AMANTADINE HYDROCHLORIDE 10 MG / ML ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amantadine hydrochloride 10 mg/ml oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of Oral Solution contains 10 mg of amantadine hydrochloride.

Excipient(s) with known effect:

Each ml also contains:

0.8 mg of Methyl Parahydroxy Benzoate

0.1 mg of Propyl Parahydroxy Benzoate.

0.2 g of Sorbitol and

8 mg of propylene glycol

For the full list of excipients, see section 6.1.

Oral Solution

Clear colorless liquid with slightly sweet taste and lemon flavour.

4.1 Therapeutic indications

Symptomatic treatment of Parkinson’s di­sease.

Amantadine can be given as monotherapy at the start of treatment of the Parkinson's disease or in combination with levodopa.

4.2 Posology and method of administration

Posology

Parkinson's disease

Initial dose: 10 ml (100 mg) daily after a meal, preferably in the morning.

Maintenance dose: 10 ml (100 mg) twice daily after meals.

The interval between the initial dose and the maintenance dose should be at least 7 days.

In individual cases, the dose can be increased further depending on the clinical picture. It is recommended that this should be done gradually with intervals of at least 1 week.

The maximum dose of 40 ml (400 mg)/day should not be exceeded.

Withdrawal: Amantidine withdrawal should be gradual, e.g. half the dose at weekly intervals. Abrupt discontinuation may exacerbate Parkinsonism, regardless of the patient’s response to therapy (see section 4.4).

Combination treatment: If Amantadine Oral Solution is added to existing treatment for Parkinson, it should be commenced at the lowest possible dose and the dosage should then be titrated slowly and carefully.

Special populations

Paediatric population

This medicine is not indicated for use in paediatric population. The safety and efficacy of this product in children aged below 10 years has not been established. No data are available.

Elderly (over 65 years of age): Since patients over 65 years of age tend to show lower renal clearance and consequently higher plasma concentrations, the lowest effective dose should be used. If the patient has a renal function disorder, the dosing interval should be adapted (see ‘Renal impairment’ below).

Renal impairment

In patients with renal impairment, the clearance is significantly reduced, which results in elevated plasma concentrations of amantadine. The dosage should be carefully adjusted for these patients by extending the dosing interval depending on the creatinine clearance (see Table 1), after a loading dose on day 1 of the treatment.

When Parkinson’s disease is diagnosed in a patient who already has impaired renal function (with or without haemodialysis), treatment should be started with a loading dose of 10 ml (100 mg)/day on day 1 of the treatment. After the initial dose, the dosing interval should be monitored immediately, depending on the creatinine clearance (see Table 1).

If impaired renal function is diagnosed in patients with Parkinson’s disease who are already being treated with the maintenance dose of Amantadine Oral solution (100 mg twice daily), switching immediately to the dosing interval based on the creatinine clearance (see Table 1) is possible without any loading dose.

Table 1. 100 mg dosing interval based on the creatinine clearance

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

Method of administration

This medicine should be taken orally after a meal.

4.3 Contraindications

– Known hypersensitivity to amantadine or any of the excipients listed in section 6.1

– Patients with chronic heart failure or cardiomyopathy

– Bradycardia

– Patients with history of QT prolongation (congenital, documented acquired QT prolongation or relatives with congenital QT syndrome) or arrhythmias

– Concomitant use with drugs that prolong QT interval (see section 4.5)

– Patients with electrolyte disorders (hypokalemia, hypomagnesemia)

– Gastric ulceration

– Individuals subject to uncontrolled convulsions

– Psychosis

– Untreated angle closure glaucoma.

4.4 Special warnings and precautions for use

There have been reports that patients with pre-existing epilepsy with seizures may develop an increased frequency of severe motor seizures during treatment with amantadine. Reducing the dose can minimise this risk. Such patients should be monitored carefully. Amantadine is contraindicated for refractory epilepsy.

An electrocardio­graphic control should be performed to detect a possible prolongation of the QT interval. If symptoms such as palpitations, dizziness or syncope appear, treatment should be discontinued immediately (see section 4.8).

Because Amantadine oral solution does not completely inhibit the host’s immune response to an influenza A infection, people who use this medicinal product may still develop immune responses to the natural illness or vaccination later on and may be protected if they are exposed to antigen-related viruses at a later date.

Special care is needed in patients who are suffering from or who have suffered from recurrent eczema or cardiovascular conditions.

