4.1. Therapeutic indications

Prophylaxis and treatment of signs and symptoms of infection caused by influenza A virus . It is suggested that Lysovir/Amantadine capsules be given to patients suffering from clinical influenza in which complications might be expected to occur. In addition, Lysovir/Amantadine capsules is recommended prophylactically in cases particularly at risk. This can include those with chronic respiratory disease or debilitating conditions, the elderly and those living in crowded conditions. It can also be used for individuals in families where influenza has already been diagnosed, for control of institutional outbreaks or for those in essential services who are unvaccinated or when vaccination is unavailable or contra-indicated.

Lysovir/Amantadine capsules does not completely prevent the host immune response to influenza A infection, so individuals who take this drug still develop immune responses to the natural disease or vaccination and may be protected when later exposed to antigenically related viruses. Lysovir/Amantadine capsules may also be used in post-exposure prophylaxis in conjunction with inactivated vaccine during an outbreak until protective antibodies develop, or in patients who are not expected to have a substantial antibody response (immunosuppression).

4.2. Posology and method of administration

Posology

Treatment: It is advisable to start treating influenza as early as possible and to continue for 4 to 5 days. When amantadine is started within 48 hours of symptoms appearing, the duration of fever and other effects is reduced by one or two days and the inflammatory reaction of the bronchial tree that usually accompanies influenza resolves more quickly.

Prophylaxis: Treat daily for as long as protection from infection is required. In most instances this is expected to be for 6 weeks. When used with inactivated influenza A vaccine, amantadine is continued for 2 to 3 weeks following inoculation.

Children over 10 years of age, adolescents and adults: 100mg daily for the recommended period.

Children under 10 years of age: Dosage not established.

Elderly: Plasma amantadine concentrations are influenced by renal function. In elderly patients, the elimination half-life is longer and renal clearance of the compound is diminished in comparison to young people. A daily dose of less than 100mg, or 100mg given at intervals of greater than one day, may be appropriate.

Renal impairment

In patients with renal impairment the dose of amantadine should be reduced. This can be achieved by either reducing the total daily dose, or by increasing the dosage interval in accordance with the creatinine clearance. For example,

Creatinine clearance (ml/min)

Dose

< 15

Lysovir/Amantadine capsules contra-indicated.

15 – 35

100mg every 2 to 3 days.

> 35

100mg every day

The above recommendations are for guidance only and physicians should continue to monitor their patients for signs of unwanted effects.

Method of administration

For oral administration.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Individuals subject to convulsions.

A history of gastric ulceration.

Severe renal disease.

Pregnancy.

4.4. Special warnings and precautions for use

Lysovir/Amantadine capsules should be used with caution in patients with confusional or hallucinatory states or underlying psychiatric disorders, in patients with liver or kidney disorders, and those suffering from, or who have a history of, cardiovascular disorders. Caution should be applied when prescribing Lysovir/Amantadine capsules with other medications having an effect on the CNS (See Section 4.5, Interactions with other medicaments and other forms of interaction).

Discontinuation of amantadine

Lysovir/Amantadine capsules should not be stopped abruptly in patients who are treated concurrently with neuroleptics. There have been isolated reports of precipitation or aggravation of neuroleptic malignant syndrome or neuroleptic-induced catatonia following the withdrawal of amantadine in patients taking neuroleptic agents. A similar syndrome has also been reported rarely following withdrawal of amantadine and other anti-Parkinson agents in patients who were not taking concurrent psychoactive medication.

Resistance to amantadine occurs during serial passage of influenza virus strains in vitro or in vivo in the presence of the drug. Apparent transmission of drug-resistant viruses may have been the cause of failure of prophylaxis and treatment in household contacts and in nursing-home patients. However, there is no evidence to date that the resistant virus produces a disease that is in any way different from that produced by sensitive viruses.

Some individuals have attempted suicide and cases of suicidal ideation and behaviour have been reported during treatment with amantadine. Patients should be monitored for signs of suicidal ideation and behaviour and treatment initiated as needed. Patients (and caregivers of patients) should be advised to seek medical advice if any signs of suicidal ideation or behaviour emerge. Prescriptions should be written for the smallest quantity consistent with good patient management.

