Symmetrel Capsules Ref.[2494] Active ingredients: Amantadine

Absorption: Amantadine is absorbed slowly but almost completely. Peak plasma concentrations of approximately 250ng/ml and 500ng/ml are seen 3 to 4 hours after single oral administration of 100mg and 200mg amantadine, respectively. Following repeated administration of 200mg daily, the steady-state plasma concentration settles at 300ng/ml within 3 days.

Distribution: Amantadine accumulates after several hours in nasal secretions and crosses the blood-brain barrier (this has not been quantified). In vitro, 67% is bound to plasma proteins, with a substantial amount bound to red blood cells. The concentration in erythrocytes in normal healthy volunteers is 2.66 times the plasma concentration. The apparent volume of distribution is 5 to 10L/kg, suggesting extensive tissue binding. This declines with increasing doses. The concentrations in the lung, heart, kidney, liver and spleen are higher than in the blood.

Biotransformation: Amantadine is metabolised to a minor extent, principally by N-acetylation.

Elimination: The drug is eliminated in healthy young adults with a mean plasma elimination half-life of 15 hours (10 to 31 hours). The total plasma clearance is about the same as renal clearance (250ml/min). The renal amantadine clearance is much higher than the creatinine clearance, suggesting renal tubular secretion. After 4 to 5 days, 90% of the dose appears unchanged in urine. The rate is considerably influenced by urinary pH: a rise in pH brings about a fall in excretion.

Characteristics in special patient populations

Elderly patients: compared with healthy young adults, the half-life may be doubled and renal clearance diminished. Tubular secretion diminishes more than glomerular filtration in the elderly. In elderly patients with renal impairment, repeated administration of 100mg daily for 14 days raised the plasma concentration into the toxic range.

Renal impairment: amantadine may accumulate in renal failure, causing severe side effects. The rate of elimination from plasma correlates to creatinine clearance divided by body surface area, although total renal elimination exceeds this value (possibly due to tubular secretion). The effects of reduced kidney function are dramatic: a reduction of creatinine clearance to 40ml/min may result in a five-fold increase in elimination half-life. The urine is the almost exclusive route of excretion, even with renal failure, and amantadine may persist in the plasma for several days. Haemodialysis does not remove significant amounts of amantadine, possibly due to extensive tissue binding.

Reproductive toxicity studies were performed in rats and rabbits. In rat oral doses of 50 and 100 mg/kg proved to be teratogenic. The maximum recommended dose of 400mg is less than 6mg/kg.

There are no other pre-clinical data of relevance to the prescriber which are additional to those already included in other sections of the Summary of Product Characteristics.