This medicine should be used with caution in patients with hepatic or renal function disorders. Where renal function is reduced, the dose should be adjusted correspondingly and the amantadine plasma concentrations should ideally be monitored. Given that only small quantities of amantadine are removed by haemodialysis, the dose should be accurately adjusted in patients with renal impairment in order to avoid side effects (see sections 4.2 and 4.9).

Caution is required in patients with hypotension and dopamine-related endocrine disorders.

Exacerbation of hallucinations, confusion and nightmares can occur. Amantadine should be given with caution in these cases. Hallucinations, confusion and nightmares occur more often when amantadine is administered together with anticholinergic agents or if the patient has an underlying psychiatric disorder.

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.

Discontinuation of the treatment

Abrupt discontinuation of amantadine may result in worsening of Parkinsonism or in symptoms resembling neuroleptic malignant syndrome (NMS), as well as in cognitive manifestations (e.g. catatonia, confusion, disorientation, worsening of mental status, delirium), See section 4.2 (Withdrawal).

Amantadine oral solution 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.

Attempted suicide

Given the severity of the side effects of overdoses, caution should be exercised when prescribing this medicine to patients with an elevated risk of suicidal behaviour. The smallest quantity consistent with good patient management should be prescribed, as there have been cases of attempted suicide with amantadine.

Peripheral oedema/Glaucoma

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

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 hydrochloride. Dose reduction or tapered discontinuation should be considered if such symptoms develop. (see section 4.8).

Excipients

This medicine contains parahydroxyben­zoates (see section 6.1). This one parahydroxyben­zoates can cause allergic reactions (possibly delayed). This medicine also contains sorbitol. Patients with rare hereditary disorders such as fructose intolerance must not use this medicinal product.

This medicine contains 0.2 g sorbitol in each ml dose.

This medicine contains 8 mg propylene glycol in each ml dose.

4.5 Interaction with other medicinal products and other forms of interaction

The concomitant use of amantadine and certain medications that induce prolongation of the QT interval is contraindicated (see section 4.3):

class IA antiarrhythmics (e.g. quinidine, disopyramide, procainamide) and class III (e.g. amiodarone, sotalol)

antipsychotics such as thioridazine, chlorpromazine, haloperidol, pimozide

tricyclic and tetracyclic antidepressants (e.g. amitriptyline)

antihistamines (e.g. astemizole, terfenadine)

macrolide antibiotics (e.g. erythromycin, clarithromycin)

some quinolones, such as sparfloxacin and grepafloxacin

antifungals (azoles) and other substances such as budipine, halofantrine, cotrimoxazole, pentamidine, cisapride and bepridil

As it is not an exhaustive list, any potential interaction of amantadine with other drugs should be taken into account, with special attention to the possible prolongation of the QT interval caused by the association.

Anticholinergic agents or levodopa:

Concurrent administration may increase confusion, hallucinations, nightmares, gastrointestinal disturbances or other anticholinergic side effects such as disrupted accommodation, dry mouth and urinary retention. This is something that should be monitored during concomitant use.

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.

Drugs or substances acting on the CNS (e.g. alcohol):

Concomitant use may result in additive toxicity in the central nervous system. Careful monitoring is recommended (see also section 4.9).

Combination diuretics (hydrochlorot­hiazide + potassium sparing diuretics):

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 reduces the clearance of amantadine, leading to higher plasma concentrations and toxic effects (confusion, hallucinations, ataxia and myoclonus). Concurrent administration is therefore not recommended.

The administration of amantadine in combination with other antiparkinsonians is possible. To avoid adverse reactions (such as psychotic reactions), it may be necessary to reduce the dose of any of the drugs or their combination.

Other substances:

Concomitant use with hydrochlorothiazide or triamterene, quinidine or quinine may reduce the renal clearance of amantadine with the corresponding increase in toxicity and / or side effects.

Amantadine interferes with the tubular secretion of trimethoprim and vice versa.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is insufficient data about the use of amantadine during pregnancy. Observations in humans have provided indications that the substance could be harmful to the pregnancy (including miscarriages, hydatidiform moles and cardiac abnormalities).

Animal studies have demonstrated reprotoxicity (see section 5.3).

Women of childbearing potential should have a pregnancy test prior to starting treatment. Women who could become pregnant should use effective contraception during the treatment and for 5 days after the final dose of amantadine.

This medicine must not be used during pregnancy unless it is strictly necessary. After exposure during the first three months, a detailed ultrasound scan can be considered as a check.

