Consumer medicine information

Symmetrel

Amantadine hydrochloride

BRAND INFORMATION

Brand name

Symmetrel

Active ingredient

Amantadine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Symmetrel.

What is in this leaflet

This leaflet answers some common questions about Symmetrel.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. Some more recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will provide.

If you have any concerns about this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Symmetrel is used for

Symmetrel capsule has two very different uses:

  1. to treat the symptoms of Parkinson's disease
  2. to prevent a type of influenza ("the flu") caused by Type A influenza virus.

Parkinson's Disease
This is caused by a disturbance in the balance of two substances, dopamine and acetylcholine, that the brain uses to send signals to other parts of the body.

Symmetrel helps to fix the imbalance of too little dopamine and/or too much acetylcholine; and to relieve the symptoms, such as shaking of the limbs, stiffness and slowness of movement which make it difficult to perform usual tasks.

Symmetrel can be used alone or with other medicines to treat this condition.

Type A influenza virus
Symmetrel is usually used for people who could become very ill if they get the flu infections (for example, people who have a serious illness such as lung disease or diabetes). Usually these people will have been vaccinated (had a flu shot). But if, for some reason, they have not been vaccinated, Symmetrel can be given.

Symmetrel is only used to prevent Type A influenza. It will not help once you have the flu. This medicine cannot prevent or treat colds, other types of flu not caused by Type A virus, or other viral infections.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another purpose.

This medicine is only available with a doctor's prescription.

It is not habit-forming.

There is not enough information to recommend this medicine for children under five years of age.

Before you take Symmetrel

When you must not take it

Do not take Symmetrel if you have ever had an allergy to:

  • amantadine hydrochloride (the active ingredient in Symmetrel) or
  • to any of the other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take Symmetrel if you are pregnant. It may affect your unborn baby if you take it while you are pregnant.

Do not take Symmetrel after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Before you start to take it

Tell your doctor if you have any of the following health problems or medical conditions:

  • kidney or liver disease
  • seizures (fits)
  • a mental disorder
  • heart disease or circulation problems
  • stomach ulcers
  • low blood pressure
  • increased pressure in the eyes (glaucoma)
  • prostate trouble
  • recurring skin problems (eczema)

Your doctor may want to take special precautions if you have any of the above conditions.

Tell your doctor if you are breast-feeding. The active ingredient in Symmetrel passes into the breast milk and could affect your baby. Your doctor can discuss with you the risks and benefits of breast-feeding while you are taking this medicine.

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives. Your doctor will want to know if you are prone to allergies.

Ask your doctor for advice if you think you may be allergic, if you have ever had any unusual sensitivity, rash or other possible signs of allergy.

If you have not told your doctor about any of these things, tell him/ her before you take Symmetrel.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and Symmetrel may interfere with each other. These include:

  • other medicines for Parkinson's disease
  • medicines for depression or other mental disorders
  • other medicines that affect the nervous system (e.g. medicines to help you sleep or calm you down, pain relievers, alcohol)
  • medicines for abdominal or stomach cramps or spasms
  • some combination diuretics (water or fluid pills) used to treat high blood pressure (hydrochlorothiazide and triamterene)

You may need to take different amounts of your medicines or to take different medicines while you are taking Symmetrel. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Symmetrel.

If you have not told your doctor about any of these things, tell him/ her before you start taking this medicine.

How to take Symmetrel

Take the capsule after a meal or snack.

Swallow the whole capsule with a full glass of water. Do not chew, break, or crush the capsule.

Follow all directions given to you by your doctor and pharmacist carefully. These instructions may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Follow your doctor's instructions on how many Symmetrel capsules to take.

This is important as there are two different ways to take this medicine, depending on whether you are being treated for Parkinson's disease or for Type-A influenza.

1. For Parkinson's disease

Start treatment with one capsule taken daily and gradually increase to one capsule taken twice a day.

Occasionally, higher doses are needed.

2. For Type A influenza

Children aged 5 to 9 years:
Take only one capsule each day.

Children aged 10 or older:
Take one capsule twice daily.

Adolescents and adults up to age 65 years:
Take one capsule twice daily.

