Amantadine

Before taking amantadine, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to amantadine or to any of its ingredients
• have epilepsy or a history of seizures
• have liver problems
• have kidney problems especially in patients older than 65 years
• have heart problems such as congestive heart failure
• have swelling of arms, legs, or feet
• have untreated vision problems such as angle closure glaucoma
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of amantadine can be fatal.

Overdose symptoms may include fever, aggression, behavior changes, hallucinations, severe headache or pounding in your ears, muscle stiffness, problems with balance or walking, fast heart rate, urinating less than usual, trouble breathing, seizure (convulsion), or fainting.

Amantadine hydrochloride should not be discontinued abruptly in patients with Parkinson's disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of Amantadine hydrochloride should be reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.

Neuroleptic Malignant Syndrome (NMS): Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of Amantadine hydrochloride therapy. Therefore, patients should be observed carefully when the dosage of Amantadine hydrochloride is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin.

The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies.

Renal disease: Because Amantadine hydrochloride is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of Amantadine hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older (see DOSAGE AND ADMINISTRATION: Dosage for Impaired Renal Function).

Liver disease: Care should be exercised when administering Amantadine hydrochloride to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving Amantadine hydrochloride, though a specific relationship between the drug and such changes has not been established.

Melanoma: Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Amantadine hydrochloride capsules for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Other: The dose of Amantadine hydrochloride may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering Amantadine hydrochloride to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents.

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Amantadine hydrochloride has not been shown to prevent such complications.

Patients should be advised of the following information:

Blurry vision and/or impaired mental acuity may occur.

Gradually increase physical activity as the symptoms of Parkinson's disease improve.

Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, light-headedness and orthostatic hypotension.

Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs, notify physician.

Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness of breath occur.

Do not take more medication than prescribed because of the risk of overdose. If there is no improvement in a few days, or if medication appears less effective after a few weeks, discuss with a physician.

Consult physician before discontinuing medication.

Seek medical attention immediately if it is suspected that an overdose of medication has been taken.

There have been reports of patients experiencing intense urges to gamble, increased sexual urges and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease, including Amantadine. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Amantadine. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Amantadine. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Amantadine.

Drug Interactions

Careful observation is required when Amantadine hydrochloride is administered concurrently with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of Amantadine.

Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson's disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of triamterene and hydrochlorothiazide capsules resulted in a higher plasma Amantadine concentration in a 61 year-old man receiving Amantadine hydrochloride capsules 100 mg t.i.d. for Parkinson's disease.1 It is not known which of the components of triamterene and hydrochlorothiazide capsules contributed to the observation or if related drugs produce a similar response.

Coadministration of quinine or quinidine with Amantadine was shown to reduce the renal clearance of Amantadine by about 30%.

The concurrent use of Amantadine hydrochloride with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of Amantadine hydrochloride, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of Amantadine hydrochloride.

Carcinogenesis and Mutagenesis

Long-term in vivo animal studies designed to evaluate the carcinogenic potential of Amantadine hydrochloride have not been performed. In several in vitro assays for gene mutation, Amantadine hydrochloride did not increase the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed either with or without a liver metabolic activation extract. Further, there was no evidence of chromosome damage observed in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test (140 to 550 mg/kg; estimated human equivalent doses of 11.7 to 45.8 mg/kg based on body surface area conversion).

Impairment of Fertility

The effect of Amantadine on fertility has not been adequately tested, that is, in a study conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. In a three litter, non-GLP, reproduction study in rats, Amantadine hydrochloride at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m2 basis) administered to both males and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m2 basis); intermediate doses were not tested.

Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested Amantadine 2 weeks prior to, and during the IVF cycle.

Pregnancy

Pregnancy Category C

The effect of Amantadine on embryofetal and peri-postnatal development has not been adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. However, in two non-GLP studies in rats in which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7 to 14 of gestation, Amantadine hydrochloride produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m2 basis). In the non-GLP rat study in which females were dosed on Days 7 to 14 of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a mg/m2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m2 basis). The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate and well-controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of Amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to Amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to Amantadine (100 mg/d) administered during the first 2 weeks of pregnancy.

Amantadine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

Nursing Mothers

Amantadine hydrochloride is excreted in human milk. Use is not recommended in nursing mothers.

Pediatric Use

The safety and efficacy of Amantadine hydrochloride in newborn infants and infants below the age of 1 year have not been established.

