AMANTADINE 100 UNIMED

Indications

• Influenza A virus infection
• Parkinson's disease
• Drug-induced extrapyramidal symptoms

Dosage

Children: Refer to the BNF for Children for appropriate dosing in paediatric populations.

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated.

Mechanism of action

Amantadine's antiviral mechanism involves interference with the M2 protein of the influenza A virus, which functions as an ion channel necessary for viral uncoating and replication. By inhibiting this ion channel, amantadine prevents the disassembly of the virus and regulates the ionic environment critical for viral replication. Additionally, for its antiparkinsonian effects, amantadine appears to increase dopamine release in the brain and stimulate norepinephrine responses, although its precise action in this context is not fully elucidated.

Pharmacodynamics

Amantadine exhibits both antiviral and antiparkinsonian pharmacological effects. As an antiviral agent, it inhibits the replication of influenza A virus. As an antiparkinsonian agent, it is often used in conjunction with L-DOPA to counteract the decline in response typically seen with prolonged L-DOPA therapy. Unlike many other antiparkinsonian medications, amantadine does not have anticholinergic activity, making it a suitable option for certain patients.

Pharmacokinetics

Amantadine is well absorbed from the gastrointestinal tract, and its bioavailability is approximately 90%. It has a volume of distribution of about 4-5 L/kg, indicating extensive tissue distribution. The drug is primarily excreted unchanged in the urine, with renal clearance being a significant route of elimination. The half-life of amantadine is approximately 15 hours, but this can be prolonged in patients with renal impairment.

Adverse effects

• Nausea
• Vomiting
• Insomnia
• Dizziness
• Anxiety
• Confusion
• Hallucinations

Interactions

• amantadine+memantine: Moderate (increases risk of cnstoxicity)

Precautions

• Use with caution in patients with a history of seizures
• Use with caution in patients with renal impairment
• Discontinue if significant CNS effects occur

Pregnancy

Amantadine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data on human use.

Breast-feeding

Amantadine is excreted in breast milk, and caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from direct light. Keep out of reach of children.

Formulations

• Capsules
• Tablets
• Oral solution

Indications

• Parkinson's disease
• Drug-induced movement disorders
• Fatigue in multiple sclerosis (off-label use)
• Influenza A prophylaxis (not recommended)

Dosage

Children: Dosage for paediatric patients should be obtained from the BNF for Children, as specific dosing guidelines are not provided here.

Adults: The usual adult dose is 100 mg daily for the treatment of Parkinson's disease. For fatigue in multiple sclerosis, the dose should be initiated by a specialist and may vary based on individual response.

Mechanism of action

Amantadine increases the release of dopamine and inhibits its reuptake, thereby enhancing dopaminergic neurotransmission. It also has antagonistic effects on NMDA (N-methyl-D-aspartate) receptors, which may contribute to its efficacy in managing symptoms of Parkinson’s disease and movement disorders.

Pharmacodynamics

The pharmacodynamic effects of amantadine include improvement in motor function in Parkinson's disease, reduction in fatigue in multiple sclerosis, and potential antiviral activity against influenza A. The drug has a relatively rapid onset of action, with effects noticeable within days of administration.

Pharmacokinetics

Amantadine is well absorbed orally and reaches peak plasma concentrations within 2 to 6 hours. It has a volume of distribution of approximately 4-5 L/kg. The drug is primarily excreted unchanged in the urine, with a half-life of about 10 to 30 hours depending on renal function. Dosing adjustments may be necessary in patients with renal impairment.

Contra-indications

• Epilepsy
• History of gastric ulceration

Adverse effects

• Dizziness
• Dry mouth
• Hallucinations
• Headache
• Hyperhidrosis
• Lethargy
• Mood alterations
• Movement disorders
• Myalgia
• Nausea
• Palpitations
• Peripheral oedema
• Postural hypotension
• Skin reactions
• Sleep disorders
• Slurred speech
• Tremor
• Vomiting
• Reddish-brown urine

Interactions

• Dopamine receptor agonists
• Concomitant use with levodopa
• Entacapone and standard-release co-careldopa or co-beneldopa

Precautions

• Confused or hallucinatory states
• Congestive heart disease (may exacerbate oedema)
• Elderly patients may develop tolerance to effects
• Management of excessive daytime sleepiness should focus on underlying causes
• Counsel patients on improving sleep behaviour

Pregnancy

There are no adequate and well-controlled studies in pregnant women; use only if clearly needed.

Breast-feeding

Avoid; amantadine is present in milk and may cause toxicity in the infant.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• 100 mg tablets
• 50 mg/12.5 mg/200 mg tablets
• 125 mg/31.25 mg/200 mg tablets
• 100 mg/25 mg/200 mg tablets

Mechanism of action

The mechanism of its antiparkinsonic effect is not fully understood, but it appears to be releasing dopamine from the nerve endings of the brain cells, together with stimulation of norepinephrine response. It also has NMDA receptor antagonistic effects. The antiviral mechanism seems to be unrelated. The drug interferes with a viral protein, M2 (an ion channel), which is needed for the viral particle to become "uncoated" once it is taken inside the cell by endocytosis. Amantadine, like rimantadine, inhibits viral replication by interfering with the influenza A virus M2 protein, an integral membrane protein. The M2 protein of influenza A functions as a ion channel and is important in at least 2 aspects of virus replication, disassembly of the infecting virus particle and regulation of the ionic environment of the transport pathway. By interfering with the ion channel function of the M2 protein, amantadine inhibits 2 stages in the replicative cycle of influenza A. Early in the virus replicative cycle, amantadine inhibits uncoating of the virus particle, presumably by inhibiting the acid-mediated dissociation of the virion nucleic acid and proteins, which prevents nuclear transport of viral genome material. Amantadine also prevents viral maturation in some strains of influenza A (e.g., H7 strains) by promoting pH-induced conformational changes in influenza A hemagglutinin during its intracellular transport late in the replicative cycle. Adsorption of the virus to and penetration into cells do not appear to be affected by amantadine. In addition, amantadine does not interfere with the synthesis of viral components (e.g., RNA-directed RNA polymerase activity). The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that symmetrel may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (Ki = 10 uM). Although amantadine has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation. The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine. In isolated ventricular muscle preparations (frog, rabbit, cat, dog, and calf) amantadine increased the action potential duration, decreased the amplitude and max diastolic potential, and induced phase 4 depolarization. These changes may be due to the effect of amantadine on potassium ion conductance.

Pharmacodynamics

Amantadine is an antiviral drug which also acts as an antiparkinson agent, for which it is usually combined with L-DOPA when L-DOPA responses decline (probably due to tolerance). It is a derivate of adamantane, like a similar drug rimantadine. The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. It has been shown to cause an increase in dopamine release in the animal brain, and does not possess anticholinergic activity.