Adults over 65 years:
Take one capsule each day.

In elderly patients without impaired kidney function:
Do not take more than 100 mg daily unless prescribed by your doctor.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions that they give you.

For people who are elderly or have reduced kidney function, the dose may need to be reduced or taken less frequently.

Do not change the dose or dosing interval yourself, without your doctor's advice, regardless of how well you may feel.

When to take it

Try to take the capsules at about the same times each day, as directed by your doctor or pharmacist. Taking your medicine at the same times each day will have the best effect. It will also help you remember when to take your capsules.

To treat Parkinson's disease

Adults up to 65 years old:
For the first week, take your medicine once daily. After the first week, take one capsule twice daily.

Adults over 65 years old:
Take only one capsule daily.

To treat Type A influenza

Children aged 5 to 9, and adults over 65 years old
Take only one capsule daily.

Children aged 10 and older & adults to 65 years:
Take one capsule twice each day, starting as soon as possible after exposure to the flu virus.

If side effects occur, the dose can be reduced to one capsule daily.

People with reduced kidney function due to increasing age or kidney disease:
Take as directed by your doctor, as you may be reduced to one capsule every 2 to 7 days to help prevent side effects.

How long to take it

To treat Parkinson's disease

You may need to take Symmetrel for a long time to control your symptoms.

Do not stop taking this medicine or lower the dose without first checking with your doctor. If it is necessary to stop your medicine, your doctor will gradually reduce the amount you take each day before stopping it completely.

Some people find that this medicine loses some of its effect after several weeks. In this case, your doctor may gradually reduce the dose and stop it for a few weeks, and then start it again to see if the benefit can be regained.

Do not let yourself run out of medicine over the weekend or on holidays. Stopping your medicine may make your condition worse or cause severe side effects.

To treat Type A influenza virus

Keep taking Symmetrel for at least 10 days. Sometimes it may be necessary to keep taking it until the outbreak of influenza is over.

If you forget to take it

If it is almost time for your next dose, skip the missed dose and take the next one when you are meant to.

Otherwise, take the dose as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for the one that you missed. This may increase the chance of you getting an unwanted side effect.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Symmetrel. Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy.

Some of the symptoms of an overdose may include stiffness or unusual muscle movements, seizures (fits), vomiting, difficulty breathing, fast or irregular heartbeat.

While you are taking Symmetrel

Things you must do

Continue taking Symmetrel as your doctor tells you.

Talk to your doctor or your pharmacist if you have questions about how long to take Symmetrel.

Women of child-bearing potential should use an efficient contraceptive method during treatment and for 5 days after taking their last dose of Symmetrel. If you become pregnant while taking Symmetrel, tell your doctor immediately.

You should not take it while you are pregnant.

When you are outdoors, wear protective clothing and use at least a 15+ sunscreen. Do not use a sunlamp or tanning bed or booth. This medicine may cause your skin to be much more sensitive to sunlight than it normally is. Exposure to sunlight may cause a skin rash, itching, redness or severe sunburn.

If your skin does appear to be burning, tell your doctor.

If you develop blurred vision or other visual problems, tell your doctor straight away.

Your doctor can refer you to an ophthalmologist who will evaluate and may advise you to stop your treatment with Symmetrel.

Tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. These are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high sex drive or an increase in sexual thoughts or feelings.

Your doctor may need to adjust or stop your dose.

Be sure to keep all of your doctor's appointments so that your progress can be checked. This helps your doctor to give you the best treatment and to prevent unwanted side effects.

Before having any surgery or emergency treatment, tell the doctor or dentist in charge that you are taking Symmetrel.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Symmetrel.

Tell any other doctor, dentist or pharmacist who treats you that you are taking Symmetrel.

Things you must not do

Do not exceed the recommended dosage.

Do not give this medicine to anyone else, even if their condition seems similar to yours.

Do not use it to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving, operating machinery, using tools, or doing jobs that require you to be alert while you are taking Symmetrel until you know how it affects you.

Children should avoid doing things like riding bicycles or climbing trees. This medicine may cause dizziness, confusion, difficulty concentrating, impair your reactions, or cause blurred vision in some people.