Usage in the Elderly

Because Amantadine hydrochloride is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of Amantadine hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of Amantadine hydrochloride capsules may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see DOSAGE AND ADMINISTRATION).

The adverse reactions reported most frequently at the recommended dose of Amantadine hydrochloride (5% to 10%) are: nausea, dizziness (lightheadedness), and insomnia.

Less frequently (1% to 5%) reported adverse reactions are: depression, anxiety and irritability, hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral edema, orthostatic hypotension, headache, somnolence, nervousness, dream abnormality, agitation, dry nose, diarrhea and fatigue.

Infrequently (0.1% to 1%) occurring adverse reactions are: congestive heart failure, psychosis, urinary retention, dyspnea, skin rash, vomiting, weakness, slurred speech, euphoria, thinking abnormality, amnesia, hyperkinesia, hypertension, decreased libido, and visual disturbance, including punctate subepithelial or other corneal opacity, corneal edema, decreased visual acuity, sensitivity to light, and optic nerve palsy.

Rare (less than 0.1%) occurring adverse reactions are: instances of convulsion, leukopenia, neutropenia, eczematoid dermatitis, oculogyric episodes, suicidal attempt, suicide, and suicidal ideation (see WARNINGS).

Other adverse reactions reported during postmarketing experience with Amantadine hydrochloride usage include:

Nervous System/Psychiatric – coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, and tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech;

Cardiovascular – cardiac arrest, arrhythmias including malignant arrhythmias, hypotension, and tachycardia;

Respiratory – acute respiratory failure, pulmonary edema, and tachypnea;

Gastrointestinal – dysphagia;

Hematologic – leukocytosis, agranulocytosis;

Special Senses – keratitis and mydriasis;

Skin and Appendages – pruritus and diaphoresis;

Miscellaneous - neuroleptic malignant syndrome (see WARNINGS), allergic reactions including anaphylactic reactions, edema, fever, pathological gambling, increased libido including hypersexuality and impulse control symptoms.

Laboratory Test – elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and SGPT.

The dose of Amantadine hydrochloride capsules may need reduction in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function (see Dosage for Impaired Renal Function).

Dosage for Prophylaxis and Treatment of Uncomplicated Influenza A Virus Illness:

Adult

The adult daily dosage of Amantadine hydrochloride capsules is 200 mg; two 100 mg capsules as a single daily dose. The daily dosage may be split into one capsule of 100 mg twice a day. If central nervous system effects develop in once-a-day dosage, a split dosage schedule may reduce such complaints. In persons 65 years of age or older, the daily dosage of Amantadine hydrochloride capsules is 100 mg.

A 100 mg daily dose has also been shown in experimental challenge studies to be effective as prophylaxis in healthy adults who are not at high risk for influenza-related complications. However, it has not been demonstrated that a 100 mg daily dose is as effective as a 200 mg daily dose for prophylaxis, nor has the 100 mg daily dose been studied in the treatment of acute influenza illness. In recent clinical trials, the incidence of central nervous system (CNS) side effects associated with the 100 mg daily dose was at or near the level of placebo. The 100 mg dose is recommended for persons who have demonstrated intolerance to 200 mg of Amantadine hydrochloride capsules daily because of CNS or other toxicities.

Pediatric Patients

1 yr. to 9 yrs. of age: The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day), but not to exceed 150 mg per day.

9 yrs. to 12 yrs. of age: The total daily dose is 200 mg given as one capsule of 100 mg twice a day. The 100 mg daily dose has not been studied in this pediatric population. Therefore, there are no data which demonstrate that this dose is as effective as or is safer than the 200 mg daily dose in this patient population.

Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or after contact with individuals with influenza A virus respiratory tract illness.

Amantadine hydrochloride capsules should be continued daily for at least 10 days following a known exposure. If Amantadine hydrochloride capsules are used chemoprophylactically in conjunction with inactivated influenza A virus vaccine until protective antibody responses develop, then it should be administered for 2 to 4 weeks after the vaccine has been given. When inactivated influenza A virus vaccine is unavailable or contraindicated, Amantadine hydrochloride capsules should be administered for the duration of known influenza A in the community because of repeated and unknown exposure.

Treatment of influenza A virus illness should be started as soon as possible, preferably within 24 to 48 hours after onset of signs and symptoms, and should be continued for 24 to 48 hours after the disappearance of signs and symptoms.

