Amantadine Hydrochloride: Package Insert and Label Information (Page 2 of 3)

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 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.

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.

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 hydrochloride.

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/hydrochlorothiazide resulted in a higher plasma amantadine hydrochloride concentration in a 61-year-old man receiving amantadine hydrochloride 100 mg TID for Parkinson’s disease. It is not known which of the components of triamterene/hydrochlorothiazide contributed to the observation or if related drugs produce a similar response. 1

Coadministration of quinine or quinidine with amantadine hydrochloride was shown to reduce the renal clearance of amantadine hydrochloride 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, 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 hydrochloride 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 hydrochloride 2 weeks prior to, and during the IVF cycle.

Pregnancy Category C

The effect of amantadine hydrochloride 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 to14 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 to14 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 hydrochloride is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine hydrochloride 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 hydrochloride (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 may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see ). DOSAGE AND ADMINISTRATION

Adverse Reactions to Amantadine Hydrochloride

The adverse reactions reported most frequently at the recommended dose of amantadine hydrochloride (5 to10%) 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:

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; Nervous System/Psychiatric:

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

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

dysphagia; Gastrointestinal:

leukocytosis and agranulocytosis; Hematologic:

keratitis and mydriasis; Special Senses:

pruritus and diaphoresis; Skin and Appendages:

neuroleptic malignant syndrome (see ), allergic reactions including anaphylactic reactions, edema, and fever; Miscellaneous: WARNINGS

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

OVERDOSAGE

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

Acute toxicity may be attributable to the anticholinergic effects of amantadine hydrochloride. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome –– ARDS) have been reported; renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur.

Central nervous system effects that have been reported include insomnia, anxiety, agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, gait abnormality, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.

There is no specific antidote for an overdose of amantadine hydrochloride. However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an 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 hydrochloride. Since the excretion rate of amantadine hydrochloride increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. The blood pressure, pulse, respiration and temperature should be monitored. The patient should be observed for hyperactivity and convulsions; if required, sedation, and anticonvulsant therapy should be administered. The patient should be observed for the possible development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and antihypotensive therapy should be given. Electrocardiographic monitoring may be required after ingestion, since malignant tachyarrhythmias can appear after overdose. 2 3

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

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

DOSAGE AND ADMINISTRATION

The dose of amantadine hydrochloride 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 is 200 mg (four teaspoonfuls of oral solution) as a single daily dose. The daily dosage may be split into two teaspoonfuls of oral solution 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 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 two teaspoonfuls of oral solution 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 should be continued daily for at least 10 days following a known exposure. If amantadine hydrochloride 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 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 is 100 mg twice a day when used alone. Amantadine hydrochloride has an onset of action usually within 48 hours.

The initial dose of amantadine hydrochloride 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 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 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 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. When amantadine hydrochloride or anticholinergic antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional benefit.

When amantadine hydrochloride and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic benefits. Amantadine hydrochloride 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 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.

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