Be careful when drinking alcohol while you are taking Symmetrel. The combination could make you more dizzy or lightheaded than usual.

If this medicine makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position. These symptoms may be a sign of low blood pressure. You can usually prevent them by getting up slowly and flexing leg muscles and toes to get the blood flowing. When getting out of bed, dangle your legs over the side for a minute or two before standing up.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Symmetrel. All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects.

If you are over 65 years old, you should be especially careful while taking this medicine. Report any side effects promptly to your doctor. Symmetrel can cause confusion or disorientation, especially in older people. Your family or carer should be made aware of this.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following side effects and they worry you:

  • strong impulse to gamble excessively
  • increased sexual drive or interest
  • uncontrollable excessive shopping or spending
  • binge eating or compulsive eating
  • dizziness or lightheadedness, especially when you get up too quickly from a sitting or lying position
  • purplish-red blotchy spots on the skin, especially of the legs or feet and sometimes in a fish-net pattern.
    These may appear after taking Symmetrel for a few months and usually go away gradually within a few weeks after stopping the medicine.
  • symptoms of sunburn (such as redness, itching, swelling or blistering of the skin) that happen more quickly than normal
  • indigestion, loss of appetite, nausea (feeling sick) or vomiting
  • constipation or diarrhoea
  • blurred vision
  • dry mouth
  • swelling of feet or lower legs due to fluid buildup
  • feeling of fast or irregular heartbeat
  • tiredness or listlessness
  • difficulty concentrating
  • nervousness, anxiety or depression
  • disturbed sleep or nightmares
  • weakness, shakiness or trembling
  • difficulty urinating (passing water) or inability to hold your urine (incontinence)
  • excessive sweating
  • headache
  • hair loss

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; shortness of breath, wheezing, accelerated or troubled breathing
  • stiff, rigid muscles accompanied by a sudden increase in body temperature, sweating, fast heartbeat and feeling disoriented
  • movement disorders
  • constant "flu-like" symptoms such as chills, fever, sore throat, aching joints, sores in mouth, swollen glands
  • fainting spells or seizures (fits)
  • difficulty in speaking or slurred speech
  • confusion, disorientation or hallucinations (seeing, hearing or feeling things that are not there)
  • abnormally high energy or level of activity (mania)
  • sudden loss of vision or trouble focussing your eyes properly
  • yellow colour to the skin and eyes
  • abnormally low body temperatures (below 35°C) in children treated for influenza

Tell your doctor if you notice anything else that is making you feel unwell.

Some people may have other side effects not yet known or mentioned in this leaflet. Some side effects can only be found when laboratory tests are done.

After using Symmetrel

Storage

  • Keep your medicine in the original container until it is time to take it.
  • Store it in a cool dry place.
  • Do not store Symmetrel or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on window sills.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Symmetrel or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Symmetrel capsules are soft brown gelatin capsules, marked GEIGY on one side and GB on the other. Each pack contains 100 capsules.

Ingredients

Active Ingredient
Symmetrel capsules contain 100 mg of amantadine hydrochloride.

Inactive ingredients

  • rape seed oil
  • lecithin
  • a wax blend composed of yellow beeswax, hydrogenated and partially hydrogenated soya oils
  • sodium ethyl hydroxybenzoate
  • sodium propyl hydroxybenzoate
  • gelatin
  • glycerol
  • iron oxide red
  • Karion 83 (a mixture of sorbitol, mannitol and hydrolysed starch in water)
  • titanium dioxide
  • white, edible branding ink

Symmetrel contains hydroxbenzoates and sulfites (gelatin capsules). It does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Symmetrel is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone: 1 800 671 203

® = Registered Trademark

This leaflet was prepared in April 2020.

Australian Registration Number.
Symmetrel 100 mg capsule AUST R 11057

(CMI sym080420c is based on the PI sym080420i)

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Symmetrel

Active ingredient

Amantadine hydrochloride

Schedule

S4

 

1 Name of Medicine

Amantadine hydrochloride.