Dosage for Parkinsonism:

Adult

The usual dose of Amantadine hydrochloride capsules is 100 mg twice a day when used alone. Amantadine Hydrochloride Capsules have an onset of action usually within 48 hours.

The initial dose of Amantadine hydrochloride capsules is 100 mg daily for patients with serious associated medical illnesses or who are receiving high doses of other antiparkinson drugs. After one to several weeks at 100 mg once daily, the dose may be increased to 100 mg twice daily, if necessary.

Occasionally, patients whose responses are not optimal with Amantadine hydrochloride capsules at 200 mg daily may benefit from an increase up to 400 mg daily in divided doses. However, such patients should be supervised closely by their physicians.

Patients initially deriving benefit from Amantadine hydrochloride capsules not uncommonly experience a fall-off of effectiveness after a few months. Benefit may be regained by increasing the dose to 300 mg daily. Alternatively, temporary discontinuation of Amantadine hydrochloride capsules for several weeks, followed by reinitiation of the drug, may result in regaining benefit in some patients. A decision to use other antiparkinson drugs may be necessary.

Dosage for Concomitant Therapy

Some patients who do not respond to anticholinergic antiparkinson drugs may respond to Amantadine hydrochloride capsules. When Amantadine hydrochloride capsules or anticholinergic antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional benefit.

When Amantadine hydrochloride capsules and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic benefits. Amantadine hydrochloride capsules should be held constant at 100 mg daily or twice daily while the daily dose of levodopa is gradually increased to optimal benefit.

When Amantadine hydrochloride capsules are added to optimal well-tolerated doses of levodopa, additional benefit may result, including smoothing out the fluctuations in improvement which sometimes occur in patients on levodopa alone. Patients who require a reduction in their usual dose of levodopa because of development of side effects may possibly regain lost benefit with the addition of Amantadine hydrochloride capsules.

Dosage for Drug-Induced Extrapyramidal Reactions:

Adult

The usual dose of Amantadine hydrochloride capsules is 100 mg twice a day. Occasionally, patients whose responses are not optimal with Amantadine hydrochloride capsules at 200 mg daily may benefit from an increase up to 300 mg daily in divided doses.

Dosage for Impaired Renal Function:

Depending upon creatinine clearance, the following dosage adjustments are recommended:

The recommended dosage for patients on hemodialysis is 200 mg every 7 days.

Influenza A treatment/prophylaxis: Note: Due to issues of resistance, amantadine is no longer recommended for the treatment or prophylaxis of influenza A (CDC 2011). Please refer to the current ACIP recommendations. The following is based on the manufacturer’s labeling:

Influenza A treatment: Oral: 200 mg once daily or 100 mg twice daily (may be preferred to reduce CNS effects); Note: Initiate within 24 to 48 hours after onset of symptoms; continue for 24 to 48 hours after symptom resolution (duration of therapy is generally 5 days [CDC 2011]).

Influenza A prophylaxis: Oral: 200 mg once daily or 100 mg twice daily (may be preferred to reduce CNS effects). Note: Continue prophylaxis throughout the peak influenza activity in the community or throughout the entire influenza season in patients who cannot be vaccinated. Development of immunity following vaccination takes ~2 weeks; amantadine therapy should be considered for high-risk patients from the time of vaccination until immunity has developed.

Drug-induced extrapyramidal symptoms: Oral: 100 mg twice daily; may increase to 300 mg/day in divided doses, if needed

Parkinson disease: Oral: Usual dose: 100 mg twice daily as monotherapy; may increase to 400 mg/day in divided doses, if needed, with close monitoring. Note: Patients with a serious concomitant illness or those receiving high doses of other antiparkinson drugs should be started at 100 mg once daily; may increase to 100 mg twice daily, if needed, after one to several weeks.

Chorea of Huntington disease (off-label use): 100 mg 3 to 4 times daily. Additional data may be necessary to further define the role of amantadine in this condition (Armstrong 2012; O'Suilleabhain 2003; Verhagen 2002).

Multiple sclerosis-related fatigue (off-label use): 100 mg twice daily. Additional data may be necessary to further define the role of amantadine in this condition (Ledinek 2013; Shaygannejad 2012).

Restless legs syndrome (off-label use): Initial: 100 mg daily; increase by 100 mg every 3 to 5 days based on response and tolerability up to 300 mg/day in 1 to 3 divided doses. Additional data may be necessary to further define the role of amantadine in this condition (Evidente 2000).

