Amantadine Hydrochloride

Amantadine hydrochloride tablets are indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Amantadine hydrochloride tablets are also indicated in the treatment of parkinsonism and drug-induced extrapyramidal reactions. Influenza A Prophylaxis Amantadine hydrochloride tablets are indicated for chemoprophylaxis against signs and symptoms of influenza A virus infection. Because amantadine hydrochloride tablets do 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 tablets prophylaxis should be considered for the 2- to 4- week time period required to develop an antibody response. Influenza A Treatment Amantadine hydrochloride tablets 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 tablets 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 tablets 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 tablets: Amantadine hydrochloride tablets 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 tablets. Parkinson's Disease/Syndrome Amantadine hydrochloride tablets 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 tablets 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 tablets are indicated in the treatment of drug-induced extrapyramidal reactions. Although anticholinergic-type side effects have been noted with amantadine hydrochloride tablets 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.

Amantadine hydrochloride tablets are contraindicated in patients with known hypersensitivity to amantadine hydrochloride or to any of the other ingredients in amantadine hydrochloride tablets.

Deaths Deaths have been reported from overdose with amantadine hydrochloride. 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 hydrochloride, 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 hydrochloride 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 tablets 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 tablets 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 tablets. Patients with Parkinson's disease improving on amantadine hydrochloride tablets should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis. Because amantadine hydrochloride tablets have 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 tablets. If corneal edema occurs, taper and discontinue Amantadine hydrochloride tablets [see Dosage and Administration].

Amantadine hydrochloride should not be discontinued abruptly in patients with Parkinson's disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of amantadine hydrochloride should be reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech. Neuroleptic Malignant Syndrome (NMS) Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of amantadine hydrochloride therapy. Therefore, patients should be observed carefully when the dosage of amantadine hydrochloride is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin. The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring, and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled studies. Renal disease Because amantadine hydrochloride is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of amantadine hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older (see DOSAGE AND ADMINISTRATION: Dosage for Impaired Renal Function ). Liver disease Care should be exercised when administering amantadine hydrochloride to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine hydrochloride, though a specific relationship between the drug and such changes has not been established. 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 hydrochloride tablets 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, 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, 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. 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 hydrochloride 100 mg TID for Parkinson's disease. 1 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 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. […]

The adverse reactions reported most frequently at the recommended dose of amantadine hydrochloride (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 hydrochloride usage include: Nervous System/Psychiatric coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, and tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech; Cardiovascular cardiac arrest, arrhythmias including malignant arrhythmias, hypotension and tachycardia; Respiratory acute respiratory failure, pulmonary edema, and tachypnea; Gastrointestinal dysphagia; Hematologic leukocytosis, agranulocytosis; Special Senses keratitis, mydriasis, and corneal edema; Skin and Appendages pruritus and diaphoresis; Miscellaneous neuroleptic malignant syndrome (see WARNINGS ), allergic reactions including anaphylactic reactions, edema, fever. Laboratory Test elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and SGPT.

Careful observation is required when amantadine hydrochloride is administered concurrently with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson's disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine concentration in a 61-year-old man receiving amantadine hydrochloride 100 mg TID for Parkinson's disease. 1 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 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.

Teratogenic Effects 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 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/m 2 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 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 6 th and 7 th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy. Amantadine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

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 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/m 2 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 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 6 th and 7 th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy. Amantadine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.

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

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 tablets may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see DOSAGE AND ADMINISTRATION ).

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.

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.

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 hydrochloride 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 i = 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.