6.7 Physicochemical Properties

Amantadine, the active ingredient of Symmetrel, is a stable, white, crystalline powder with a bitter taste, readily soluble in water and soluble in ethanol and chloroform.

Chemical structure.

Chemical name: 1-adamantanamine hydrochloride.
Molecular weight: 187.71.
Molecular formula: C10H18NCl.

CAS number.

665-67-7.

2 Qualitative and Quantitative Composition

Each capsule contains amantadine hydrochloride 100 mg.
Excipients with known effect: contains hydroxybenzoates and sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

100 mg capsules: brown, soft gelatin, marked "GEIGY" on one side and "GB" on reverse.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Therapeutic/ pharmacological group: antiparkinsonian agent and anti-influenzal virostatic (ATC code N04B B01).

Mechanism of action.

As antiparkinsonian agent.

The mechanism of action of amantadine is not fully understood. There is evidence to suggest that amantadine acts as an indirect dopamine receptor agonist by enhancing the synthesis and release of dopamine from central neurons and delaying the reuptake into synaptic vesicles. Other evidence suggests an alteration of striatal D2 receptors towards a high affinity state. Amantadine may also exert some anticholinergic activity. When administered either alone or in combination with other drugs, amantadine produces an improvement in the cardinal signs and symptoms of parkinsonism and improves functional capacity. In Parkinson's disease, the clinical response usually occurs within 24 to 48 hours or, at the most, one week. An optimal effect is obtained during a period extending from several days to a few weeks.

As anti-influenzal virostatic.

Amantadine specifically inhibits the replication of influenza A viruses at low concentrations. Using a sensitive plaque-reduction assay, human influenza viruses, including H1N1, H1N2, H2N2, H3N2 subtypes, are inhibited by 0.2 to 0.7 microgram/mL or less of amantadine. It is recognised, however, that not all strains susceptible under in vitro conditions will be similarly affected in clinical practice. The exact mechanism of action of amantadine is unclear.
Amantadine does not completely prevent the host immune response to influenza A infection. Individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically related viruses.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Symmetrel is completely absorbed from the gastrointestinal tract after oral administration, producing a peak concentration of amantadine in plasma 1 to 4 hours after ingestion. Peak plasma concentrations of approximately 250 nanogram/mL and 500 nanogram/mL are attained after single oral administration of 100 mg and 200 mg amantadine, respectively. Following repeated administration of 200 mg daily, the trough steady-state plasma concentration is approximately 300 nanogram/mL within 3 days.

Distribution.

67% of amantadine is bound to plasma proteins in vitro. A substantial amount of amantadine is bound to red blood cells. The erythrocyte amantadine concentration in normal healthy volunteers is 2.66 times the plasma concentration. The apparent volume of distribution of the drug is approximately 5-10 L/kg, suggesting extensive tissue binding. It declines with increasing doses. The concentration of amantadine in the lung, heart, kidney, liver and spleen is higher than in the blood. The drug accumulates after several hours in nasal secretions, is found in saliva in concentrations similar to those in plasma, and in CSF in concentrations about 60% of those in plasma.

Metabolism.

Amantadine is metabolised to a minor extent, principally by N-acetylation. Whether this metabolic pathway is affected by acetylator phenotype remains to be determined.

Excretion.

Amantadine is eliminated in healthy young adults with a mean plasma elimination half-life of approximately 15 hours (10-31 hours). The total plasma clearance is about the same as renal clearance (250 mL/min). Renal clearance of amantadine is much higher than the creatinine clearance, suggesting renal tubular secretion.
A single dose of amantadine is excreted over 72 hours as follows: 65-85% unchanged, 5-15% as the acetyl metabolite in urine and 1% in the stool. After 4-5 days, approximately 90% of the dose appears unchanged in the urine. The rate is considerably influenced by urinary pH, a rise in pH bringing about a fall in excretion.

Effect of age and disease on pharmacokinetics.

Elderly patients.

Compared with data from healthy young adults, the elimination half-life is doubled and renal clearance is diminished. The renal/ creatinine clearance ratio in elderly subjects is smaller than in young people. Tubular secretion diminishes more than glomerular filtration. In elderly patients, repeated administration of 100 mg amantadine daily may raise the plasma concentration into the toxic range.

