Amantadine Hydrochloride

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.

• Deaths Deaths have been reported from overdose with amantadine.
• 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.
• Corneal Edema Corneal edema has been reported in patients taking amantadine.
• Symptoms include sudden onset of blurry vision, or progressive vision loss, with or without eye pain.
• Corneal involvement is usually bilateral.
• Onset can occur from a few weeks to several years after starting amantadine.
• Resolution of symptoms typically begins within weeks of amantadine cessation.
• However, corneal grafts have been required in some patients when the condition is not recognized.
• Permanent damage can occur if amantadine is continued.
• Ask patients if their vision has changed and obtain ophthalmologic examinations to rule out corneal edema should vision changes occur after initiation of therapy with Amantadine Hydrochloride Capsules, USP.
• If corneal edema occurs, taper and discontinue Amantadine Hydrochloride Capsules, USP [see Dosage and Administration ] .
• 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.
• 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:
• 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.
• Impulse Control/Compulsive Behaviors Postmarketing reports suggest that patients treated with anti-Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges.
• Patients may be unable to control these urges while taking one or more of the medications that are generally used for the treatment of Parkinson's disease and that increase central dopaminergic tone, including amantadine hydrochloride.
• In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued.
• Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with amantadine hydrochloride.
• Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking amantadine hydrochloride.
• 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 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, eye pain, loss of 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.
• 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.
• 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 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 at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m 2 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 2 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 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.
• 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 may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension [see Dosage and Administration].

• 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.