after a single oral dose of 1 mg of labelled Sandomigran and peak concentrations occurred at 5 to 7 hours. Blood concentrations decreased slowly thereafter and small but significant amounts were still found after 96 hours. No data on metabolism and distribution are available. Excretion was relatively slow. In three subjects, the total excretion of the drug over a period of 120 hours accounted for 86% of the administered dose. The biological half-life averaged 26 hours.
Sandomigran has been found useful in the prophylactic management of vascular headaches. In various clinical trials, about 1/3 to 2/3 of patients with migraine experienced some benefit from Sandomigran and in most trials it was more effective than placebo in reducing the frequency or severity of attacks. Therefore, a therapeutic trial of Sandomigran may be indicated for prophylactic management of severe vascular headaches which are difficult to control. However, the drug is of no value in the treatment of the acute migrainous attack or in the treatment of tension headaches. As with other antiserotonin agents, the benefits of Sandomigran decrease after a period of time in a certain number of patients.
Although peripheral anticholinergic effects are minimal in the recommended doses, anticholinergic agents, including Sandomigran, are contraindicated in patients taking MAO inhibitors, in patients with pyloroduodenal obstruction and stenosing pyloric ulcer. Sandomigran is contraindicated for patients who have a known sensitivity to the drug. Until further studies are completed, the drug is not recommended for children under the age of 12.
In view of the weak anticholinergic effect of Sandomigran, caution is required in patients with narrow-angle glaucoma or with urinary retention (e.g., prostatic hypertrophy). In general, patients with narrow-angle glaucoma should not be given drugs with possible anticholinergic effects, unless they are required and the patient is under special care and medical supervision for this condition. Since drowsiness may occur with Sandomigran, sensitive patients should be cautioned against activities requiring rapid and precise responses such as driving an automobile or operating dangerous machinery until their response has been determined. Since the effects of antihistamines can potentiate those of other drugs affecting the CNS, patients should be cautioned against drinking alcoholic beverages or taking hypnotics, sedatives, psychotherapeutic agents or other drugs with CNS depressant effects during Sandomigran therapy. Since it is desirable to keep drug administration to a minimum during pregnancy, Sandomigran should be given only when the benefits derived from treatment exceed the possible risks to mother and fetus. Some patients developed tolerance to Sandomigran with prolonged use of the drug. Increase in dosage may overcome this tolerance. After prolonged use hepatotoxic effects might occur and patients should be advised to report for adequate laboratory evaluation. Patients with diabetes, cardiovascular disease and known or suspected impaired renal or hepatic function should be given Sandomigran with caution, and appropriate laboratory tests should be done at regular intervals. Lens opacities occurred in 2 cases but did not appear to be drug-related. However, it is recommended that any impairment in vision be reported to the attending physician for further investigation. As with all drugs, Sandomigran should be kept out of the reach of children.
Increased appetite, weight gain and drowsiness are the most frequent side effects. An appropriate diet should be recommended by the physician for patients benefiting from the drug but gaining excessive weight. A gradual increase in the dosage of Sandomigran is recommended to minimize or reduce the incidence of drowsiness. Relative to the occurrence of the above-mentioned reactions the following adverse effects have been less frequently observed: fatigue, nausea, dizziness, headache, confusion, edema, hypotension, depression, weakness, epigastric distress, dry mouth, nervousness, impotence and muscle pain.
The symptoms of overdosage are sedation, drowsiness, tachycardia, ataxia, nausea and CNS depression. Antihistamine poisoning in children exhibits excitation, hallucinations, ataxia, in coordination, convulsions, fixed dilated pupils, flushed facies, and fever, leading to coma and cardiorespiratory collapse. In adults, drowsiness precedes excitement, convulsions and postictal depression. If vomiting has not occurred spontaneously, induce emesis or perform gastric lavage. Supportive measures should be instituted to maintain respiration and vital signs should be monitored; benzodiazepines for excitatory states or convulsions. Analeptics should be avoided.
Treatment should be initiated with a dose of 0.5 mg at bedtime. This is increased gradually to 0.5 mg 3 times daily. Since vascular headache is a paroxysmal but basically chronic disorder, treatment must extend over an adequate period of time in order to obtain maximal benefit. While some patients have responded rather quickly, most investigators agree that a 4-week trial period should be instituted to determine the true efficacy of Sandomigran in specific cases. The periodic nature of the disorder will have to be considered in determining when and for how long therapy should be maintained. Since some investigators have observed a change in headache pattern after several months of therapy, a drug-free interval is advisable to reassess the necessity of continuing treatment. The dosage should be reduced gradually during the last 2 weeks of each treatment course to avoid a "headache rebound". The average maintenance dose is 1.5 mg/day. The dosage range is 1 to 6 mg/day. DOSAGE FORMS: Sandomigran: Each ivory, sugar-coated tablet contains: 0.5 mg of Sandomigran as the hydrogen maleate. Available in bottles of 100 and 500. Sandomigran DS: Each whitish, compressed tablet contains: 1 mg of Sandomigran as the hydrogen maleate. Available in bottles of 100.
Sandomigran is a white to yellowish crystalline powder, readily soluble in water and organic solvents, and is designated chemically as 4 -(9,10-Dihydro-4H-benzo[4,5] cycloheptal [1,2-b]thien-4-ylidene)-1- methylpiperidine hydrogen maleate. It has the following structural formula: A variety of in vitro and in vivo laboratory investigations indicated antagonistic or blocking actions of Sandomigran towards serotonin and histamine and relatively weak anticholinergic activity. Sandomigran had very little effect as an epinephrine or bradykinin antagonist. Tests for potentiation of barbiturate anesthesia and inhibition of locomotion in the mouse indicated that Sandomigran had weak sedative properties. However, Sandomigran was found to be more active in rats than either imipramine or amitriptyline in the antagonism of tetrabenazine-induced depression. Sandomigran given orally (40 mg/kg), subcutaneously (5 mg/kg) and intravenously (1.25 mg/kg) to male Rhesus monkeys produced slight sedation, but no change in cardiac or respiratory rates during the subsequent four hours. Sandomigran (1 to 10 mg/kg i.v.) rapidly produced hypotension in dogs; reversion to normal pressures occurred within 30 minutes. Immediate increased heart rates were produced by the maximal dose but they quickly subsided. Blood pressure response to adrenaline was enhanced (2 mg/kg i.v. ). Blood sugar studies of normal and alloxan-treated rats did not indicate any hypoglycemic effects of Sandomigran.. Pharmacokinetics: Studies in dogs with tritium-labelled Sandomigran indicated that the drug is well absorbed. Fifty percent of the label was excreted via the kidneys and up to 33% in the feces within 24 hours. After 72 hours, 25% still had not been excreted.
Acute Toxicity: Acute toxicity studies were conducted in mice, rats and rabbits: LD50 (mg/kg) Mouse Rat Rabbit Oral I.V. Oral I.V. Oral I.V. 880 43 1500 17 700 19 "102 "2 "330 "1 "252 "2 Signs of toxicity after oral administration to mice and rats included motor disturbances (ataxia, jumping, twitching, sporadic convulsions, hyperreflexia), ventral decubitus, prostration, stupor, dyspnea and bradypnea. The signs lasted several hours in mice and up to 60 hours in rats. In rabbits, ventral decubitus, weakness and drooping of the head were observed. In all three species prior to death, ataxia, ventral or lateral decubitus, convulsions, dyspnea, paralysis and cyanosis were observed. Chronic Toxicity: Chronic oral toxicity studies were done in both rats and dogs for durations of 26 weeks and two years. Sandomigran was administered orally to rats at 3 dosage levels (5, 16 and 55 mg/kg/day) for 26 weeks. Weights of livers, adrenals and thyroids were increased in the high-dose group and there were mild signs of dose-dependent, centrolobular hepatic lipidosis and thyroidal hyperactivity in the mid and high-dose groups. There was no evidence of cholestasis. Doses of 3, 9 and 27 mg/kg/day were administered to rats for 2 years. Cellular and clinical hematologic, ophthalmoscopic and histologic examinations did not indicate drug-induced abnormalities in animals sacrificed after 16 months. The only changes observed after 2 years of treatment were increased liver and kidney weights in high-dose females and increased liver weights in mid-dose females. Sandomigran was administered to dogs at levels of 3, 10 and 30 mg/kg/day for 26 weeks. Increased relative organ weights of spleens, livers and thyroids were observed in the mid- and high-dose dogs. Microscopy indicated thyroidal hyperactivity and increased hepatic cellular turnover in a high-dose dog. Serum alkaline phosphatase was slightly increased in one mid-dose and one high-dose dog at the end of the experiment. There was no evidence of cholestasis. Doses of 1, 3 and 9 mg/kg/day also were administered to dogs for 2 years. Mean SGPT values were increased in high-dose dogs compared to control means. Other liver function tests were within normal range. The effect was more pronounced in males. Concomitant histopathologic changes were not evident. Reproductive Studies: Sandomigran was administered orally at the dose levels of 3, 10, and 30 mg/kg/day to female rats and rabbits from the 6th to 15th, and 6th to 18th days of pregnancy respectively. The animals were sacrificed at term and examined together with their fetuses. Embryotoxic or teratogenic drug effects could not be detected in either animal species. Male and female fertility tests were done. Conception rates, litter sizes and litter weights were not affected.
CLINICAL
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