Renal failure.

Accumulation of amantadine may occur in renal failure, causing severe adverse reactions. A creatinine clearance of less than 40 mL/min/1.73 m2 causes a 3 to 5-fold increase in elimination half-life and a 5-fold decrease in total and renal clearance. Renal elimination is dominant even in cases of renal failure.
Renal function declines steadily after early adulthood (at about 10% per decade from the fourth decade on). By age 65, renal function will typically have declined to a level at which reduced doses of Symmetrel (or increased dosing interval) are appropriate. Elderly patients or patients with renal failure should receive an adequately reduced dosage in accordance with the individual creatinine clearance (see Section 4.2 Dose and Method of Administration). The target plasma amantadine concentration should not exceed a maximum of 300 nanogram/mL.

Haemodialysis.

Little amantadine is removed by haemodialysis. This inefficiency may be related to its extensive tissue binding. Less than 5% (7-15 mg) of a single 300 mg dose is eliminated after a 4-hour haemodialysis. The mean elimination half-life reaches 24 dialysis hours.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Parkinson's disease.

Idiopathic Parkinson's disease; post-encephalitic parkinsonism; symptomatic parkinsonism (e.g. following CNS injury from carbon monoxide poisoning); arteriosclerotic parkinsonism; drug-induced extrapyramidal reactions.
Symmetrel can be given alone for initial therapy or combined with anticholinergic drugs or L-dopa (see Section 4.2 Dose and Method of Administration).

Note.

Symmetrel is not indicated for the treatment of tardive dyskinesia.

Type A viral influenza.

Prophylaxis of respiratory tract illness caused by influenza type A.
Prophylaxis in non-immunised individuals (including children) for whom influenza may have serious consequences (e.g. persons with chronic respiratory disease or diabetes mellitus).

4.3 Contraindications

Pregnancy, lactation; hypersensitivity to amantadine or to any of the excipients in Symmetrel.

4.4 Special Warnings and Precautions for Use

Medical supervision during treatment with Symmetrel is essential. The margin between the therapeutically effective dose and that producing toxic manifestations may be only 100 to 200 mg per day. The usual daily dose should, therefore, not be exceeded.

Use with caution in the following circumstances.

Patients with pre-existing seizure disorders have been reported to develop an increased frequency of major motor seizures during amantadine ingestion. A reduction in dosage may minimise this risk. These patients should be closely monitored.
Those patients with confusional, hallucinatory or psychotic states should receive Symmetrel with caution as an increase in confusion, hallucinations and nightmares may occur in patients with underlying psychiatric disorders.
Because of the possibility of serious adverse effects, caution should be observed when prescribing Symmetrel to patients being treated with drugs having CNS effects or for whom the potential risks outweigh the benefit of treatment. Because some patients have attempted suicide by using an overdose of amantadine, prescriptions should be written for the smallest quantity consistent with good patient management.
Particular care is called for in patients suffering from or with a history of recurrent eczema, gastric ulceration or cardiovascular disorders.
Peripheral oedema, probably due to local vascular disturbance, may occur in some patients during treatment with Symmetrel capsules. This should be considered if Symmetrel is prescribed for patients with a history of heart failure.
The dosage of Symmetrel may need careful adjustment in patients with orthostatic hypotension.
The possible occurrence of anticholinergic effects should be borne in mind particularly when treating patients with glaucoma or prostatic enlargement.
Symmetrel should be used with care in patients suffering from or with a history of recurrent eczematoid rash, and should be withdrawn if allergic skin reactions occur.
Isolated cases of corneal lesions have been reported, e.g. punctate sub-epithelial opacities which might be associated with superficial punctate keratitis, corneal epithelial oedema and markedly reduced visual acuity.
Because 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.

Discontinuation of Symmetrel in Parkinson's disease.

