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Amantadine

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MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Amantadine may be confused with ranitidine, rimantadine
Symmetrel® may be confused with Synthroid®

International issues:
Symmetrel® may be confused with Somatrel® which is a brand name for somatorelin in Denmark

SPECIAL ALERTS
CDC Updated Interim Recommendations for the Use of Antivirals During 2009-2010 Influenza Season – September 2009

The Centers for Disease Control and Prevention (CDC) has issued interim recommendations for the use of antivirals for the treatment and prevention of influenza during the 2009-2010 season. These recommendations apply to seasonal influenza and the 2009 H1N1 influenza (formerly known as novel influenza A [H1N1]). Antiviral doses and schedules for treatment or chemoprophylaxis of 2009 H1N1 influenza are the same as those recommended for seasonal influenza. Additionally, the U.S. Food and Drug Administration (FDA) has issued a temporary Emergency Use Authorization to allow the use of oseltamivir in children <1 year of age. The following is a summary of the updated interim recommendations:
(1) Treatment with oseltamivir or zanamivir is recommended in any patient hospitalized with suspected or confirmed influenza.
(2) Treatment with oseltamivir or zanamivir is generally recommended for patients who are at higher risk for influenza-related complications (eg, children <5 years of age, adults ≥ 65 years of age, pregnant women, immunosuppressed patients, patients <19 years of age receiving long-term aspirin therapy, and persons with chronic health conditions such as pulmonary, cardiovascular, renal, hepatic, hematologic, neurologic, neuromuscular, or metabolic disorders).
(3) Any suspected influenza patient with warning signs/symptoms (eg, dyspnea, tachypnea, unexplained oxygen desaturation) consistent with an acute lower respiratory tract illness should promptly receive empiric antiviral therapy.
(4) Treatment, when indicated, should be started without delay (within 48 hours of illness onset) and should not await laboratory confirmation. Early initiation is more likely to provide benefit.
(5) Treatment or prophylaxis is generally not required in patients with suspected influenza who present with uncomplicated febrile illness or are not at higher risk for complications.
(6) Postexposure antiviral chemoprophylaxis with oseltamivir or zanamivir may be considered in the following populations after an exposure or close contact of a person with suspected, probable, or confirmed influenza during that person’s infectious period (“infectious period” is defined as 1 day before through 24 hours after fever ends):
– Persons at higher risk of influenza complications
– Healthcare and public health workers or first responders
(7) Chemoprophylaxis is generally not recommended if more than 48 hours has lapsed since last exposure to the infectious person, and is not indicated if the exposure did not occur during the infectious period. Chemoprophylaxis is not recommended in healthy children or adults after a potential exposure in the community, school, camp, or other setting.
(8) Currently circulating 2009 H1N1 viruses are susceptible to oseltamivir and zanamivir, but resistant to amantadine and rimantadine. Oseltamivir-resistant 2009 H1N1 viruses have been identified, most commonly observed during chemoprophylaxis or in immunocompromised patients receiving treatment for influenza. Conversely, regular seasonal influenza A (H1N1) is commonly resistant to oseltamivir, but is typically susceptible to rimantadine and amantadine. However, at present, oseltamivir or zanamivir is appropriate for the treatment of seasonal H1N1 influenza. If oseltamivir-resistant seasonal H1N1 viruses become more common or are identified in community outbreaks, zanamivir (or a combination of oseltamivir and rimantadine or amantadine) should be considered for empiric treatment of suspected oseltamivir-resistant seasonal human influenza A (H1N1) virus infection.

CDC recommendations are changing frequently as more information on antiviral susceptibilities and effectiveness becomes available. For the most recent recommendations and information from the CDC, please refer to:
http://www.cdc.gov/h1n1flu/recommendations.htm
http://www.cdc.gov/h1n1flu/guidance/

U.S. BRAND NAMES — Symmetrel®

PHARMACOLOGIC CATEGORY
Anti-Parkinson’s Agent, Dopamine Agonist
Antiviral Agent
Antiviral Agent, Adamantane