Traumatic brain injury (off-label use): Initial: 100 mg twice daily (morning and afternoon); may increase total daily dose by 100 mg every week based on response and tolerability up to 200 mg twice daily. Additional data may be necessary to further define the role of amantadine in this condition (Giacino 2012; Hammond 2014).

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Alcohol (Ethyl): May enhance the CNS depressant effect of Amantadine. Monitor therapy

Alkalinizing Agents: May increase the serum concentration of Amantadine. Monitor therapy

Amisulpride: Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Amisulpride. Amisulpride may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Avoid combination

Anticholinergic Agents: Amantadine may enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Antipsychotic Agents (First Generation [Typical]): Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

BuPROPion: Anti-Parkinson Agents (Dopamine Agonist) may enhance the adverse/toxic effect of BuPROPion. Monitor therapy

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Carbonic Anhydrase Inhibitors: May increase the serum concentration of Amantadine. Monitor therapy

Glycopyrrolate (Systemic): Amantadine may enhance the anticholinergic effect of Glycopyrrolate (Systemic). Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Influenza Virus Vaccine (Live/Attenuated): Antiviral Agents (Influenza A and B) may diminish the therapeutic effect of Influenza Virus Vaccine (Live/Attenuated). Management: Avoid anti-influenza antivirals during the period beginning 48 hours prior to and ending 2 weeks after vaccine administration. Persons receiving these agents within 2 weeks of the live intranasal spray vaccine should receive a repeat vaccine dose. Consider therapy modification

Memantine: NMDA Receptor Antagonists may enhance the adverse/toxic effect of Memantine. Monitor therapy

Methylphenidate: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Propiverine: May enhance the adverse/toxic effect of Amantadine. Monitor therapy

Sulpiride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Avoid combination

Trimethoprim: May enhance the adverse/toxic effect of Amantadine. Specifically, the risk of myoclonus and/or delirium may be increased. Amantadine may increase the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Amantadine. Monitor therapy

Urinary Acidifying Agents: May decrease the serum concentration of Amantadine. Monitor therapy

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Impulse control disorders: Dopamine agonists used for Parkinson disease or restless legs syndrome have been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), and/or binge eating. Causality has not been established, and controversy exists as to whether this phenomenon is related to the underlying disease, prior behaviors/addictions, and/or drug therapy. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.

• Melanoma: Risk for melanoma development is increased in Parkinson’s disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed.

• Neuroleptic malignant syndrome: Has been associated with neuroleptic malignant syndrome (associated with dose reduction or abrupt discontinuation).

• Suicidal ideation: There have been reports of suicidal ideation/attempt in patients with and without a history of psychiatric illness. May exacerbate mental problems in patients with a history of mental illness.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with heart failure, peripheral edema, or orthostatic hypotension; dosage reduction may be required.

• Eczema: Use with caution in patients with a history of recurrent and eczematoid dermatitis.

• Glaucoma: Avoid in untreated angle closure glaucoma.

• Hepatic impairment: Use with caution in patients with hepatic impairment; rarely, reversible elevations in transaminases have been reported.

• Influenza A: Appropriate use: Consult current guidelines. Due to increased resistance, the ACIP has recommended that rimantadine and amantadine no longer be used for the treatment or prophylaxis of influenza A in the United States until susceptibility has been re-established (CDC 2011).

• Parkinson's disease: Appropriate use: When treating Parkinson disease, do not discontinue abruptly. In many patients, the therapeutic benefits of amantadine are limited to a few months.

• Psychosis: Use with caution in patients with uncontrolled psychosis or severe psychoneurosis.

• Renal impairment: Use with caution in patients with renal impairment; dosage reduction recommended.

• Seizure disorder: Use with caution in patients with a history of seizure disorder.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in the elderly; may be more susceptible to CNS effects (using 2 divided daily doses may minimize this effect). These patients may require dosage reductions.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007).

Other warnings/precautions:

• Tolerance: Tolerance has also been reported with long-term use (Zubenko1984).

• Withdrawal syndrome: May cause agitation, anxiety, delirium, delusions, depression, hallucinations, paranoia, parkinsonian crisis, slurred speech, or stupor. Upon discontinuation of amantadine therapy, gradually taper dose.