Abrupt discontinuation of anti-parkinsonian drugs, including Symmetrel, may result in worsening of the symptoms of Parkinson's disease or in symptoms resembling neuroleptic malignant syndrome (NMS), catatonia as well as in cognitive manifestations (e.g. confusion, disorientation, worsening of mental status, delirium). There have been isolated reports on a possible association between the aggravation of NMS or neuroleptic-induced catatonia and the withdrawal of amantadine in patients treated concurrently with neuroleptic agents and amantadine, following abrupt cessation of the latter. Therefore, treatment with amantadine should not be stopped abruptly.

Development of resistance during use for influenza A.

Resistance to amantadine is readily achieved by serial passage of influenza virus strains in vitro or in vivo in the presence of the drug. Influenza A viruses cross resistant to amantadine can emerge when this drug is used to treat influenza infections. Apparent transmission of drug-resistant viruses may have been the reason for 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.

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 dopamine agonists including Symmetrel. Dose reduction/ tapered discontinuation should be considered if such symptoms develop.

Use in renal or liver impairment.

Symmetrel should be used cautiously in patients with renal or liver disorders. In cases of impaired renal function the dosage should be adjusted according to the creatinine clearance of the individual patient and, ideally, amantadine plasma concentrations should be monitored. Since only small amounts of amantadine are eliminated by patients undergoing haemodialysis for renal failure, these patients should have their dosage carefully adjusted in order to avoid adverse reactions (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in the elderly.

Elderly patients are often especially susceptible to adverse reactions or exacerbation of pre-existing central nervous system symptoms (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).
Plasma amantadine concentrations are influenced by renal function. In the elderly, the elimination half-life tends to be longer and renal clearance lower than in younger subjects. A dose not exceeding 100 mg daily is recommended in elderly patients without renal disease. If the patient has any renal function impairment, the dosing interval should be adjusted (see Section 4.2 Dose and Method of Administration, Adults over 65 years, Dosage in renal impairment).

Paediatric use.

Symmetrel is not recommended for use in patients below the age of 5 years. Hypothermia has been observed in children. Caution should be exercised when prescribing Symmetrel to children for the prevention and treatment of influenza type A virus (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Observed interactions resulting in concomitant use not being recommended.

Concomitant administration of amantadine and anticholinergic agents may increase confusion, hallucinations, nightmares, gastrointestinal disturbances or other atropine-like side effects (also see Section 4.9 Overdose).
In isolated cases psychotic decompensation has been reported in patients receiving amantadine and concomitant antipsychotic drugs or levodopa.
Concomitant administration of amantadine with fixed dose combination of hydrochlorothiazide and triamterene may reduce the systemic clearance of the drug leading to increased plasma concentrations and toxic effects (confusion, hallucinations, ataxia, and myoclonus).

Anticipated interactions to be considered.

Drugs acting on the central nervous system.

Concomitant administration of amantadine and drugs or substances (e.g. alcohol) acting on the central nervous system may result in additive CNS toxicity. Close observation is recommended (also see Section 4.9 Overdose).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Symmetrel administered to both male and female rats at a dose equivalent to the maximum recommended human dose on a mg/m2 basis impaired fertility.
(Category B3)
Amantadine-related complications during pregnancy have been reported. Symmetrel is contraindicated during pregnancy. Women of child-bearing potential must use highly effective contraception during treatment, and for 5 days after their last dose of amantadine.
Amantadine passes into breast milk. Adverse drug reactions have been reported in breast-fed infants. Nursing mothers should not take Symmetrel.

4.8 Adverse Effects (Undesirable Effects)

The undesirable effects of amantadine usually appear within the first 1-4 days of treatment and promptly disappear in 24-48 hours after discontinuation of amantadine.
A direct relationship between dose and incidence of side effects has not been demonstrated. However, there seems to be a tendency towards more common adverse drug reactions, particularly affecting the central nervous system, with increasing doses.
The adverse reactions (Table 2) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common: ≥ 1/10 (≥ 10%); common: ≥ 1/100 to < 1/10 (≥ 1% to < 10%); uncommon: ≥ 1/1,000 to < 1/100 (≥ 0.1% to < 1%); rare: ≥ 1/10,000 to < 1/1,000 (≥ 0.01% to < 0.1%); very rare: < 1/10,000 (< 0.01%); not known: frequency has not been assessed.