DOSING: ADULTS
Influenza A treatment/prophylaxis:Note: Due to issues of resistance, amantadine is no longer recommended for the treatment or prophylaxis of influenza A. Please refer to the current ACIP recommendations. The following is based on the manufacturer’s labeling:
Influenza A treatment: Oral: 200 mg once daily or 100 mg twice daily (may be preferred to reduce CNS effects); Note: Initiate within 24-48 hours after onset of symptoms; continue for 24-48 hours after symptom resolution (duration of therapy is generally 3-5 days).
Influenza A prophylaxis: Oral: 200 mg once daily or 100 mg twice daily (may be preferred to reduce CNS effects). Note: Continue prophylaxis throughout the peak influenza activity in the community or throughout the entire influenza season in patients who cannot be vaccinated. Development of immunity following vaccination takes ~2 weeks; amantadine therapy should be considered for high-risk patients from the time of vaccination until immunity has developed.

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Drug-induced extrapyramidal symptoms: Oral: 100 mg twice daily; may increase to 300 mg/day in divided doses, if needed

Parkinson’s disease: Oral: Usual dose: 100 mg twice daily as monotherapy; may increase to 400 mg/day in divided doses, if needed, with close monitoring. Note: Patients with a serious concomitant illness or those receiving high doses of other anti-parkinson drugs should be started at 100 mg/day; may increase to 100 mg twice daily, if needed, after one to several weeks.

DOSING: PEDIATRIC

(For additional information see “Amantadine: Pediatric drug information”)
Influenza A treatment/prophylaxis: Oral: Note: Due to issues of resistance, amantadine is no longer recommended for the treatment or prophylaxis of influenza A. Please refer to the current ACIP recommendations. The following is based on the manufacturer’s labeling and past ACIP dosing recommendations:
Influenza A treatment:
1-9 years: 5 mg/kg/day in 2 divided doses (manufacturers range: 4.4-8.8 mg/kg/day); maximum dose: 150 mg/day
≥ 10 years and <40 kg: 5 mg/kg/day in 2 divided doses; maximum dose: 150 mg/day (CDC, 2003)
≥ 10 years and ≥ 40 kg: 100 mg twice daily (CDC, 2003)
Note: Initiate within 24-48 hours after onset of symptoms; continue for 24-48 hours after symptom resolution (duration of therapy is generally 3-5 days)
Influenza A prophylaxis: Refer to “Influenza A treatment” dosing. Note: Continue prophylaxis throughout the peak influenza activity in the community or throughout the entire influenza season in patients who cannot be vaccinated. Development of immunity following vaccination takes ~2 weeks; amantadine therapy should be considered for high-risk patients from the time of vaccination until immunity has developed. For children <9 years receiving influenza vaccine for the first time, amantadine prophylaxis should continue for 6 weeks (4 weeks after the first dose and 2 weeks after the second dose). DOSING: ELDERLY — Patients ≥ 65 years: Adjust dose based on renal function; some patients tolerate the drug better when it is given in 2 divided daily doses (to avoid adverse neurologic reactions). Influenza A treatment/prophylaxis: 100 mg once daily DOSING: RENAL IMPAIRMENT
Clcr 30-50 mL/minute: Administer 200 mg on day 1, then 100 mg/day

Clcr 15-29 mL/minute: Administer 200 mg on day 1, then 100 mg on alternate days

Clcr <15 mL/ minute: Administer 200 mg every 7 days Hemodialysis: Administer 200 mg every 7 days Peritoneal dialysis: No supplemental dose is needed Continuous arteriovenous or venous-venous hemofiltration: No supplemental dose is needed DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. Capsule, as hydrochloride: 100 mg Capsule, softgel, as hydrochloride: 100 mg Solution, oral, as hydrochloride: 50 mg/5 mL (473 mL) Syrup, oral, as hydrochloride: 50 mg/5 mL (10 mL, 480 mL) Tablet, as hydrochloride: 100 mg
Symmetrel®: 100 mg

DOSAGE FORMS: CONCISE
Capsule: 100 mg

Capsule, softgel: 100 mg

Solution, oral: 50 mg/5 mL

Syrup, oral: 50 mg/5 mL

Tablet: 100 mg
Symmetrel®: 100 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Prophylaxis and treatment of influenza A viral infection (per manufacturer labeling; also refer to current ACIP guidelines for recommendations during current flu season); treatment of parkinsonism; treatment of drug-induced extrapyramidal symptoms

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Note: In certain circumstances, the ACIP recommends use of amantadine in combination with oseltamivir for the treatment or prophylaxis of influenza A infection when resistance to oseltamivir is suspected.

ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Cardiovascular: Orthostatic hypotension, peripheral edema
Central nervous system: Agitation, anxiety, ataxia, confusion, delirium, depression, dizziness, dream abnormality, fatigue, hallucinations, headache, insomnia, irritability, lightheadedness, nervousness, somnolence
Dermatologic: Livedo reticularis
Gastrointestinal: Anorexia, constipation, diarrhea, nausea, xerostomia
Respiratory: Dry nose

<1% (Limited to important or life-threatening): Aggressive behavior, agranulocytosis, alkaline phosphatase increased, allergic reaction, ALT increased, AST increased, amnesia, anaphylaxis, arrhythmia, bilirubin increased, BUN increased, cardiac arrest, coma, CPK increased, creatinine increased, delusions, diaphoresis, dysphagia, dyspnea, eczematoid dermatitis, euphoria, GGT increased, heart failure, hyperkinesis, LDH increased, leukopenia, mania, neutropenia, neuroleptic malignant syndrome (NMS; associated with dosage reduction or abrupt withdrawal of amantadine), oculogyric episodes, paresthesia, photosensitivity, psychosis, pulmonary edema, rash, respiratory failure (acute), seizures, suicidal ideation, suicide, urinary retention, withdrawal reactions (may include delirium, hallucinations, and psychosis), visual disturbances
Reported with dopamine agonists: Impulsive/compulsive behaviors (eg, pathological gambling, hypersexuality, binge eating)

CONTRAINDICATIONS — Hypersensitivity to amantadine or any component of the formulation

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Impulse control disorders: Dopamine agonists used for Parkinson’s disease or restless legs syndrome have been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, libido increases (hypersexuality), and/or binge eating. Causality has not been established, and controversy exists as to whether this phenomenon is related to the underlying disease, prior behaviors/addictions and/or drug therapy. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases. Melanoma: Risk for melanoma development is increased in Parkinson’s disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed. Neuroleptic malignant syndrome: Has been associated with neuroleptic malignant syndrome (associated with dose reduction or abrupt discontinuation). Suicidal ideation: There have been reports of suicidal ideation/attempt in patients with and without a history of psychiatric illness. May exacerbate mental problems in patients with a history of mental illness.

Disease-related concerns: Cardiovascular disease: Use with caution in patients with heart failure, peripheral edema, or orthostatic hypotension; dosage reduction may be required. Eczema: Use with caution in patients with a history of recurrent and eczematoid dermatitis. Glaucoma: Avoid in untreated angle closure glaucoma. Hepatic impairment: Use with caution in patients with hepatic impairment; rarely, elevations in transaminases have been reported. Influenza A: Appropriate use: Consult current guidelines. Due to increased resistance, the ACIP has recommended that rimantadine and amantadine no longer be used for the treatment or prophylaxis of influenza A in the United States until susceptibility has been re-established. Parkinson’s disease: Appropriate use: When treating Parkinson’s disease, do not discontinue abruptly. In many patients, the therapeutic benefits of amantadine are limited to a few months. Psychosis: Use with caution in patients with uncontrolled psychosis or severe psychoneurosis. Renal impairment: Use with caution in patients with renal impairment; dosage reduction recommended. Seizure disorder: Use with caution in patients with a history of seizure disorder.

Concurrent drug therapy issues: CNS stimulants: Use with caution in patients receiving CNS stimulant drugs.

Special populations: Elderly: Use with caution in the elderly; may be more susceptible to CNS effects (using 2 divided daily doses may minimize this effect). These patients may require dosage reductions based on renal function. Pediatrics: Safety and efficacy have not been established in children <1 year of age. Other warnings/precautions: Withdrawal syndrome: May cause agitation, anxiety, delirium, delusions, depression, hallucinations, paranoia, parkinsonian crisis, slurred speech, or stupor. Upon discontinuation of amantadine therapy, gradually taper dose.