Renal function, Parkinson's symptoms, mental status, influenza symptoms, blood pressure

Normally recommended dose: 200 mg orally per day in 1 to 2 divided doses

Comments:
-Twice-daily dosing may minimize central nervous system (CNS) side effects.
-In healthy adults not at risk for influenza-related complications, 100 mg per day may be effective for prophylaxis; not known if 100 mg/day is as effective as 200 mg/day.
-For patients with intolerance to 200 mg/day due to CNS or other toxicities, 100 mg/day is recommended.

Approved indications: For treatment of uncomplicated respiratory tract illness due to influenza A virus strains, especially when used early in course of illness; for chemoprophylaxis against signs/symptoms of influenza A virus infection

Normally recommended dose: 200 mg orally per day in 1 to 2 divided doses

Comments:
-Twice-daily dosing may minimize central nervous system (CNS) side effects.
-In healthy adults not at risk for influenza-related complications, 100 mg per day may be effective for prophylaxis; not known if 100 mg/day is as effective as 200 mg/day.
-For patients with intolerance to 200 mg/day due to CNS or other toxicities, 100 mg/day is recommended.

Approved indications: For treatment of uncomplicated respiratory tract illness due to influenza A virus strains, especially when used early in course of illness; for chemoprophylaxis against signs/symptoms of influenza A virus infection

Monotherapy:
100 mg orally twice a day; onset usually within 48 hours

In patients with serious associated medical illnesses or receiving high doses of other antiparkinson drugs:
Initial dose: 100 mg once a day
After 1 to several weeks at initial dose: The dose may be increased to 100 mg orally twice a day, if needed.

Comments:
-Patients whose responses are not optimal at 200 mg/day may benefit from an increase up to 400 mg per day in divided doses; close supervision recommended.
-Amantadine's efficacy can wane after a few months. If patient is not at maximum tolerated dose, increasing dose may help. Alternatively, temporary discontinuation of drug for several weeks may help to recover some of the drug's effects when it is reinstated. The use of other antiparkinson drugs may be necessary.

Concomitant therapy:
-When amantadine and levodopa are started concurrently, rapid therapeutic benefits may occur. Amantadine dose should remain constant at 100 mg orally once or twice a day while the daily dose of levodopa is gradually increased to optimal benefit.
-Additional benefit may result from adding amantadine to optimal well-tolerated doses of levodopa; such benefit includes smoothing out improvement fluctuations that can occur with levodopa alone. Patients who reduce levodopa dose due to side effects may regain lost benefit with the addition of amantadine.

Approved indication: For treatment of parkinsonism

Normally recommended dose:
65 years or older: 100 mg orally per day

Approved indications: For treatment of uncomplicated respiratory tract illness due to influenza A virus strains, especially when used early in course of illness; for chemoprophylaxis against signs/symptoms of influenza A virus infection

CrCl 30 to 50 mL/min: 200 mg orally the first day and 100 mg each day thereafter
CrCl 15 to 29 mL/min: 200 mg orally the first day followed by 100 mg on alternate days
CrCl less than 15 mL/min: 200 mg orally every 7 days

Dosage Forms & Strengths

capsule or tablet (generic)

• 100mg

syrup (generic)

• 50mg/5mL

capsule, extended-release (Gocovri)

• 68.5mg
• 137mg

Parkinson Disease

Monotherapy: 100 mg/day PO initially; may be increased to 100 mg q12hr after at least 1 week; dose may increase up to 400 mg/day in divided doses with close monitory if necessary

Serious concomitant illness or those receiving high doses of other antiparkinson drugs: 100 mg PO qDay; may increase to 100 mg q12hr, if needed, after one to several week

Dyskinesia Associated with Parkinson Disease

Indicated for dyskinesia in patients with Parkinson disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications

Extended-release capsule: 137 mg PO once qHS; increase to recommended dose of 274 mg (two 137 mg extended-release capsules) PO qHS after 1 week

see Administration

Drug-Induced Extrapyramidal Symptoms

100 mg PO q12hr; not to exceed 300 mg/day

Influenza A Prophylaxis or Treatment

NOTE: Because of resistance, amantadine is no longer recommended for prophylaxis or treatment of influenza A; refer to current CDC recommendations

200 mg; two 100 mg tablets (or 4 teaspoonfuls of syrup) as a single daily dose; may split daily dosage to one 100 mg tablet (or 2 teaspoonfuls of syrup) q12hr; if central nervous system effects develop in once-a-day dosage, a split dosage schedule may reduce such complaints

