Amantadine

Common Side Effects of Amantadine:

Tell your doctor if you experience any of the following common side effects.

• Blurred vision
• Lightheadedness
• Trouble sleeping
• Dizziness
• Feeling as if you are going to faint

Serious Side Effects of Amantadine:

Call your doctor immediately if you experience any of the following serious side effects.

• Swelling of the hands, legs, or feet
• Shortness of breath
• Depression or anxiety
• Difficulty urinating
• Rash

Mechanism of Action

Antiviral

• The mechanism of antiviral activity is unknown; appears to primarily prevent the release of infectious viral nucleic acid into the host cell by interfering with transmembrane domain of viral M2 protein; amantadine is also known to prevent viral assembly during replication and inhibits replication of influenza A virus isolates from each of the subtypes (ie, H1N1, H2N2 and H3N2), but has very little or no activity against influenza B virus isolates

Parkinson disease

• The exact mechanism of amantadine in the treatment of Parkinson disease, drug-induced extrapyramidal reactions, dyskinesia associated with Parkinson disease is not known; amantadine is a weak, noncompetitive NMDA receptor antagonist
• Data from early animal studies suggest that amantadine may have direct and indirect effects on dopamine neurons; amantadine may have direct and indirect effects on dopamine neurons; it exerts dopaminergic-like side effects such as hallucinations and dizziness in humans; although amantadine has not been shown to possess direct anticholinergic activity, clinically, it exhibits anticholinergic-like side effects (dry mouth, urinary retention, and constipation)

Absorption

Bioavailability: 86-90%

Onset: Within 48 hr (antidyskinetic)

Peak plasma time: 2-4 hr (capsule, tablets, syrup); 12hrs (capsule, ER)

Peak plasma concentration (100-mg single dose): 0.24 mcg/mL

AUC (steady-state for single ER capsule dose): 20-30% higher

Distribution

Protein bound: 67%

Vd: 1.5-6.1 L/kg (capsule, tablet, syrup); 3-8 L/kg (capsule ER)

Metabolism

Not appreciably metabolized; small amounts of acetyl metabolite identified

Elimination

Half-life: 16 hr

Total body clearance: 0.2-0.3 L/hr/kg (capsule, tablet, syrup); 0.27 L/hr/kg (capsule, ER)

Excretion: Urine (80-90% unchanged) by glomerular filtration and tubular secretion

Amantadine is part of the drug class:

• Adamantane derivatives

You should not use amantadine if you are allergic to it, or:

• if you have received a nasal flu vaccine (FluMist) within the past 14 days.

To make sure amantadine is safe for you, tell your doctor if you have:

• epilepsy or other seizure disorder;

• congestive heart failure;

• kidney disease;

• liver disease;

• low blood pressure or a history of fainting;

• eczema;

• glaucoma;

• a history of alcoholism or drug addiction; or

• a history of mental illness, psychosis, or suicidal thoughts or actions.

Older adults may be more sensitive to the effects of this medicine.

You may have increased sexual urges, unusual urges to gamble, or other intense urges while taking this medicine. Talk with your doctor if this occurs.

People with Parkinson's disease may have a higher risk of skin cancer (melanoma). Talk to your doctor about this risk and what skin symptoms to watch for.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Amantadine can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

Amantadine should not be given to a child younger than 1 year old.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

If you take amantadine to treat influenza A, start taking the medicine within 24 to 48 hours after flu symptoms begin. Keep taking amantadine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

If you take this medicine for Parkinson symptoms, your doctor may occasionally change your dose to make sure you get the best results.

Amantadine will not treat an infection caused by bacteria. Call your doctor if your symptoms do not improve, or if you have a fever with a headache, cough, skin rash, or other new symptoms.

If you take amantadine for Parkinson symptoms: You should not stop using amantadine suddenly or your condition may become worse.

Store at room temperature away from moisture, heat, and light. Keep the bottle tightly closed when not in use.

Do not receive a "live" nasal flu vaccine (FluMist) while using amantadine, and for at least 48 hours after you stop taking amantadine. The vaccine may not work as well during this time, and may not fully protect you from disease.

Amantadine can cause side effects that may impair your vision, thinking, or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Drinking alcohol with this medicine can cause side effects.

Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with amantadine can increase your risk of unpleasant side effects.

Other drugs may interact with amantadine, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

In the U.S.

• Symmetrel

Available Dosage Forms:

• Capsule, Liquid Filled
• Solution
• Tablet
• Capsule
• Syrup

Therapeutic Class: Antiparkinsonian

Pharmacologic Class: Anticholinergic

Chemical Class: Adamantane

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For amantadine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to amantadine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of amantadine in children. Safety and efficacy have not been established in children younger than 1 year of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of amantadine in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart disease which may require an adjustment in the dose for patients receiving amantadine.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking amantadine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using amantadine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Potassium Chloride

Using amantadine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Bupropion
• Donepezil
• Memantine

Using amantadine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Betel Nut
• Bromperidol
• Triamterene
• Trimethoprim

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of amantadine. Make sure you tell your doctor if you have any other medical problems, especially:

• Congestive heart failure or
• Eczema, recurrent, history of or
• Epilepsy or seizures, history of or
• Liver disease or
• Low blood pressure (hypotension) or
• Neuroleptic malignant syndrome (NMS), history of or
• Peripheral edema (swelling of the hands, ankles, or feet) or
• Psychosis (a mental disease), history of—Use with caution. May make these conditions worse.

• Glaucoma, angle-closure, untreated (narrow-angle glaucoma)—Should not be used in patients with this condition.

• Kidney disease—Use with caution. The effects of amantadine may be increased because of slower removal from the body.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Blurred vision
• confusion
• difficult urination
• dizziness or lightheadedness
• fainting
• seeing, hearing, or feeling things that are not there
• swelling of the hands, feet, or lower legs

• Convulsions (seizures)
• decreased vision or any change in vision
• difficulty in coordination
• fever, chills, or sore throat
• increased blood pressure
• increase in body movements
• irritation and swelling of the eye
• loss of memory
• mental depression
• severe mood or mental changes
• skin rash
• slurred speech
• thoughts of suicide or attempts at suicide
• unexplained shortness of breath

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Agitation, anxiety, or nervousness
• difficulty concentrating
• headache
• irritability
• loss of appetite
• nausea
• purplish red, net-like, or blotchy spots on the skin
• trouble in sleeping or nightmares

• Constipation
• decrease in sexual desire
• diarrhea
• drowsiness
• dryness of the mouth, nose, and throat
• false sense of well-being
• vomiting
• unusual tiredness or weakness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Deaths have been reported from overdose with Amantadine hydrochloride. The lowest reported acute lethal dose was 1 gram. Because some patients have attempted suicide by overdosing with Amantadine, prescriptions should be written for the smallest quantity consistent with good patient management.

Acute toxicity may be attributable to the anticholinergic effects of Amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome – ARDS) have been reported; renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, gait abnormality, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.

There is no specific antidote for an overdose of Amantadine hydrochloride. However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult2 at 1- to 2-hour intervals and 0.5 mg doses in a child3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported to be effective in the control of central nervous system toxicity caused by Amantadine hydrochloride. For acute overdosing, general supportive measures should be employed along with immediate gastric lavage or induction of emesis. Fluids should be forced, and if necessary, given intravenously. The pH of the urine has been reported to influence the excretion rate of Amantadine hydrochloride. Since the excretion rate of Amantadine hydrochloride increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. The blood pressure, pulse, respiration and temperature should be monitored. The patient should be observed for hyperactivity and convulsions; if required, sedation, and anticonvulsant therapy should be administered. The patient should be observed for the possible development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and antihypotensive therapy should be given. Electrocardiographic monitoring may be required after ingestion, since malignant tachyarrhythmias can appear after overdose.

Care should be exercised when administering adrenergic agents, such as isoproterenol, to patients with an Amantadine hydrochloride overdose, since the dopaminergic activity of Amantadine hydrochloride has been reported to induce malignant arrhythmias.

The blood electrolytes, urine pH and urinary output should be monitored. If there is no record of recent voiding, catheterization should be done.

1.W.W. Wilson and A.H. Rajput, Amantadine-Dyazide Interaction, Can. Med. Assoc. J. 129:974-975, 1983.

2. D.F. Casey, N. Engl. J. Med. 298:516, 1978.

3. C.D. Berkowitz, J. Pediatr. 95:144, 1979.

Manufactured for
UPSHER-SMITH LABORATORIES, LLC
Maple Grove, MN 55369
MADE IN CANADA

Revised 0617

Elimination half-life is increased 2- to 3-fold or greater when CrCl is less than 40 mL/minute/1.73 m2.

Drug-induced extrapyramidal reactions: Treatment of drug-induced extrapyramidal reactions.

Influenza A prophylaxis: Chemoprophylaxis against signs and symptoms of influenza A virus infection; also refer to current Advisory Committee on Immunization Practices (ACIP) guidelines for recommendations during current influenza season.

Influenza A treatment: Treatment of uncomplicated respiratory tract illness caused by influenza A virus strains; also refer to current ACIP guidelines for recommendations during current influenza season.

Parkinson disease: Treatment of idiopathic Parkinson disease (paralysis agitans), postencephalitic parkinsonism, parkinsonism in association with cerebral arteriosclerosis, and symptomatic parkinsonism, which may follow injury to the nervous system by carbon monoxide intoxication.