Impulse control disorders.

Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Symmetrel (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Before use in elderly patients or those with impaired liver or kidney function, see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties. In patients over 65 years of age, both age and renal function should be taken into consideration. By age 65, renal function will typically have declined to a level at which reduced doses of Symmetrel or increased dosing interval are appropriate. Specific dosage schedules for patients over 65 years of age and those with impaired renal function are shown below.

Recommended dosages. Parkinson's disease.

Adults to 65 years.

When used alone, 100 mg daily for the first week of treatment, increasing in the second week to 100 mg twice daily. The dose can be titrated against signs and symptoms. Amounts exceeding 200 mg daily may provide some additional relief but may also be associated with increasing toxicity. In these cases the dose should be raised gradually, at intervals of not less than 1 week.

Adults over 65 years.

Since patients in this age group tend to have lower renal clearance and consequently higher plasma concentrations (see Section 5.2 Pharmacokinetic Properties), the recommended dose is 100 mg daily. If the patient has, or develops, any renal impairment, the dosing interval should be adjusted (see Section 4.2 Dose and Method of Administration, Dosage in renal impairment).

Note.

Patients deriving benefit initially from Symmetrel not uncommonly experience a reduction in effectiveness after a few weeks. Temporary discontinuation of Symmetrel for several weeks, followed by re-introduction of therapy, may result in regaining of benefit in some patients. The use of other anti-Parkinson drugs may be necessary. Treatment with Symmetrel must be reduced gradually because abrupt discontinuation may exacerbate Parkinson's syndrome, regardless of the patient's response to therapy (see Section 4.4 Special Warnings and Precautions for Use).

Combined treatment.

Any anti-Parkinson drug with which the patient is already being treated should be continued during the first stage of treatment with Symmetrel. In many cases it is then possible to gradually reduce the dosage of the other drug without prejudicing the treatment response. If increased side effects occur, however, its dosage should be reduced more quickly. In patients receiving high doses of L-dopa or anticholinergic drugs, the initial period of low dosage with Symmetrel should be extended to two weeks.

Drug induced extrapyramidal reactions.

Adults.

The most appropriate treatment is to reduce the dosage of the drug inducing the reactions. Where this is not practical, the usual dose of Symmetrel is 100 mg twice daily. Occasionally, a patient may require 100 mg three times daily in order to obtain an optimal response.
As drug-induced extra-pyramidal reactions may decrease or disappear without treatment, an attempt should be made to discontinue treatment with Symmetrel when the reactions have been controlled for a period.

Type A virus influenza.

Children aged 5-9 years.

100 mg once daily.

Children and adults aged 10-65 years.

100 mg twice daily. Effective prevention of influenza A has been reported with a dosage of 100 mg daily. This dosage may be indicated for persons who have demonstrated intolerance to 200 mg daily.

Adults over 65 years.

100 mg daily.
Dosage with Symmetrel should start immediately after suspected exposure and continue for at least 10 days. When exposure to infection is recurrent or prolonged, treatment throughout the epidemic may be indicated. Symmetrel is effective for prophylaxis only during the period of its administration. The recommended dosage should not be exceeded.

Dosage in renal impairment.

In patients with compromised renal function and in those on haemodialysis, the elimination half-life of amantadine is substantially prolonged, resulting in elevated plasma concentrations (see Section 5.2 Pharmacokinetic Properties). Careful adjustment of the dose of Symmetrel by increasing the dosing interval according to the creatinine clearance (see Table 1) is required in these patients. Ideally, amantadine plasma concentrations should be monitored. Careful surveillance of the patient is recommended (see Section 5.2 Pharmacokinetic Properties, Renal failure, Haemodialysis).

Loading dose on the first day of treatment with Symmetrel.

Starting dose as recommended for patients without renal impairment (see Section 4.2 Dose and Method of Administration, Parkinson's disease, Type A virus influenza).

Dose thereafter.

100 mg at interval shown in Table 1.
When it is not possible to measure creatinine clearance, the value may be estimated in patients with stable renal function using the formula of Cockcroft and Gault (see Equation 1).
This formula should only be used if the patient is in a steady state with respect to serum creatinine concentration.