Dosage Modifications

Renal impairment

• capsule, tablet, or syrup
  • CrCl 30-50 mL/min: 200 mg PO on 1st day, then 100 mg/day PO
  • CrCl 15-29 mL/min: 200 mg PO on 1st day, then 100 mg PO every other day
  • CrCl <15 mL/min; hemodialysis: 200 mg PO weekly
• capsule, extended-release
  • CrCl 30-59 mL/min: 68.5 mg PO qHS initially; not to exceed 137 mg PO qHS
  • CrCl 15-29 mL/min: 68.5 mg PO qHS
  • CrCl <15 mL/min: Contraindicated

Dosing Considerations

Concomitant use of alcohol when using amantadine extended-release is not recommended owing to increased CNS effects and may result in dose-dumping

Dosage Forms & Strengths

capsule or tablet (generic)

• 100mg

syrup (generic)

• 50mg/5mL

Influenza A Treatment

NOTE: Because of resistance, amantadine is no longer recommended for prophylaxis or treatment of influenza A; refer to current CDC recommendations

1-9 years or <40 kg (any age): 5 mg/kg/day PO in single dose or divided q12 hr; not to exceed 150 mg/day

≥10 years and <40 kg: 5 mg/kg/day PO divided q12hr

≥10 years and ≥40 kg: 100 mg PO q12hr

Parkinson Disease

>65 years: Therapy should be based on renal function

Influenza A Prophylaxis or Treatment

≥65 years: 100 mg PO as a single dose

>10%

capsule, extended-release

• Hallucinations (21%)
• Dizziness (16%)
• Dry mouth (16%)
• Peripheral edema (16%)
• Constipation (13%)
• Fall (13%)
• Orthostatic hypotension (13%)

1-10%

capsule, syrup, tablet

• Agitation, irritability
• Anorexia
• Anxiety, hallucinations, insomnia, depression, confusion
• Ataxia
• Constipation, diarrhea, xerostomia
• Depression
• Diarrhea
• Dizziness, headache
• Dry nose
• Fatigue, somnolence
• Livedo reticularis
• Nervousness
• Orthostatic hypotension
• Peripheral edema

capsule, extended-release

• Urinary tract infection (10%)
• Anxiety (7%)
• Insomnia (7%)
• Depression/depressed mood (6%)
• Contusion (6%)
• Livedo reticularis (6%)
• Decreased appetite (6%)
• Benign prostatic hyperplasia (6%)
• Blurred vision (4%)
• Abnormal dreams (4%)
• Confusional state (3%)
• Vomiting (3%)
• Dystonia (3%)
• Pigmentation disorder (3%)
• Cataract (3%)

<1%

capsule, syrup, tablet

• Amnesia
• CHF
• Decreased libido
• Dyspnea
• Eczematoid dermatitis
• Euphoria
• Hyperkinesis
• Hypertension
• Instances of convulsions
• Leukopenia
• Neutropenia
• Oculogyric episodes
• Psychosis
• Rash
• Slurred speech

Frequency Not Defined

capsule, extended-release

• Somnolence
• Falling asleep during daily activities
• Suicidality
• Psychotic behavior
• Dizziness
• Orthostatic hypotension
• Withdrawal-emergent hyperpyrexia
• Confusion
• Impulse control/compulsive disorders

Contraindications

capsule, tablet, syrup

• Hypersensitivity to amantadine, rimantadine
• Untreated narrow-angle glaucoma
• Breastfeeding

capsule, extended-release

• End-stage renal disease (CrCl <15 mL/min)

Cautions

Reports of falling asleep while engaged in activities of daily living (eg, operation of motor vehicles); patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event; advise patients of the potential to develop drowsiness

Avoid abrupt withdrawal; abrupt discontinuation of amantadine may cause an increase in symptoms of Parkinson disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech

In clinical trials, suicidal ideation, depression, and/or depressed mood were reported; monitor for depression, including suicidal ideation or behavior

capsule, tablet, syrup

• Since 2008-09 influenza season, Centers for Disease Control and Prevention (CDC) advises against use for treatment or prophylaxis of influenza in US
• Reports of congestive heart failure (CHF), peripheral edema, and hypotension with amantadine; monitor patients with history of CHF, peripheral edema, and/or orthostatic hypotension
• Amantadine may accumulate in the plasma and body when renal function declines; see Dosing Considerations
• Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine, though the mechanism is unknown
• History of seizures, eczematoid rash, severe psychosis or psychoneurosis
• Consider reducing anticholinergic dosages before initiating amantadine therapy
• Risk of neuroleptic malignant syndrome (NMS) with dosage reduction or withdrawal; management of NMS should include intensive symptomatic treatment, medical monitoring, and treatment of any concomitant serious medical problems for which specific treatments are available
• Possibility of reduced effectiveness after several months; may regain efficacy if dosage is increased

capsule, extended-release

• Patients with a major psychotic disorder should ordinarily not be treated with amantadine because of the risk of exacerbating psychosis; observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases
• In controlled clinical trials, patients experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension; monitor patients for dizziness and orthostatic hypotension, especially after starting amantadine extended-release or increasing the dose

Parkinson patients

• Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and inability to control these urges while taking one or more of the medications, including amantadine, that increase central dopaminergic tone
• May be linked to higher melanoma risk; ; monitor for melanomas frequently and on a regular basis when using amantadine for any indication; periodic skin examinations should be performed by appropriately qualified individuals

Pregnancy

No adequate data on developmental risk associated with amantadine use in pregnant women; animal studies suggest a potential risk for fetal harm with amantadine; in mice and rats, adverse developmental effects (embryo lethality, increased incidence of malformations, and reduced fetal body weight) were observed when amantadine was administered to pregnant animals at clinically relevant doses

In mice, oral administration of amantadine (0, 10, or 40 mg/kg/day) to pregnant animals during organogenesis (gestation days 7-12) resulted in embryo lethality and reduced fetal body weight at highest dose tested, which was associated with maternal toxicity; the no-effect dose for developmental toxicity in mice (10 mg/kg/day) is less than the recommended human dose (RHD) of 274 mg/day, based on body surface area (mg/m²)

Lactation

Amantadine is excreted into human milk, but amounts have not been quantified; there is no information on the risk to a breastfed infant; amantadine may alter breast milk production or excretion

In published studies, amantadine reduced serum prolactin levels and symptoms of galactorrhea in patients taking neuroleptic drugs; the effect of amantadine on milk supply has not been evaluated in nursing mothers

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

OSMOLEX ER is available as extended-release tablets in the following configurations:

129 mg tablets: Round, biconvex, white coated tablets, imprinted on one side with a black “VP” over “075”

Unit-dose cards of 10: NDC 68025-075-11
Bottles of 30: NDC 68025-075-30
Bottles of 90: NDC 68025-075-90

193 mg tablets: Round, biconvex, green coated tabled, imprinted on one side with a black “VP” over “076”

Unit-dose cards of 10: NDC 68025-076-11
Bottles of 30: NDC 68025-076-30
Bottles of 90: NDC 68025-076-90

258 mg tablets: Round, biconvex, blue coated tablets, imprinted on one side with a black “VP” over “077”

Unit-dose cards of 10: NDC 68025-077-11
Bottles of 30: NDC 68025-077-30
Bottles of 90: NDC 68025-077-90

Storage And Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

Dispense in a tight container as defined in the USP.

Vertical Pharmaceuticals, LLC, Bridgewater, NJ 08807 USA. Revised: Feb 2018

Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 1 gram of amantadine hydrochloride (equivalent to 0.8 g amantadine). Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal, or central nervous system toxicity. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome, ARDS) have been reported with amantadine; renal dysfunction can occur, including increased BUN, decreased creatinine clearance, and renal insufficiency.

Central nervous system adverse reactions that have been reported with amantadine overdose include: agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, tremor disorientation, depersonalization, fear, delirium, psychotic reactions, lethargy, and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has occurred with amantadine overdose.

For acute overdose, general supportive measures should be employed along with immediate gastric decontamination if appropriate. Give intravenous fluids if necessary. The excretion rate of amantadine increases with acidification of the urine, which may increase the elimination of the drug. Monitor patients for arrhythmias and hypotension. Electrocardiographic monitoring may be needed after ingestion because arrhythmias have been reported after overdose, including arrhythmias with fatal outcomes. Adrenergic agents, such as isoproterenol, in patients with an amantadine overdose has been reported to induce arrhythmias.

Monitor blood electrolytes, urine pH, and urinary output. Although hemodialysis does not efficiently remove amantadine, it may be useful in the treatment of amantadine toxicity in patients with renal failure.