May interfere with urine detection of amphetamines/methamphetamines (false-positive).

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea or insomnia. Have patient report immediately to prescriber behavioral changes, confusion, severe dizziness, passing out, hallucinations, seizures, shortness of breath, excessive weight gain, swelling of arms or legs, difficult urination, blurred vision, uncontrollable urges, change in balance, signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), agitation, irritability, panic attacks, mood changes, skin growths, mole changes, or signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, tachycardia, abnormal heartbeat, or sweating a lot) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Applies to amantadine: compounding powder, oral capsule, oral syrup, oral tablet

General

The adverse effects of amantadine are generally mild and, when they occur, may diminish or cease after a week or more on the medication. The most commonly reported side effects have included nausea, dizziness/lightheadedness, and insomnia in 5% to 10% of patients. All side effects, particularly those involving the central nervous system, may be more likely and more severe in patients with renal dysfunction and/or advanced age. Close monitoring for undue adverse effects is highly recommended.[Ref]

Nervous system

Nervous system side effects have included dizziness/lightheadedness and insomnia in 5% to 10% of patients. Hallucinations, confusion, ataxia, headache, somnolence, agitation, and fatigue have been reported in 1% to 5% of patients. Weakness, slurred speech, and hyperkinesia have been reported in 0.1% to 1% of patients and instances of convulsion have been reported in less than 0.1% of patients. At least one case of dropped head syndrome (associated with unbalanced contraction of the neck muscles) has been reported. Neuroleptic malignant syndrome, involuntary muscle contractions, coma, stupor, hypokinesia, hypertonia, gait abnormalities, paresthesia, EEG changes, and tremor have been reported during postmarketing experience. Agitation, hallucinations, stupor, and slurred speech have also occurred after abrupt discontinuation.[Ref]

Most cases of CNS toxicity have occurred in patients with renal insufficiency, seizure disorders, or psychiatric illnesses, and in elderly patients receiving 200 mg/day for influenza prophylaxis.[Ref]

Psychiatric

A case report describes a psychotic episode consisting of abnormal behavior in a young woman following a week of concomitant therapy with Naldecon. The patient had no personal or family history of psychiatric illness and no history of recreational substance use. It is not clear whether the episode was due to the amantadine, the phenylpropanolamine in the Naldecon, or an interaction between the two.

An exacerbation of panic occurred in one patient approximately 2 weeks after the initiation of amantadine therapy for Parkinson's disease. The causal relationship is unclear.

Severe CNS adverse effects have most often been associated with dosages greater than approximately 2 mg/kg/day and/or amantadine blood levels exceeding 1 mcg/mL. Most cases of CNS toxicity have occurred in patients with renal insufficiency, seizure disorders, or psychiatric illnesses, and in elderly patients receiving 200 mg/day for influenza prophylaxis.[Ref]

Psychiatric side effects have included depression, anxiety, irritability, nervousness, and dream abnormality in 1% to 5% of patients. Psychosis, euphoria, thinking abnormality, amnesia, and decreased libido have been reported in 0.1% to 1% of patients and suicidal attempt, suicidal ideation, and suicide have been reported in less than 0.1% of patients. Aggressive behavior, delirium, delusions, manic reaction, paranoid reaction, delusions of parasitosis, pathological gambling, increased libido (including hypersexuality), and impulse control symptoms have been reported during postmarketing experience. Delirium, delusions, paranoid reaction, anxiety, and depression have also occurred after abrupt discontinuation.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea in 5% to 10% of patients; diarrhea, constipation, anorexia, and dry mouth in 1% to 5% of patients; and vomiting in 0.1% to 1% of patients. Dysphasia has been reported during postmarketing experience.[Ref]

Cardiovascular

Cardiovascular side effects have included orthostatic hypotension in 1% to 5% of patients, and congestive heart failure and hypertension in 0.1% to 1% of patients. Cardiac arrest, arrhythmias (including malignant arrhythmias), hypotension, and tachycardia have been reported during postmarketing experience.[Ref]

Congestive heart failure with severe lower limb edema was diagnosed in one patient receiving amantadine, but resolved following drug discontinuation. A positive correlation with amantadine therapy could not be established, although no other cause for this patient's heart failure was found.[Ref]

Ocular

At least two cases of decreased visual acuity have been reported following approximately three weeks of amantadine therapy. Both resolved after drug discontinuation. In one case, the visual disturbance was related to a corneal edema similar to that seen with amiodarone.[Ref]

Ocular side effects have included visual disturbance, including punctuate subepithelial or other corneal opacity, corneal edema, decreased visual acuity, sensitivity to light, and optic nerve palsy in 0.1% to 1% of patients and oculogyric episodes in less than 0.1% of patients. Keratitis and mydriasis have been reported during postmarketing experience.[Ref]

