LOCAL PRODUCT DOCUMENT PFIZER VENEZUELA, S.A.

1. MEDICINAL PRODUCT BRAND NAME SERMION®

2. CUALITATIVE AND CUANTITATIVE COMPOSITION Every coated tablet contains 10 and 30 mg of Nicergoline.

3. PHARMACEUTICAL FORM Coated tablets.

4. CLINICAL PARTICULARS

4.1 THERAPEUTIC INDICATIONS 1. Cerebrovascular insufficiency of senile source. 2. Peripheral Vasodilator. 3. Treatment of Senile dementia from light to medium level of vascular type and Alzheimer.

4.2 DOSAGE 1. 30 mg/day and Cerebrovascular insufficiency of senile source. 2. 30 mg twice per day, as Peripheral Vasodilator and on treatment of Senile dementia from light to medium level of vascular type and Alzheimer.

4.3 CONTRAINDICATIONS Hypersensitivity to Nicergoline.

4.4 WARNINGS AND PRECAUTIONS Nicergoline, as other adrenergic blocking agents, may significantly reduce blood pressure (arterial hypotension) in some patients. Likewise, as other sympatholytic agents, it has been associated to different degrees of sexual impotence and libido reduction.

Do not administer this product if pregnant, if pregnancy is suspected or during breast-feeding.

4.5 ADVERSE EFFECTS Drowsiness, cephalea, tiredness, constipation, pyrosis, vomiting, diarrhea, facial flushing, sexual impotence and libido reduction, uric acid and L.H increment.

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacokinetics Properties A) Onset and Duration - Benign prostatic hypertrophy, intramuscular: 2 hours. - Two hours after a single 4-mg intramuscular injection, average peak and mean urinary flow rates increased by 50% and 77%, respectively.

B) Drug Concentration Levels - ORAL: 1 to 1.5 hours. - Maximal blood levels are reached 1 to 1.5 hours after oral dosing. - The mean maximum plasma concentrations after daily administration of a 30-mg film-coated tablet and a 30-mg effervescent tablet solution are 88 ng/mL and 41 ng/mL, respectively). - Mean area under the plasma concentration-time curve (AUC) for 24 hours was bioequivalent for a 60-mg controlled-release formulation given once daily (938 mcg/L) and a standard 30-mg tablet given twice daily (949 mcg/L) in 22 healthy subjects.

5.2 ADME

5.2.1 Absorption ORAL: 90% to 100%.

5.2.2 Distribution Protein Binding 82% to 87% (in vitro).

5.2.3 Metabolism - Blood, hydrolyzed by esterases: Nicergoline is almost completely metabolized by hydrolysis (presumably in the blood and other tissues containing esterases), by demethylation, and by glucuronidation in the liver and possibly other tissues - Liver, glucuronidation: Ninety percent or more of a nicergoline dose is rapidly metabolized by three reactions: First, rapid hydrolysis occurs in the blood and other tissues containing esterases. Next, demethylation of both the unchanged drug and of the hydrolysis product occurs. Thirdly, glucuronidation of the hydrolysis products takes place; however, this is a minor metabolic pathway.

Metabolites - 10-Methoxy-6-methylergoline-8, beta-methanol (MDL), active: The major active metabolite is MDL. Three and one-half hours after 15-mg oral doses in healthy volunteers, the MDL concentration in plasma was 30 ng/mL, the concentrations of 1-MMDL and 1-OHMMDL were 5 to 7 ng/mL. - 10-Methoxy-1,6-dimethylergoline-8, beta-methanol (1-MMDL) (activity unspecified): 1-Hydroxymethyl-10-methoxy-6-methylergoline-8, beta- methanol (1-OHMMDL) (activity unspecified).

5.2.4 Excretion - Kidney: 66% to 80% Two-thirds of an intravenous dose was excreted in the urine within 3 days in two healthy subjects. - FECES, 10% to 20%

5.2.5 Elimination Half-life - Parent Compound 2.5 hours. - Metabolites - 10-Methoxy-6-methylergoline-8, beta-methanol (MDL), 12 to 17 hours. - 10-Methoxy-1,6-dimethylergoline-8, beta-methanol (1-MMDL), 2 to 4 hours.

6. Mechanism of Action/Pharmacology

A) MECHANISM OF ACTION Nicergoline is a semisynthetic ergot derivative with actions similar to ergoloid mesylates. Various actions have been attributed to nicergoline including alpha- adrenergic blocking activity, vasodilating activity, serotonergic and dopaminergic effects, improved energy metabolism during and after cerebral ischemia and hypoxia, antiplatelet activity, and improvement of EEG patterns. It is unknown what effect these actions have on the treatment of cerebral insufficiency. Although clinical trials have demonstrated some favorable effects in treating symptoms associated with cerebrovascular and peripheral vascular insufficiency and other conditions, the clinical efficacy of nicergoline is still unclear (Yamagami et al, 1992; Caine et al, 1984; Arcamone et al, 1972; Boismare & Lefrancois, 1980; Moretti, 1979).

B) CIRCULATORY EFFECTS After 2 mg IV nicergoline, cerebral blood flow increased in 7 and decreased in 4 of 13 patients with moderate multi-infarct dementia or TIAs (Iliff et al, 1977). There were no significant changes in blood pressure or PaCO2. The authors feel this indicates a vasodilator action. Other researchers have disputed the vasodilator action of nicergoline.

C) EEG EFFECTS Nicergoline has favorable EEG effects by decreasing delta and theta activities, increasing alpha and slow beta activities, and tending to decrease fast beta activities. These changes indicate improved vigilance, which is the adaptive ability of the CNS. Some investigators have been able to demonstrate that these EEG changes were associated with clinical improvements.

D) METABOLIC EFFECTS Animal studies have demonstrated that nicergoline may improve energy metabolism during and after cerebral hypoxia and ischemia by inhibiting phosphodiesterase and stimulating adenyl cyclase resulting in higher concentrations of cyclic AMP. A possible clinical advantage is that its protective action against the effects of cerebral ischemia may be due to the effect on cellular metabolism or stability of cell membranes, not vasodilatation.

E) PLATELET EFFECTS

Nicergoline is a strong inhibitor of platelet aggregation in vitro. It inhibits prostaglandin production induced by thrombin or collagen but not by arachidonic acid. It appears to have strong antiphospholipase activity. Nicergoline is able to induce some changes in platelet ultrastructure, mainly a depolymerization of microtubules. Its antiphospholipase activity could be a consequence of this structural effect. Nicergoline does not elevate cAMP in platelets (Lagarde et al, 1980). In vitro, nicergoline also inhibits epinephrine- induced platelet aggregation and is synergistic with prostacyclin in inhibiting epinephrine-induced platelet aggregation.

F) SYMPATHOLYTIC EFFECTS Nicergoline is an effective and potent blocker of alpha-receptors in the canine urethra and human prostate. Its proposed advantage over other alpha-blockers is that it is more selective for alpha-1 postsynaptic receptors than for alpha-2 presynaptic receptors; therefore, it causes no tachycardia. It has been proposed that nicergoline has an immediate peripheral alpha-adrenergic blocking effect which decreases arterial blood pressure and a delayed central action which may lead to bradycardia and decreased blood pressure.

7. STORAGE CONDITIONS Store at temperatures under 30°C.

Document revised and approved by:

Regulatory Affairs Manager Medical Director

Dra. Esther Date: Dr. Juan Date: Avila Marques

Signature: Signature: