AMANTADINE HCL- amantadine hydrochloride capsule

United States - English - NLM (National Library of Medicine)

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Active ingredient:
AMANTADINE HYDROCHLORIDE (UNII: M6Q1EO9TD0) (AMANTADINE - UNII:BF4C9Z1J53)
Available from:
Rebel Distributors Corp.
INN (International Name):
AMANTADINE HYDROCHLORIDE
Composition:
AMANTADINE HYDROCHLORIDE 100 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. Amantadine Hydrochloride Capsules, USP are indicated for chemoprophylaxis against signs and symptoms of influenza A virus infection. Because Amantadine Hydrochloride 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 Hydrochloride Capsules, USP prophylaxis should be considered for the 2- to 4-week time period required to develop an antibody response. Amantadine Hydrochloride Capsules, USP are also indicated in the treatment of uncomplicated respirat
Product summary:
Amantadine Hydrochloride Capsules, USP are available as yellow, soft gelatin capsules containing 100 mg of amantadine hydrochloride, in bottles of 10's (NDC 21695-564-10). Each capsule is imprinted with “1704” in black ink. Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature]. Protect from moisture.  Dispense in a tight, light-resistant container, as defined in the USP. Keep out of reach of children. 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 by: Banner Pharmacaps Inc. 4125 Premier Drive High Point, NC 27265 Manufactured for Lannett Company, Inc. Philadelphia, PA 19136 Repackaged by: Rebel Distributors Corp. Thouand Oaks, CA 91320
Authorization status:
Abbreviated New Drug Application
Authorization number:
21695-564-10

AMANTADINE HCL- amantadine hydrochloride capsule

Rebel Distributors Corp.

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DESCRIPTION

Amantadine hydrochloride is designated chemically as 1-adamantanamine hydrochloride.

Amantadine hydrochloride is a stable white or nearly white crystalline powder, freely soluble in water

and soluble in alcohol and in chloroform.

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

Each capsule intended for oral administration contains 100 mg amantadine hydrochloride and has the

following inactive ingredients: Yellow Iron Oxide, gelatin, glycerin, hydrogenated vegetable oil,

lecithin-bleached, soybean oil, sorbitol, sorbitan, mannitol, titanium dioxide, white beeswax, vegetable

shortening, simethicone and iron oxide (black imprint ink).

USP Dissolution Test Pending.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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.

Antiviral Activity

Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e., H1N1,

H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A quantitative

relationship between the in vitro susceptibility of influenza A virus to amantadine and the clinical

response to therapy has not been established in man. Sensitivity test results, expressed as the

concentration of amantadine required to inhibit by 50% the growth of virus (ED ) in tissue culture vary

greatly (from 0.1 µg/mL to 25.0 µg/mL) depending upon the assay protocol used, size of virus

inoculum, isolates of influenza A virus strains tested, and the cell type used. Host cells in tissue culture

readily tolerated amantadine up to a concentration of 100 µg/mL.

Drug Resistance

Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from epidemic

strains in areas where adamantane derivatives are being used. Influenza viruses with reduced in vitro

sensitivity have been shown to be transmissible and to cause typical influenza illness. The quantitative

relationship between the in vitro sensitivity of influenza A variants to amantadine and the clinical

response to therapy has not been established.

Mechanism of Action: Parkinson's Disease

The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced

extrapyramidal reactions is not known. Data from earlier animal studies suggest that amantadine may

have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that

amantadine is a weak, non-competitive NMDA receptor antagonist (K = 10µM). Although amantadine

has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits

anticholinergic-like side effects such as dry mouth, urinary retention, and constipation.

Pharmacokinetics

Amantadine is well absorbed orally. Maximum plasma concentrations are directly related to dose for

doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase in

maximum plasma concentrations. It is primarily excreted unchanged in the urine by glomerular filtration

and tubular secretion. Eight metabolites of amantadine have been identified in human urine. One

metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5-15% of the

administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent amantadine

plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg dose of

amantadine. Acetylamantadine was not detected in the plasma of the remaining seven volunteers. The

contribution of this metabolite to efficacy or toxicity is not known.

There appears to be a relationship between plasma amantadine concentrations and toxicity. As

concentration increases, toxicity seems to be more prevalent, however, absolute values of amantadine

concentrations associated with adverse effects have not been fully defined.

Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral

administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean ± SD maximum

plasma concentration was 0.22 ± 0.03 µg/mL (range: 0.18 to 0.32 µg/mL). The time to peak

concentration was 3.3 ± 1.5 hours (range: 1.5 to 8.0 hours). The apparent oral clearance was 0.28 ± 0.11

L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17 ± 4 hours (range: 10 to 25 hours). Across

other studies, amantadine plasma half-life has averaged 16 ± 6 hours (range: 9 to 31 hours) in 19 healthy

volunteers.

After oral administration of a single dose of 100 mg amantadine syrup to five healthy volunteers, the

mean ± SD maximum plasma concentration C

was 0.24 ± 0.04 µg/mL and ranged from 0.18 to 0.28

µg/mL. After 15 days of amantadine 100 mg b.i.d., the C

was 0.47 ± 0.11 µg/mL in four of the five

volunteers. The administration of amantadine tablets as a 200 mg single dose to 6 healthy subjects

resulted in a C

of 0.51 ± 0.14 µg/mL. Across studies, the time to C

) averaged about 2 to 4

hours.

Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg

intravenous doses of amantadine to 15 healthy volunteers.

In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma clearance was

0.79 ± 0.17 (mean ± SD).

The volume of distribution determined after the intravenous administration of amantadine to 15 healthy

subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg doses to 6

healthy young subjects and to 6 healthy elderly subjects has been found in nasal mucus at mean ± SD

concentrations of 0.15 ± 0.16, 0.28 ± 0.26, and 0.39 ± 0.34 µg/g at 1, 4, and 8 hours after dosing,

respectively. These concentrations represented 31 ± 33%, 59 ± 61%, and 95 ± 86% of the

corresponding plasma amantadine concentrations. Amantadine is approximately 67% bound to plasma

proteins over a concentration range of 0.1 to 2.0 µg/mL. Following the administration of amantadine 100

mg as a single dose, the mean ± SD red blood cell to plasma ratio ranged from 2.7 ± 0.5 in 6 healthy

subjects to 1.4 ± 0.2 in 8 patients with renal insufficiency.

The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma

concentrations are increased in healthy elderly individuals age 60 and older. After single dose

administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma clearance of

amantadine was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and half-life was 29 ± 7 hours (range

20 to 41 hours). Whether these changes are due to decline in renal function or other age related factors

is not known.

In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for body

mass index, was 1.5 fold higher in males compared to females (p<0.032).

Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly reduced

in adult patients with renal insufficiency. The elimination half-life increases two to three fold or greater

when creatinine clearance is less than 40 mL/min/1.73m and averages eight days in patients on chronic

maintenance hemodialysis. Amanatadine is removed in negligible amounts by hemodialysis.

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.

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 Hydrochloride 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 Hydrochloride Capsules, USP

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 is 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 Hydrochloride Capsules, USP are 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 Capsules, USP are indicated in the treatment of drug-induced extrapyramidal

reactions. Although anticholinergic-type side effects have been noted with Amantadine Hydrochloride

Capsules, USP 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.

CONTRAINDICATIONS

Amantadine Hydrochloride Capsules, USP are contraindicated in patients with known hypersensitivity to

amantadine hydrochloride or to any of the other ingredients in Amantadine Hydrochloride Capsules,

USP.

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).

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, USP 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, USP 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, USP.

Patients with Parkinson's disease improving on Amantadine Hydrochloride Capsules, USP 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.

PRECAUTIONS

Amantadine 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 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 therapy. Therefore, patients should be observed

carefully when the dosage of amantadine 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 is mainly 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 (see DOSAGE AND

ADMINISTRATION ; Dosage for Impaired Renal Function ).

Liver disease

Care should be exercised when administering amantadine to patients with liver disease. Rare instances

of reversible elevation of liver enzymes have been reported in patients receiving amantadine, 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 for any indication. Ideally, periodic skin

examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Other

The dose of amantadine may need careful adjustment in patients with congestive heart failure, peripheral

edema, or orthostatic hypotension. Care should be exercised when administering amantadine 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 has not been shown to prevent such

complications.

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, lightheadedness 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 hydrochloride. 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 hydrochloride.

Patients should inform their physician if they experience new or increased gambling urges, increased

sexual urges or other intense urges while taking amantadine hydrochloride. Physicians should consider

dose reduction or stopping the medication if a patient develops such urges while taking amantadine

hydrochloride.

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 Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine

concentration in a 61-year-old man receiving amantadine 100 mg TID for Parkinson's disease.

It is not

known which of the components of Dyazide 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.

Carcinogenesis and Mutagenesis

Long-term in vivo animal studies designed to evaluate the carcinogenic potential of amantadine have not

been performed. In several in vitro assays for gene mutation, amantadine 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 (140-550

mg/kg; estimated human equivalent doses of 11.7-45.8 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 at a dose of 32 mg/kg/day (equal to the maximum

recommended human dose on a mg/m 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/m 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 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 7-14 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

basis). In the non-GLP rat study in which females were dosed on Days 7-14 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

basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human

dose on a mg/m 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.

Nursing Mothers

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

Pediatric Use

The safety and efficacy of amantadine in newborn infants and infants below the age of 1 year have not

been established.

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, USP may need reduction in patients with congestive heart failure, peripheral edema, or

orthostatic hypotension (see DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

The adverse reactions reported most frequently at the recommended dose of amantadine (5-10%) are:

nausea, dizziness (lightheadedness), and insomnia.

Less frequently (1-5%) 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 (0.1-1%) 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 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, and 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.

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

at 1- to 2-hour intervals and 0.5 mg doses in a child 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.

DOSAGE AND ADMINISTRATION

The dosage of Amantadine Hydrochloride Capsules, USP may need to be reduced 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, USP 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, USP 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, USP daily

because of CNS or other toxicities.

Pediatric Patients

1 yr.-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.-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, USP should be continued daily for at least 10 days following a

known exposure. If Amantadine Hydrochloride Capsules, USP 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, USP 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, USP is 100 mg twice a day when used alone.

Amantadine Hydrochloride Capsules, USP have an onset of action usually within 48 hours.

The initial dose of Amantadine Hydrochloride Capsules, USP 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, USP

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, USP 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,

USP 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, USP. When Amantadine Hydrochloride Capsules, USP or anticholinergic

antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional

benefit.

When Amantadine Hydrochloride Capsules, USP and levodopa are initiated concurrently, the patient can

exhibit rapid therapeutic benefits. Amantadine Hydrochloride Capsules, USP 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, USP 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, USP.

Dosage for Drug-Induced Extrapyramidal Reactions

Adult

The usual dose of Amantadine Hydrochloride Capsules, USP is 100 mg twice a day. Occasionally,

patients whose responses are not optimal with Amantadine Hydrochloride Capsules, USP 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/1.73 m )

Amantadine Hydrochloride Capsules, USP

DOSAGE

30-50

200 mg 1st day and 100 mg each day

thereafter

15-29

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.

HOW SUPPLIED

Amantadine Hydrochloride Capsules, USP are available as yellow, soft gelatin capsules containing 100

mg of amantadine hydrochloride, in bottles of 10's (NDC 21695-564-10). Each capsule is imprinted

with “1704” in black ink.

Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight, light-resistant container, as defined in the USP. Keep out of reach of children.

REFERENCES

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

1983.

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

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

Manufactured by:

Banner Pharmacaps Inc.

4125 Premier Drive

High Point, NC 27265

Manufactured for

Lannett Company, Inc.

Philadelphia, PA 19136

Repackaged by:

Rebel Distributors Corp.

Thouand Oaks, CA 91320

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL- 100 mg 100 count

NDC 21695-564-10

Lannett

Amantadine HCl Capsules, USP

100 mg

Rx only

10 Capsules

AMANTADINE HCL

amantadine hydrochloride capsule

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:216 9 5-56 4(NDC:0 0 527-170 4)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

AMANTADINE HYDRO CHLO RIDE (UNII: M6 Q1EO9 TD0 ) (AMANTADINE -

UNII:BF4C9 Z1J53)

AMANTADINE

HYDROCHLORIDE

10 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

GELATIN (UNII: 2G8 6 QN327L)

GLYCERIN (UNII: PDC6 A3C0 OX)

SO YBEAN O IL (UNII: 241ATL177A)

SO RBITO L (UNII: 50 6 T6 0 A25R)

SO RBITAN (UNII: 6 O9 2ICV9 RU)

MANNITO L (UNII: 3OWL53L36 A)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

WHITE WAX (UNII: 7G1J5DA9 7F)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

Product Characteristics

Color

YELLOW

S core

no sco re

Rebel Distributors Corp.

S hap e

CAPSULE

S iz e

16 mm

Flavor

Imprint Code

170 4

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:216 9 5-56 4-10

10 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 720

11/0 1/20 0 8

Labeler -

Rebel Distributors Corp. (118802834)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Rebel Distributo rs Co rp.

118 8 0 28 34

RELABEL, REPACK

Revised: 9/2010

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