AMANTADINE HCL- amantadine hydrochloride_capsule, liquid filled

CLINICAL PHARMACOLOGY
Mechanism of Action: Antiviral Antiviral Activity: in vitro 50 Drug Resistance: in vitro in vitro in vitro Mechanism of Action: Parkinson''s Disease 1 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 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. 03 mcg/mL (range: 0. The time to peak concentration was 3. 5 hours (range: 1. The apparent oral clearance was 0. 11 L/hr/kg (range: 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 max max max max max Plasma amantadine clearance ranged from 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. 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. 34 mcg/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. Following the administration of amantadine 100 mg as a single dose, the mean +/- SD red blood cell to plasma ratio ranged from 2. 5 in 6 healthy subjects to 1. 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. 04 L/hr/kg (range 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. 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. 73 m 2 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.
Pharmacodynamics
Mechanism of Action: Antiviral Antiviral Activity: in vitro 50 Drug Resistance: in vitro in vitro in vitro Mechanism of Action: Parkinson''s Disease 1
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 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 mcg/mL (range: 0.18 to 0.32 mcg/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 max max max max max 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 mcg/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 mcg/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/1.73 m 2 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.

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: 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: 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: Drug-Induced Extrapyramidal Reactions:

The dosage of Amantadine Hydrochloride Capsules 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: 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 daily because of CNS or other toxicities. Pediatric Patients: 1 yr. of age: The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4. 8 mg/kg/day), but not to exceed 150 mg per day. 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: 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: 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 are 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: Dosage for Impaired Renal Function: CREATININE CLEARANCE 2 Amantadine Hydrochloride Capsules, USP 30 to 50 200 mg 1st day and 100 mg each day 15 to 29 200 mg 1st day followed by 100 mg on < 15 200 mg every 7 days The recommended dosage for patients on hemodialysis is 200 mg every 7 days.

ADVERSE REACTIONS
The adverse reactions reported most frequently at the recommended dose of amantadine hydrochloride (5 to 10%) 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 Nervous System/Psychiatric Cardiovascular Respiratory Gastrointestinal Hematologic Special Senses Skin and Appendages Miscellaneous WARNINGS Laboratory Test To report SUSPECTED ADVERSE REACTIONS, contact Bionpharma at 1-888-235-2466 or FDA at 1-800-FDA-1088 or www. gov/medwatch.
Other adverse reactions reported during postmarketing experience with amantadine hydrochloride usage include:
Nervous System/Psychiatric Cardiovascular Respiratory Gastrointestinal Hematologic Special Senses Skin and Appendages Miscellaneous WARNINGS Laboratory Test To report SUSPECTED ADVERSE REACTIONS, contact Bionpharma at 1-888-235-2466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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

WARNINGS
Deaths: OVERDOSAGE Deaths due to drug accumulation (overdose) have been reported in patients with renal impairment, who were prescribed higher than recommended doses of SYMMETREL (amantadine) for their level of renal function (see DOSAGE AND ADMINISTRATION; Dosage of Impaired Renal Function OVERDOSAGE Suicide Attempts: CNS Effects: 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 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 has anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma. Corneal Edema: Dosage and Administration
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, 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 hydrochloride. However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult 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.
REFERENCES
1 registered Can. Med. Assoc. J. 2 N. Engl. J. Med. 3 J. Pediatr. Manufactured for: Bionpharma Inc. Rev. 04/25

Bionpharma Inc.

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  2014-11-07 00:00:00

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