Peripheral oedema

Peripheral oedema (thought to be due to an alteration in the responsiveness of peripheral vessels) may occur in some patients during chronic treatment (not usually before 4 weeks) with amantadine. This should be taken into account in patients with congestive heart failure.

Anticholinergic effects

Amantadine has anticholinergic effects, it should not be given to patients with untreated angle closure glaucoma.

If blurred vision or other visual problems occur an ophthalmologist should be contacted to exclude corneal oedema. In case that corneal oedema is diagnosed treatment with amantadine should be discontinued.

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with products with a dopaminergic effect, including amantadine. Dose reduction or tapered discontinuation should be considered if such symptoms develop.

Hypothermia

Hypothermia has been observed in children, especially in those younger than 5 years of age. Caution should be exercised when prescribing Lysovir/Amantadine capsules to children for the prevention and treatment of influenza type A virus (see also section 4.2 Posology and method of administration).

Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Special precautions

Concurrent administration of amantadine and anticholinergic agents or levodopa may increase confusion, hallucinations, nightmares, gastro-intestinal disturbances, or other atropine-like side effects (see Section 4.9 “Overdose”). Psychotic reactions have been observed in patients receiving amantadine and levodopa.

In isolated cases, worsening of psychotic symptoms has been reported in patients receiving amantadine and concomitant neuroleptic medication.

Concurrent administration of amantadine and drugs or substances (e.g. alcohol) acting on the CNS may result in additive CNS toxicity. Close observation is recommended (see Section 4.9 “Overdose”).

There have been isolated reports of a suspected interaction between amantadine and combination diuretics (hydrochlorothiazide + potassium sparing diuretics). One or both of the components apparently reduce the clearance of amantadine, leading to higher plasma concentrations and toxic effects (confusion, hallucinations, ataxia, myoclonus).

4.6. Fertility, pregnancy and lactation

Pregnancy

Amantadine-related complications during pregnancy have been reported. Lysovir/Amantadine capsules is contra-indicated during pregnancy and in women wishing to become pregnant.

Breastfeeding

Amantadine passes into breast milk. Undesirable effects have been reported in breast-fed infants. Nursing mothers should not take Lysovir/Amantadine capsules.

4.7. Effects on ability to drive and use machines

Patients should be warned of the potential hazards of driving or operating machinery if they experience side effects such as dizziness or blurred vision. If taken concomitantly with other products affecting the CNS, additive adverse effects could be seen.

4.8. Undesirable effects

Summary of the safety profile

Amantadine's undesirable effects are often mild and transient, usually appearing within the first 2 to 4 days of treatment and promptly disappearing 24 to 48 hours after discontinuation. A direct relationship between dose and incidence of side effects has not been demonstrated, although there seems to be a tendency towards more frequent undesirable effects (particularly affecting the CNS) with increasing doses.

The side effects reported after the pivotal clinical studies in influenza in over 1200 patients receiving amantadine at 100mg daily were mostly mild, transient, and equivalent to placebo. Only 7% of subjects reported adverse events, many being similar to the effects of influenza itself. The most commonly reported effects were gastro-intestinal disturbances (anorexia, nausea), CNS effects (loss of concentration, dizziness, agitation, nervousness, depression, insomnia, fatigue, weakness), or myalgia.

Tabulated list of adverse reactions

The following list of adverse reactions is based on clinical trial experience and/or post-marketing use via spontaneous case reports and literature cases. The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as “not known”.

Undesirable effects are listed by MedDRA System Organ Classes. Within each system organ class, ADRs are presented in order of decreasing seriousness. Assessment of undesirable effects is based on the following frequency groupings:

Very common: ≥ 1/10

Common: ≥ 1/100 to < 1/10

Uncommon: ≥ 1/1,000 to < 1/100

Rare: ≥ 1/10,000 to < 1/1,000

Very rare: < 1/10,000

Not known: cannot be estimated from the available data.

