24 HR amantadine 68.5 MG Extended Release Oral Capsule

INDICATIONS AND USAGE Amantadine Hydrochloride Oral Solution USP is indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Amantadine Hydrochloride Oral Solution USP is also indicated in the treatment of parkinsonism and drug-induced extrapyramidal reactions. Influenza A Prophylaxis Amantadine Hydrochloride Oral Solution USP is indicated for chemoprophylaxis against signs and symptoms of influenza A virus infection. Because Amantadine Hydrochloride Oral Solution USP 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 Oral Solution USP prophylaxis should be considered for the 2- to 4-week time period required to develop an antibody response. Influenza A Treatment Amantadine Hydrochloride Oral Solution USP is 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 Oral Solution 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 Oral Solution USP is effective in the prophylaxis or treatment of viral respiratory tract illnesses other than those caused by influenza A v irus strains. The following points should be considered before initiating treatment or prophylaxis with Amantadine Hydrochloride Oral Solution USP: Amantadine Hydrochloride Oral Solution 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 Oral Solution USP. Parkinson's Disease/Syndrome Amantadine Hydrochloride Oral Solution USP is 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 Oral Solution USP is less effective than levodopa,(-)-3-(3,4dihydroxyphenyl)-L-alanine, and its efficacy in comparison with the anticholinergic antiparkinson drugs has not yet been established. Drug-Induced Extrapyramidal Reactions Amantadine Hydrochloride Oral Solution USP is indicated in the treatment of drug-induced extrapyramidal reactions. Although anticholinergic-type side effects have been noted with Amantadine Hydrochloride Oral Solution 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.

DOSAGE AND ADMINISTRATION The dose of Amantadine Hydrochloride Oral Solution USP (Amantadine Hydrochloride, USP) 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 Oral Solution USP is 200 mg; two 100 mg tablets (or four teaspoonfuls of syrup) as a single daily dose. The daily dosage may be split into one tablet of 100 mg (or two teaspoonfuls of syrup) 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 Oral Solution 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 Oral Solution 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 tablet of 100 mg (or two teaspoonfuls of syrup) 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 Oral Solution USP should be continued daily for at least 10 days following a known exposure. If Amantadine Hydrochloride Oral Solution USP 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 Oral Solution 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 Oral Solution USP is 100 mg twice a day when used alone. Amantadine Hydrochloride Oral Solution USP has an onset of action usually within 48 hours. The initial dose of Amantadine Hydrochloride Oral Solution 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 Oral Solution 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 Oral Solution 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 Oral Solution 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 Oral Solution USP. When Amantadine Hydrochloride Oral Solution USP or anticholinergic antiparkinson drugs are each used with marginal benefit, concomitant use may produce additional benefit. When Amantadine Hydrochloride Oral Solution USP and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic benefits. Amantadine Hydrochloride Oral Solution 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 Oral Solution 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 Oral Solution USP. Dosage for Drug-Induced Extrapyramidal Reactions Adult The usual dose of Amantadine Hydrochloride Oral Solution USP is 100 mg twice a day. Occasionally, patients whose responses are not optimal with Amantadine Hydrochloride Oral Solution 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 DOSAGE Amantadine Hydrochloride Oral Solution USP (mL/min/1.73m 2 ) 30-50 200 mg 1 st day and 100 mg each day thereafter 15-29 200 mg 1 st 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.

WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living : Advise patients prior to treatment; ordinarily discontinue if occurs ( 5.1 ) Suicidality and Depression : Monitor patients for depressed mood, depression, or suicidal ideation or behavior ( 5.2 ) Hallucinations/Psychotic Behavior: Patients with major psychotic disorder should ordinarily not be treated with GOCOVRI; observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases ( 5.3 ) Dizziness and Orthostatic Hypotension : Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose ( 5.4 ) Withdrawal-Emergent Hyperpyrexia and Confusion : Avoid sudden discontinuation ( 5.5 ) Corneal Edema : Monitor patients for new changes in vision, including blurred vision, with or without eye pain, or vision loss. Taper and discontinue if corneal edema occurs ( 5.6 ) Impulse Control/Compulsive Behaviors : Ask patients about increased gambling urges, sexual urges, uncontrolled spending or other urges; consider dose reduction or discontinuation if occurs ( 5.7 ) 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated for Parkinson's disease have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. In controlled clinical trials, somnolence and fatigue were reported as adverse reactions in 4% of patients treated with GOCOVRI 274 mg and 1% for placebo. Before initiating treatment with GOCOVRI, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with GOCOVRI, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued. If a decision is made to continue GOCOVRI, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living or daytime somnolence. 5.2 Suicidality and Depression In controlled clinical trials, suicidal ideation or suicide attempt was reported in 2% of GOCOVRI-treated patients and 0% of placebo-treated patients. Depression or depressed mood was reported in 6% of GOCOVRI-treated patients and 1% of placebo-treated patients. Confusional state was reported in 3% of GOCOVRI-treated patients and 2% of placebo-treated patients. Apathy was reported in 2% of GOCOVRI-treated patients and 0% of placebo-treated patients. Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression. 5.3 Hallucinations/Psychotic Behavior Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. In controlled trials, the incidence of patients who experienced visual hallucinations, auditory hallucinations, delusions, illusions, or paranoia was 25% in patients treated with GOCOVRI 274 mg, and 3% in placebo-treated patients. Hallucinations caused discontinuation of treatment in 8% of GOCOVRI-treated patients, and in 0% of placebo-treated patients. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation, and after dose increases. 5.4 Dizziness and Orthostatic Hypotension In controlled clinical trials, 29% of GOCOVRI-treated patients and 2% of placebo-treated patients experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension. In GOCOVRI-treated patients, 3% discontinued study treatment because of dizziness, postural dizziness, or syncope, compared to 0% of placebo-treated patients. Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose. Concomitant use of alcohol when using GOCOVRI is not recommended [see Drug Interactions ( 7.4 )]. 5.5 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. Abrupt discontinuation of GOCOVRI may cause an increase in the symptoms of Parkinson's disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. It is recommended to avoid sudden discontinuation of GOCOVRI [see Dosing Information ( 2.4 )] . 5.6 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 GOCOVRI. If corneal edema occurs, taper and discontinue GOCOVRI [see Dosage and Administration ( 2.4 )] . 5.7 Impulse Control/Compulsive Behaviors Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including GOCOVRI, that increase central dopaminergic tone. In some cases, 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 GOCOVRI. Consider dose reduction or stopping the medication if a patient develops such urges while taking GOCOVRI.

CONTRAINDICATIONS GOCOVRI is contraindicated in patients with end-stage renal disease (i.e., creatinine clearance below 15 mL/min/1.73 m 2 ) [see Clinical Pharmacology ( 12.3 )]. GOCOVRI is contraindicated in patients with end-stage renal disease ( 4 )

Clinical Pharmacology Pharmacodynamics Mechanism of Action: Antiviral: The mechanism by which amantadine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride and the clinical response to therapy has not been established in man. Sensitivity test results, expressed as the concentration of amantadine hydrochloride required to inhibit by 50% the growth of virus (ED50) 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 hydrochloride up to a concentration of 100 μg/mL. Drug Resistance: Influenza A variants with reduced in vitro sensitivity to amantadine hydrochloride 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 hydrochloride and the clinical response to therapy has not been established. Mechanism of Action: Parkinson’s Disease: The mechanism of action of amantadine hydrochloride 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 hydrochloride is a weak, non-competitive NMDA receptor antagonist (Ki = 10μM). Although amantadine hydrochloride 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 hydrochloride 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 hydrochloride have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5 to 15% of the administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent amantadine hydrochloride plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg dose of amantadine hydrochloride. 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 hydrochloride concentrations and toxicity. As concentration increases, toxicity seems to be more prevalent, however, absolute values of amantadine hydrochloride concentrations associated with adverse effects have not been fully defined. Amantadine hydrochloride 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 hydrochloride 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 hydrochloride in a syrup formulation to five healthy volunteers, the mean ± SD maximum plasmaconcentration Cmax was 0.24 ± 0.04 μg/mL and ranged from 0.18 to 0.28 μg/mL. After 15 days of amantadine hydrochloride 100 mg b.i.d., the Cmax was 0.47 ± 0.11 μg/mL in four of the five volunteers. Across studies, the time to Cmax (Tmax) averaged about 2 to 4 hours. Plasma amantadine hydrochloride clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg intravenous doses of amantadine hydrochloride to 15 healthy volunteers. In six healthy volunteers, the ratio of amantadine hydrochloride 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 hydrochloride to 15 healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine hydrochloride, 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 hydrochloride concentrations. Amantadine hydrochloride is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0 μg/mL. Following the administration of amantadine hydrochloride 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 hydrochloride 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 hydrochloride was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the 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 hydrochloride, 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 hydrochloride 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/1.73 m2 and averages eight days in patients on chronic maintenance hemodialysis. Amantadine hydrochloride is removed in negligible amounts by hemodialysis. 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.