CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. There is no specific evidence which clearly establishes the mechanism by which ergoloid mesylates preparations produce mental effects, nor is there conclusive evidence that the drug particularly affects cerebral arteriosclerosis or cerebrovascular insufficiency.. Pharmacokinetic Properties. Pharmacokinetic studies have been performed in normal volunteers with the help of radiolabelled drug as well as employing specific radioimmunoassay technique. From the urinary excretion quotient of orally and intravenously administered tritium-labelled ergoloid mesylates the absorption of ergoloid was calculated to be 25%. Following oral administration, peak levels of 0.5 ngEq/mL/mg were achieved within 1.5-3 hr. Bioavailability studies with the specific radioimmunoassay confirm that ergoloid is rapidly absorbed from the gastrointestinal tract, with mean peak levels of 0.05-0.13 ng/mL/mg (with extremes of 0.03 and 0.18 ng/mL/mg) achieved within 0.6-1.3 hr (with extremes of 0.4 and 2.8 hr). The finding of lower peak levels of ergoloid compared to the total drug-metabolite composite is consistent with considerable first pass liver metabolism, with less than 50% of the therapeutic moiety reaching the systemic circulation. The elimination of radioactivity, representing ergoloid plus metabolites bearing the radiolabel, was biphasic with half-lives of and 13 hr. The mean half-life of unchanged ergoloid in plasma is about 2.6-5.1 hr; after half-lives ergoloid plasma levels are less than 10% of radioactivity levels, and by 24 hr no ergoloid is detectable.Bioequivalence studies were performed comparing ergoloid mesylates oral tablets (administered orally) with ergoloid mesylates sublingual tablets (administered sublingually). The oral tablet and sublingual tablet were shown to be bioequivalent.

DESCRIPTION SECTION.

DESCRIPTION. Each tablet for oral use contains ergoloid mesylates USP; mixture of the methanesulfonate salt of the following hydrogenated alkaloids:RDihydroergocornine-CH(CH3)2 Dihydroergocristine-CH2C6H5 Dihydro--ergocryptine-CH2CH(CH3)2 Dihydro--ergocryptine-CH(CH3)CH2CH3 C31H41N5O5 CH4O3S (dihydroergocornine mesylate) 659.79C35H41N5O5 CH4O3S (dihydroergocristine mesylate) 707.84C32H43N5O5 CH4O3S (dihydro--ergocryptine mesylate) 673.82C32H43N5O5 CH4O3S (dihydro--ergocryptine mesylate) 673.821 mgDihydroergocristine mesylate0.333 mgDihydroergocornine mesylate0.333 mgDihydroergocryptine mesylateexists as mixture of alpha and beta isomers in ratio of 2:1 0.333 mgInactive ingredients for oral tablets are: butylated hydroxyanisol, corn starch, hydrogenated vegetable oil, lactose, mannitol, polyvinyl pyrrolidone, stearic acid and talc.. Chemical Structure.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Ergoloid mesylates tablets, USP (oral) mg are white, round, unscored, debossed MP 20Bottles of 50 NDC 53489-281-02Bottles of 100 NDC 53489-281-01Bottles of 250 NDC 53489-281-03Bottles of 500 NDC 53489-281-05Bottles of 1000 NDC 53489-281-10. Store at 20 to 25C (68 to 77F).[See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

INDICATIONS & USAGE SECTION.

INDICATIONS. proportion of individuals over sixty who manifest signs and symptoms of an idiopathic decline in mental capacity (i.e., cognitive and interpersonal skills, mood, self-care, apparent motivation) can experience some symptomatic relief upon treatment with ergoloid mesylates preparations. The identity of the specific trait(s) or condition(s), if any, which would usefully predict response to ergoloid mesylates therapy is not known. It appears, however, that those individuals who do respond come from groups of patients who would be considered clinically to suffer from some ill-defined process related to aging or to have some underlying dementing condition (i.e., primary progressive dementia, Alzheimers dementia, senile onset, multi-infarct dementia).Before prescribing ergoloid mesylates, the physician should exclude the possibility that the patients signs and symptoms arise from potentially reversible and treatable condition. Particular care should be taken to exclude delirium and dementiform illness secondary to systemic disease, primary neurological disease, or primary disturbance of mood. Ergoloid mesylates preparations are not indicated in the treatment of acute or chronic psychosis, regardless of etiology (see CONTRAINDICATIONS).The decision to use ergoloid mesylates in the treatment of an individual with symptomatic decline in mental capacity of unknown etiology should be continually reviewed since the presenting clinical picture may subsequently evolve sufficiently to allow specific diagnosis and specific alternative treatment. In addition, continued clinical evaluation is required to determine whether any initial benefit conferred by ergoloid mesylates therapy persists with time.The efficacy of ergoloid mesylates was evaluated using special rating scale known as the SCAG (Sandoz Clinical Assessment-Geriatric). The specific texts on this scale on which modest but statistically significant changes were observed at the end of twelve weeks include: mental alertness, confusion, recent memory, orientation, emotional lability, self-care, depression, anxiety/fears, cooperation, sociability, appetite, dizziness, fatigue, bothersome(ness), and an overall impression of clinical status.

PHARMACOKINETICS SECTION.

Pharmacokinetic Properties. Pharmacokinetic studies have been performed in normal volunteers with the help of radiolabelled drug as well as employing specific radioimmunoassay technique. From the urinary excretion quotient of orally and intravenously administered tritium-labelled ergoloid mesylates the absorption of ergoloid was calculated to be 25%. Following oral administration, peak levels of 0.5 ngEq/mL/mg were achieved within 1.5-3 hr. Bioavailability studies with the specific radioimmunoassay confirm that ergoloid is rapidly absorbed from the gastrointestinal tract, with mean peak levels of 0.05-0.13 ng/mL/mg (with extremes of 0.03 and 0.18 ng/mL/mg) achieved within 0.6-1.3 hr (with extremes of 0.4 and 2.8 hr). The finding of lower peak levels of ergoloid compared to the total drug-metabolite composite is consistent with considerable first pass liver metabolism, with less than 50% of the therapeutic moiety reaching the systemic circulation. The elimination of radioactivity, representing ergoloid plus metabolites bearing the radiolabel, was biphasic with half-lives of and 13 hr. The mean half-life of unchanged ergoloid in plasma is about 2.6-5.1 hr; after half-lives ergoloid plasma levels are less than 10% of radioactivity levels, and by 24 hr no ergoloid is detectable.Bioequivalence studies were performed comparing ergoloid mesylates oral tablets (administered orally) with ergoloid mesylates sublingual tablets (administered sublingually). The oral tablet and sublingual tablet were shown to be bioequivalent.