Breastfeeding

Amantadine is excreted into breast milk. Undesirable effects have been reported in breast-fed infants. Amantadine should not be used during breast-feeding.

Fertility

There is insufficient data to adequately assess effects on the reproductive system

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.

4.8 Undesirable effects

Amantadine's un­desirable effects are often mild and transient, usually appearing within the first 2 to 4 days of treatment and often disappearing within 24 to 48 hours after discontinuation of amantadine.

A direct relationship between the dosage and the incidence of side effects has not been demonstrated, although there seems to be a tendency towards more frequent undesirable effects (particularly affecting the central nervous system) 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.

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). The side effects are shown within each frequency group in decreasing order of severity.

NB: The incidence and severity of some of the adverse reactions, noted below, varies according to the dosage and nature of the disease under treatment.

Table 1

1 More common when amantadine is administered concurrently with anticholinergic agents or when the patient has an underlying psychiatric disorder.

2 Reported but their incidence cannot be readily deduced from the literature.

3 Usually after very high doses or use over many months.

4 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 oral solution (see section 4.4).

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

Acute intoxication is characterized by nausea, vomiting, hyperexcitability, tremor, ataxia, blurred vision, drowsiness, depression, dysarthria and seizures. A single case of malignant cardiac arrhythmia was reported. It can also produce pulmonary edema, status epilepticus and / or toxic psychosis, in the form of confused states with visual hallucinations, including even coma and myoclonus, which were observed after simultaneous administration of amantadine with other antiparkinsonians.

Combined toxicity

The effects of anticholinergic medicinal products are increased by concomitant use of amantadine. Acute psychotic reactions, which may be identical to those caused by atropine poisoning, may occur if high doses of anticholinergic agents are being used. If alcohol or substances with a stimulant effect on the central nervous system are taken at the same time, the symptoms of acute amantadine toxicity may be aggravated or modified.

Management

There is no specific antidote.

– Removal and/or inactivation of the substance or substances responsible for the poisoning: induce vomiting and/or gastric aspiration or lavage, activated charcoal, salt laxative, if deemed appropriate. Given that amantadine is largely excreted unchanged in the urine, stimulating the excretory function of the kidneys can be an effective way of removing it from the bloodstream. Acidification of the urine promotes the excretion of amantadine with the urine. Haemodialysis does not remove significant amounts of Amantadine oral solution; in patients with renal failure, only 7 to 15 mg was removed during a 4-hour haemodialysis after 300 mg was taken.

– Monitor the blood pressure, pulse rate, ECG, respiration, body temperature and possible hypotension; treat cardiac arrhythmias if necessary. Caution is required in cases of arrhythmia and hypotension when adrenergic components are administered, as the clinical status may deteriorate due to the arrhythmogenic properties of adrenergic agents.

– Convulsions and excessive motor restlessness: administer anticonvulsants such as diazepam intravenously, paraldehyde intramuscularly or rectally, or phenobarbital intramuscularly.

– Acute psychotic symptoms, delirium, adopting a dystonic posture, myoclonic manifestations: physostigmine by slow intravenous infusion (doses of 1 mg in adults and 0.5 mg in children) with repeated administration according to the initial response and the subsequent need.

– Urinary retention: the bladder should be catheterised; an internal catheter can remain in place while it is needed.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiparkinsonian agent and anti-influenzal virostatic.

ATC code N04B B01

Mechanism of action

Influenza: Amantadine 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 <0.4^g/ml of amantadine. Amantadine 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 haemagglutinin. 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.

Parkinson's di­sease: Amantadine has been shown to be a low affinity antagonist at the N-methyl-D-aspartate (NDMA) subtype of glutamate receptors. Overactivity of glutamatergic neurotransmission has been implicated in the generation of parkinsonian symptoms.

Clinical efficacy and safety: 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.

5.2 Pharmacokinetic properties

Absorption

Amantadine is absorbed slowly but almost completely. Peak plasma concentrations of approximately 250 ng/ml and 500 ng/ml are seen within 3 to 4 hours after single oral administration of 100 mg and 200 mg amantadine respectively.

After repeated administration of 25, 100 or 150 mg twice daily, steady-state plasma concentrations of 110, 302 and 588 ng/ml respectively were achieved within 3 days.

Distribution

In vitro, 67% of the amantadine is bound to plasma proteins, with a substantial amount bound to red blood cells. The amantadine concentration in erythrocytes in healthy volunteers is 2.66 times the plasma concentration.