System Organ Class

Adverse Drug Reactions

Blood and lymphatic system disorders

Very rare

leukopenia

Psychiatric disorders

Common

depression, confusional state, hallucination, anxiety, euphoric mood, insomnia, nightmare*, nervousness

Rare

psychotic disorder, disorientation

Not known

impulse control disorders* (see section 4.4), delirium, hypomania, and mania

Nervous system disorders

Common

dizziness, headache, lethargy, ataxia, disturbance in attention, dysarthria

Rare

neuroleptic malignant syndrome (see section 4.4), seizure, dyskinesia, tremor

Not known

myoclonus

Eye disorders

Uncommon

vision blurred

Rare

corneal lesion*, corneal oedema (see section 4.4), visual acuity reduced

Cardiac disorders

Very common

oedema peripheral

Common

palpitations

Very rare

cardiac failure

Vascular disorders

Common

orthostatic hypotension

Gastrointestinal disorders

Common

dry mouth, decreased appetite, nausea, vomiting, constipation

Rare

diarrhoea

Skin and subcutaneous tissue disorders

Very common

livedo reticularis*

Common

hyperhidrosis

Rare

rash

Very rare

photosensitivity reaction

Musculoskeletal and connective tissue disorders

Common

myalgia

Renal and urinary disorders

Rare

urinary retention, urinary incontinence

General disorders and administration site conditions

Not known

hypothermia* (see section 4.4)

Investigations

Very rare

hepatic enzyme increased

*See section 'Description of selected adverse reactions'

Description of selected adverse reactions

Nightmares are more common when amantadine is administered concurrently with anticholinergic agents or when the patient has an underlying psychiatric disorder.

Impulse control disorders: pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating, and compulsive eating can occur in patients with a dopaminergic effect including amantadine (see section 4.4 Special warnings and precautions for use).

Corneal lesions such as punctate subepithelial opacities which might be associated with superficial punctate keratitis.

Livedo reticularis can develop usually after very high doses or use over many months.

In post-marketing exposure hypothermia has been reported in children mainly those younger than 5 years of age (see also section 4.4 Special warnings and precautions for use).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose with Lysovir/Amantadine capsules can lead to fatal outcome.

Signs and symptoms: Neuromuscular disturbances and symptoms of acute psychosis are prominent. Central nervous system: coma, hyperreflexia, motor restlessness, convulsions, extrapyramidal signs, torsion spasms, dystonic posturing, dilated pupils, dysphagia, confusion, disorientation, delirium, visual hallucinations, myoclonus. Respiratory system: hyperventilation, pulmonary oedema, respiratory distress, including adult respiratory distress syndrome. Cardiovascular system: cardiac arrest and sudden cardiac death have been reported. Sinus tachycardia, arrhythmia, hypertension. Gastrointestinal system: nausea, vomiting, dry mouth. Renal function: urine retention, renal dysfunction, including increase in blood urea nitrogen and decreased creatinine clearance.

Overdose from combined drug treatment: the effects of anticholinergic drugs are increased by amantadine. Acute psychotic reactions (which may be identical to those of atropine poisoning) may occur when large doses of anticholinergic agents are used. Where alcohol or central nervous stimulants have been taken at the same time, the signs and symptoms of acute poisoning with amantadine may be aggravated and/or modified.

Management: There is no specific antidote. Induction of vomiting and/or gastric aspiration (and lavage if patient is conscious), activated charcoal or saline cathartic may be used if judged appropriate. Since amantadine is excreted mainly unchanged in the urine, maintenance of renal function and copious diuresis (forced diuresis if necessary) are effective ways to remove it from the blood stream. Acidification of the urine favours its excretion. Haemodialysis does not remove significant amounts of amantadine.

Monitor the blood pressure, heart rate, ECG, respiration and body temperature, and treat for possible hypotension and cardiac arrhythmias, as necessary. Convulsions and excessive motor restlessness: administer anticonvulsants such as diazepam IV, paraldehyde IM or per rectum, or phenobarbital IM. Acute psychotic symptoms, delirium, dystonic posturing, myoclonic manifestations: physostigmine by slow iv infusion (1mg doses in adults, 0.5mg in children) repeated administration according to the initial response and the subsequent need, has been reported. Retention of urine: bladder should be catheterised; an indwelling catheter can be left in place for the time required.