Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Fontus Health Ltd, 60 Lichfield Street, Walsall, WS4 2BX, United Kingdom
Pharmacotherapeutic group: Antiparkinsonian agent and anti-influenzal virostatic
ATC code: N04BB01
Trilasym specifically inhibits the replication of influenza A viruses at low concentrations.
If using a sensitive plaque-reduction assay, human influenza viruses, including H1N1, H2N2 and H3N2 subtypes, are inhibited by ≤0.4µg/ml of amantadine. Trilasym inhibits an early stage in viral replication by blocking the proton pump of the M2 protein in the virus.
This has two actions; it stops the virus uncoating and inactivates newly synthesised viral hemagglutinin. Effects on late replicative steps have been found for representative avian influenza viruses. Data from tests with representative strains of influenza A virus indicate that amantadine is likely to be active against previously unknown strains, and could be used in the early stages of an epidemic, before a vaccine against the causative strain is widely available.
The mechanism of action of amantadine in herpes zoster has not been fully characterised.
Trilasym has been shown to be a low affinity antagonist at the N-methyl-D-aspartate (NDMA) subtype of glutamate receptors. Over activity of glutamatergic neurotransmission has been implicated in the generation of parkinsonian symptoms. The clinical efficacy of amantadine is thought to be mediated through its antagonism at the NDMA subtype of glutamate receptors. In addition, amantadine may also exert some anticholinergic activity.
Trilasym is absorbed slowly but almost completely.
Peak plasma concentrations of approximately 250 ng/ml and 500 ng/ml are seen 3 to 4 hours after single oral administration of 100 mg and 200 mg amantadine, respectively. Following repeated administration of 200 mg daily, the steady state plasma concentration settles at 300 ng/ml within 3 days.
Trilasym 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 10 L/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.
Trilasym is metabolised to a minor extent, principally by Nacetylation.
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 Trilasym 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.
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 100 mg daily for 14 days raised the plasma concentration into the toxic range.
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. This is 33-fold the recommended dose of 100 mg for influenza. The maximum recommended dose, of 400 mg in Parkinson’s disease, is less than 6 mg/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.
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