The apparent volume of distribution VD of the medicinal product is 5 to 10 l/kg, suggesting extensive tissue binding. VD declines with increasing doses. Amantadine concentrations in the lungs, heart, kidneys, liver and spleen are higher than in the blood. Amantadine accumulates after several hours in the nasal secretions.

Amantadine passes the blood-brain barrier. The mean ratio for total amantadine between the cerebrospinal fluid (CSF) and the serum is approximately 0.76.

Biotransformation

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

Elimination

Amantadine is eliminated in healthy young adults with a mean plasma elimination half-life of 15 hours (10 to 31 hours).

The elimination half-life of amantadine in brain tissue (6.5 days) is much longer than in the blood.

The total plasma clearance is about the same as the renal clearance (250 ml/min). The renal clearance of amantadine is much higher than the creatinine clearance, suggesting renal tubular secretion.

The elimination rate is affected considerably by the urine pH. A rise in the urine pH can lead to a substantial fall in the elimination rate of amantadine.

Linearity/non-linearity

Amantadine exhibits dose-proportional pharmacokinetics in dosage ranges of 100 to 200 mg.

Characteristics in special patient populations

Elderly patients

Compared with data for healthy young adults, the half-life is doubled and the renal clearance diminished. The ratio between the renal clearance and the creatinine clearance is smaller in the elderly than in young people. In general, tubular secretion diminishes more than glomerular filtration in the elderly. In elderly patients with renal impairment, repeated administration of 100 mg/day for 14 days raised the plasma concentrations into the toxic range.

Renal impairement:

Given that amantadine is primarily excreted via the kidneys, accumulation of amantadine may occur in patients with impaired renal function, which can lead to severe side effects. A creatinine clearance of less than 40 ml/min/1.73 m2 results in a half-life that is three to five times longer and total and renal clearances that are five times lower. Renal elimination predominates, even in renal insufficiency. Elderly patients or patients who suffer from impaired renal function should be given appropriately reduced doses. The target amantadine plasma concentration should not exceed a maximum of 300 ng/ml.

Patients on haemodialysis

Haemodialysis does not remove very much amantadine; this ineffectiveness may be related to its strong tissue binding. Less than 5% of a dose is removed during 4 hours of haemodialysis. The average half-life is up to 24 dialysis hours.

Patients with impaired hepatic function

The effect of reduced hepatic function on the pharmacokinetics of amantadine is not known. Only a small proportion of amantadine undergoes metabolisation in the liver (see ‚Biotransformation‘ in section 5.2).

5.3 Preclinical safety data

Amantadine hydrochloride showed a low degree of acute toxicity in various animal studies. Subchronic oral toxicity studies have been conducted in rats, dogs and monkeys. There was no evidence of specific toxicity. Chronic toxicity studies carried out in rats and dogs over periods of up to two years showed no specific toxicity.

In vitro and in vivo studies showed that amantadine is not mutagenic. Carcinogenicity studies have not been performed. No evidence of carcinogenic effects was found in a two-year oral toxicity study in rats. The number of animals in each dosage group in this study was however insufficient to evaluate the carcinogenic potential fully.

In embryotoxicity studies in rats, mice and rabbits, embryolethal effects and deformities were only seen in rats. Increases were noted in oedema, misplacement of the hind legs, bone abnormalities (missing ribs, aplasia of the tail vertebrae). In rat oral doses of 50 and 100 mg/kg proved to be teratogenic. This is 33-fold the recommended dose of 100mg for influenza. The maximum recommended dose of 400 mg in Parkinson’s di­sease, is less than 6mg/kg. The lowest dose at which effects occurred in rats was 15 times higher than the maximum human dose. The relevance for humans is unknown. Although effects on fertility have not been sufficiently investigated, there was evidence of decreased fertility in rats at the same doses at which reprotoxicity was observed.

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Methyl parahydroxy benzoate (E218)

Propyl parahydroxy benzoate (E216)

Sorbitol 70% (E420)

Sodium citrate dihydrate

Lemon flavour

Propylene glycol

Purified water

6.2 Incompatibilities

Not Applicable

6.3 Shelf life

30 months

In-use storage – 140 days, after first opening of the bottle.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Amber glass bottles with child resistant tamper evident cap containing 150 ml with a polypropylene dosing cup of 15 ml. The dosing cup is marked in ml (millilitres).

Pack size: 150 ml

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Macarthys Laboratories Limited T/A Martindale Pharma,

Bampton Road, Harold Hill,

Romford, Essex, RM3 8UG,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 01883/0353

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/04/2020