Other

Other side effects have included peripheral edema (1% to 5%). Edema and fever have been reported during postmarketing experience.[Ref]

Respiratory

Respiratory side effects have included dry nose (1% to 5%) and dyspnea (0.1% to 1%). Acute respiratory failure, pulmonary edema, and tachypnea have been reported during postmarketing experience.[Ref]

Hematologic

Hematologic side effects have included leukopenia and neutropenia in less than 0.1% of patients. Leukocytosis and agranulocytosis have been reported during postmarketing experience.[Ref]

Dermatologic

Livedo reticularis occurs mainly on the legs. It is generally reversible over weeks to months following drug discontinuation.[Ref]

Dermatologic side effects have included livedo reticularis (1% to 5%), skin rash (0.1% to 1%), and eczematoid dermatitis (less than 0.1%). Pruritus and diaphoresis have been reported during postmarketing experience.[Ref]

Hypersensitivity

Hypersensitivity side effects have included allergic reactions including anaphylactic reactions during postmarketing experience.[Ref]

Genitourinary

Genitourinary side effects have included urinary retention (0.1% to 1%).[Ref]

Renal

Renal side effects have included elevations in BUN and serum creatinine during postmarketing experience.[Ref]

Hepatic

Hepatic side effects have included elevations in bilirubin, GGT, SGOT, and SGPT during postmarketing experience.[Ref]

Metabolic

Metabolic side effects have included elevated alkaline phosphatase and lactate dehydrogenase during postmarketing experience.

Musculoskeletal

Musculoskeletal side effects have included elevated creatine kinase during postmarketing experience.[Ref]

Endocrine

A 66-year-old female patient with Parkinson disease developed syndrome of inappropriate antidiuretic hormone secretion nine days after starting amantadine and entacapone. The patient did not recover following discontinuation of entacapone. Five days after entacapone was stopped, amantadine was discontinued. The patient gradually improved following amantadine discontinuation.[Ref]

Endocrine side effects have included at least one case of syndrome of inappropriate antidiuretic hormone secretion.[Ref]

Some side effects of amantadine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Consult WARNINGS section for dosing related precautions.

Amantadine is excreted into human milk in small amounts. Due to the potential for adverse effects, the use of amantadine while breastfeeding is not recommended.

Substance Name

Amantadine

CAS Registry Number

768-94-5

Drug Class

Antiinfective Agents

Antiparkinson Agents

Antiviral Agents

Dopamine Agents

Oral Administration

Administer daily dose in 2 divided doses to decrease adverse CNS effects

Administer 2nd dose several hours before bedtime to minimize insomnia

Extended-release capsule

• Extended-release capsule should be swallowed whole
• Do not crush, chew, or divide capsules; may be administered by carefully opening and sprinkling the entire contents on a small amount (teaspoonful) of soft food, such as applesauce
• The drug/food mixture should be swallowed immediately without chewing
• Do not store mixture for future use
• Administer with or without food

Storage

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

OSMOLEX ER is indicated for the treatment of Parkinson's disease and for the treatment of drug-induced extrapyramidal reactions in adult patients.

The following serious adverse reactions are described elsewhere in the labeling:

• Falling Asleep During Activities of Daily Living and Somnolence [see WARNINGS AND PRECAUTIONS]
• Suicidality and Depression [see WARNINGS AND PRECAUTIONS]
• Hallucinations/Psychotic Behavior [see WARNINGS AND PRECAUTIONS]
• Dizziness and Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
• Withdrawal-Emergent Hyperpyrexia and Confusion [see WARNINGS AND PRECAUTIONS]
• Impulse Control/Compulsive Behaviors [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The adverse reactions listed in Table 2 were identified in clinical studies of immediate-release amantadine. The most common adverse reactions reported in ≥5% of patients at the recommended dosage of immediate-release amantadine were nausea, dizziness/lightheadedness, and insomnia.

Table 2: Incidence of Adverse Reactions from Pooled Studies of Immediate-Release Amantadine

Oral Administration

Administer daily dose in 2 divided doses to decrease adverse CNS effects

Administer 2nd dose several hours before bedtime to minimize insomnia

Amantadine immediate- or extended-release products are not interchangeable

Extended-release capsule

Administer with or without food

Swallow capsule whole; do not crush, chew, or divide capsules

Missed dose: Take next dose as scheduled

• Unable to swallow capsule
  • Administer by carefully opening and sprinkling the entire contents on small amount (teaspoonful) of soft food, such as applesauce; drug/food mixture should be swallowed immediately without chewing
  • Do not store mixture for future use

Extended-release tablet

• Swallow capsule whole
• Do not chew, crush, or divide tablets; administered without regard to food
• Missed dose: Take next dose as scheduled

Storage

All formulations: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)