4.7 Effects on Ability to Drive and Use Machines

Patients receiving treatment with Symmetrel should be warned that dizziness, blurred vision and other central nervous symptoms may occur and impair the patient's reactions, in which case they should not drive, operate potentially dangerous machinery or engage in other activities that may become hazardous because of decreased alertness (see Section 4.8 Adverse Effects (Undesirable Effects), Nervous system disorders).

4.9 Overdose

Overdose (acute overdose with multiples of the maximum recommended dose or overexposure due to high dosages for elderly and/or renally impaired patients) with Symmetrel capsules can lead to a fatal outcome (see Section 4.4 Special Warnings and Precautions for Use).

Signs and symptoms.

Neuromuscular disturbances and symptoms of acute psychosis are prominent features of acute poisoning with amantadine.

Central nervous system.

Hyper-reflexia, motor restlessness, convulsions; extrapyramidal signs: torsion spasms, dystonic posturing; confusion, disorientation, delirium, visual hallucinations, dilated pupils, dysphagia and myoclonus, aggression/ hostility, depressed level of consciousness and coma.

Respiratory system.

Hyperventilation, pulmonary oedema, respiratory distress including adult respiratory distress syndrome.

Cardiovascular system.

Disturbances of fluid, electrolyte and acid/ base balance, sinus tachycardia, arrhythmia and hypertension. Cardiac arrest and sudden cardiac death have been reported.

Gastrointestinal system.

Nausea, vomiting, dry mouth.

Renal function.

Urinary retention, renal dysfunction including increase in blood urea nitrogen (BUN) and decreased creatinine clearance.

Overdose from combined drug treatment.

The peripheral and central adverse effects of anticholinergic drugs are increased by the concomitant use of amantadine, and acute psychotic reactions (which may be identical to those caused by atropine poisoning) may occur, especially when large doses of anticholinergic agents are used (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). When overdosage of amantadine has occurred in conjunction with the use of alcohol or central nervous system stimulants, the signs and symptoms of acute poisoning with Symmetrel may be aggravated or otherwise modified.

Treatment.

There is no specific amantadine hydrochloride antidote.

Removal and/or inactivation of poisoning agent(s).

Induction of vomiting and/or gastric aspiration and lavage if patient is conscious, activated charcoal, saline cathartic, if judged appropriate. Since amantadine is largely excreted unchanged in the urine, maintenance of renal excretory function, copious diuresis, and forced diuresis, if necessary, are effective in removing it from the blood stream. Acidification of the urine favours the excretion of amantadine in the urine. Haemodialysis does not remove significant amounts of amantadine.
Monitoring of blood pressure, heart rate, ECG, respiration, body temperature, and treatment for possible hypotension and cardiac arrhythmias, as necessary. Caution is required when administering adrenergic substances in case of cardiac arrhythmias and hypotension as the clinical status may deteriorate due to arrhythmogenic nature of the adrenergic drugs.

Convulsions and excessive motor restlessness.

Administer anticonvulsants such as diazepam I.V., paraldehyde I.M. or per rectum, or phenobarbital I.M.

Acute psychotic symptoms, delirium, dystonic posturing, myoclonic manifestations.

Physostigmine by slow I.V. infusion (1 mg doses in adults, 0.5 mg in children) in repeated administration according to initial response and subsequent need has been reported.

Retention of urine.

The bladder should be catheterized; an indwelling catheter can be left in place for the time required.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

6 Pharmaceutical Particulars

6.1 List of Excipients

Symmetrel soft capsules also contain the inactive ingredients: rape seed oil, lecithin, beeswax-yellow, soya oil-hydrogenated and soya oil-partially hydrogenated. The capsule shell contains: sodium ethyl hydroxybenzoate, sodium propyl hydroxybenzoate, gelatin, glycerol, iron oxide red, Karion 83 (sorbitol, mannitol and starch-hydrolysed maize as 70% aqueous solution), titanium dioxide, edible ink-white.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from moisture.

6.5 Nature and Contents of Container

White plastic bottles of 100 capsules, fitted with a push and turn closure.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes