Amantadine Hydrochloride 100 MG Oral Capsule

WARNINGS

Deaths Deaths have been reported from overdose with amantadine.

The lowest reported acute lethal dose was 1 gram.

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 (see OVERDOSAGE ).

Deaths due to drug accumulation (overdosage) have been reported in patients with renal impairment, who were prescribed higher than recommended doses of Amantadine Hydrochloride for their level of renal function (see DOSAGE AND ADMINISTRATION: Dosage for Impaired Renal Function and OVERDOSAGE ).

Suicide Attempts Suicide attempts, some of which have been fatal, have been reported in patients treated with amantadine, many of whom received short courses for influenza treatment or prophylaxis.

The incidence of suicide attempts is not known and the pathophysiologic mechanism is not understood.

Suicide attempts and suicidal ideation have been reported in patients with and without prior history of psychiatric illness.

Amantadine can exacerbate mental problems in patients with a history of psychiatric disorders or substance abuse.

Patients who attempt suicide may exhibit abnormal mental states which include disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions and somnolence or insomnia.

Because of the possibility of serious adverse effects, caution should be observed when prescribing amantadine hydrochloride capsules to patients being treated with drugs having CNS effects, or for whom the potential risks outweigh the benefit of treatment.

CNS Effects Patients with a history of epilepsy or other “seizures” should be observed closely for possible increased seizure activity.

Patients receiving amantadine hydrochloride capsules who note central nervous system effects or blurring of vision should be cautioned against driving or working in situations where alertness and adequate motor coordination are important.

Other Patients with a history of congestive heart failure or peripheral edema should be followed closely as there are patients who developed congestive heart failure while receiving amantadine hydrochloride capsules.

Patients with Parkinson’s disease improving on amantadine hydrochloride capsules should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis.

Because Amantadine Hydrochloride Capsules, USP has anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma.

DRUG INTERACTIONS

Drug Interactions Careful observation is required when amantadine 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 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, 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.

OVERDOSAGE

Deaths have been reported from overdose with amantadine.

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.

However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult 2 at 1- to 2-hour intervals and 0.5 mg doses in a child 3 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.

Since the excretion rate of amantadine 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 overdose, since the dopaminergic activity of amantadine 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.

DESCRIPTION

Amantadine hydrochloride, USP is designated chemically as 1-adamantanamine hydrochloride.

Its molecular weight is 187.71 with a molecular formula C 10 H 18 NCl.

It has the following structural formula: Amantadine hydrochloride, USP is a stable white or nearly white crystalline powder, freely soluble in water and soluble in alcohol and in chloroform.

Amantadine hydrochloride, USP has pharmacological actions as both an anti-Parkinson and an antiviral drug.

Amantadine hydrochloride, USP is available as 100 mg capsules for oral administration.

Inactive ingredients: corn starch, croscarmellose sodium, ethylcellulose, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

The capsule shells and imprinting ink contain: ammonium hydroxide, FD&C Blue #1, FD&C Red #40, gelatin, methylparaben, propylene glycol, propylparaben, shellac, simethicone, sodium lauryl sulfate, and titanium dioxide.

amantadine chemical structure

HOW SUPPLIED

Amantadine hydrochloride capsules, USP for oral administration are available as: 100 mg: Red capsules imprinted GG 634 and supplied as: NDC 0832-2012-00 bottles of 100 NDC 0832-2012-50 bottles of 500 Store at 20° to 25°C (68° to 77°F) (see USP Controlled Room Temperature).

Dispense in a tight, light-resistant container as defined in the USP.

GERIATRIC USE

Usage in the Elderly Because amantadine is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines.

Thus, the dose of amantadine 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 ).

MECHANISM OF ACTION

Mechanism of Action Antiviral The mechanism by which amantadine exerts its antiviral activity is not clearly understood.

It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein.

In certain cases, amantadine is also known to prevent virus assembly during virus replication.

It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.

INDICATIONS AND USAGE

Amantadine hydrochloride capsules, USP are indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus.

Amantadine hydrochloride capsules, USP are also indicated in the treatment of parkinsonism and drug-induced extrapyramidal reactions.

Influenza A Prophylaxis Amantadine hydrochloride capsules, USP are indicated for chemoprophylaxis against signs and symptoms of influenza A virus infection.

Because 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.

Following vaccination during an influenza A outbreak, amantadine prophylaxis should be considered for the 2- to 4-week time period required to develop an antibody response.

Influenza A Treatment Amantadine hydrochloride capsules, USP are also indicated in the treatment of uncomplicated respiratory tract illness caused by influenza A virus strains especially when administered early in the course of illness.

There are no well-controlled clinical studies demonstrating that treatment with amantadine hydrochloride capsules, USP will avoid the development of influenza A virus pneumonitis or other complications in high risk patients.

There is no clinical evidence indicating that amantadine hydrochloride capsules, USP are effective in the prophylaxis or treatment of viral respiratory tract illnesses other than those caused by influenza A virus strains.

The following points should be considered before initiating treatment or prophylaxis with amantadine hydrochloride capsules, USP.

• Amantadine hydrochloride capsules, USP are not a substitute for early vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.

• Influenza viruses change over time.

Emergence of resistance mutations could decrease drug effectiveness.

Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs.

Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use amantadine hydrochloride capsules, USP.

Parkinson’s Disease/Syndrome Amantadine hydrochloride capsules, USP are indicated in the treatment of idiopathic Parkinson’s disease (Paralysis Agitans), postencephalitic parkinsonism and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication.

It is indicated in those elderly patients believed to develop parkinsonism in association with cerebral arteriosclerosis.

In the treatment of Parkinson’s disease, amantadine is less effective than levodopa, (-)-3-(3,4-dihydroxyphenyl)-L-alanine, and its efficacy in comparison with the anticholinergic antiparkinson drugs has not yet been established.

Drug-Induced Extrapyramidal Reactions Amantadine hydrochloride, USP is indicated in the treatment of drug-induced extrapyramidal reactions.

Although anticholinergic-type side effects have been noted with amantadine when used in patients with drug-induced extrapyramidal reactions, there is a lower incidence of these side effects than that observed with the anticholinergic antiparkinson drugs.

PEDIATRIC USE

Pediatric Use The safety and efficacy of amantadine in newborn infants and infants below the age of 1 year have not been established.

PREGNANCY

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 produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m 2 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/m 2 basis).

The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m 2 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

NUSRING MOTHERS

Nursing Mothers Amantadine is excreted in human milk.

Use is not recommended in nursing mothers.

INFORMATION FOR PATIENTS

Information for Patients 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.

DOSAGE AND ADMINISTRATION

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 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 is 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 has 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 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 is 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: CREATININE CLEARANCE (mL/min/1.73m 2 ) AMANTADINE HYDROCHLORIDE CAPSULES DOSAGE 30 to 50 200 mg 1st day and 100 mg each day thereafter 15 to 29 200 mg 1st day followed by 100 mg on alternate days <15 200 mg every 7 days The recommended dosage for patients on hemodialysis is 200 mg every 7 days.