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DRUG INTERACTIONS
Antipsychotics (Atypical): May diminish the therapeutic effect of Anti-Parkinson’s Agents (Dopamine Agonist). Risk D: Consider therapy modification

Antipsychotics (Typical): May diminish the therapeutic effect of Anti-Parkinson’s Agents (Dopamine Agonist). Risk D: Consider therapy modification

Influenza Virus Vaccine: Antiviral Agents (Influenza A and B) may diminish the therapeutic effect of Influenza Virus Vaccine. This only pertains to live, attentuated influenza virus vaccine. Risk D: Consider therapy modification

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson’s Agents (Dopamine Agonist). Risk C: Monitor therapy

Trimethoprim: May enhance the adverse/toxic effect of Amantadine. Specifically, the risk of myoclonus and/or delirium may be increased. Amantadine may increase the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Amantadine. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Avoid ethanol (may increase CNS adverse effects).

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Teratogenic effects were observed in animal studies; limited data in humans. Impaired fertility has also been reported during animal studies and during human in vitro fertilization.

LACTATION — Enters breast milk/not recommended

PRICING — (data from drugstore.com)
Capsules (Amantadine HCl)
100 mg (30): $21.99

Syrup (Amantadine HCl)
50 mg/5 mL (120): $15.98

Tablets (Amantadin
e HCl)
100 mg (30): $33.99

MONITORING PARAMETERS — Renal function, Parkinson’s symptoms, mental status, influenza symptoms, blood pressure

CANADIAN BRAND NAMES — Endantadine®; PMS-Amantadine; Symmetrel®

INTERNATIONAL BRAND NAMES — a.m.t. (DE); Amanda (TW); Amandin (TW); Amandine (UY); Amanta (KP); Amantadin (EE); Amantadin-ratiopharm (PL); Amantadina Juventus (ES); Amantadina Llorente (ES); Amantan (BE, LU); Amantix (CO, PL); Amantrel (IN); Amazolon (JP); Atarin (CL, FI); Boidan (JP); Enzil (TW); Hofcomant (AT, FI); Influ (TW); Influ-A (IL); Mantadan (IT); Mantadix (FR, LU); Mantidan (BR); Paritrel (IL); PK-Merz (AE, AT, BF, BG, BH, BJ, CH, CI, CN, CR, CY, CZ, DE, DO, EE, EG, ET, GH, GM, GN, GT, HK, HN, HU, IL, IQ, IR, JO, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, OM, PA, PK, PT, PY, QA, SA, SC, SD, SL, SN, SV, SY, TN, TW, TZ, UG, YE, ZA, ZM, ZW); Prayanol (CN); Symmetrel (AE, AT, AU, BH, CH, CY, EG, GB, GR, HR, IE, IL, IQ, IR, JO, KW, LB, LY, NL, NO, OM, QA, SA, SY, VE, YE); Viregyt-K (BG, HU, PL); Virofral (DK); Virosol (AR)

MECHANISM OF ACTION — As an antiviral, blocks the uncoating of influenza A virus preventing penetration of virus into host; antiparkinsonian activity may be due to its blocking the reuptake of dopamine into presynaptic neurons or by increasing dopamine release from presynaptic fibers

PHARMACODYNAMICS / KINETICS
Onset of action: Antidyskinetic: Within 48 hours

Absorption: Well absorbed

Distribution: Vd: Normal: 1.5-6.1 L/kg; Renal failure: 5.1 +/- 0.2 L/kg; in saliva, tear film, and nasal secretions; in animals, tissue (especially lung) concentrations higher than serum concentrations; crosses blood-brain barrier

Protein binding: Normal renal function: ~67%; Hemodialysis: ~59%

Metabolism: Not appreciable; small amounts of an acetyl metabolite identified

Bioavailability: 86% to 90%

Half-life elimination: Normal renal function: 16 +/- 6 hours (9-31 hours); Healthy, older (≥ 60 years) males: 29 hours (range: 20-41 hours); End-stage renal disease: 7-10 days

Time to peak, plasma: 2-4 hours

Excretion: Urine (80% to 90% unchanged) by glomerular filtration and tubular secretion

PATIENT INFORMATION — Do not abruptly discontinue therapy; it may precipitate a parkinsonian crisis. May impair ability to perform activities requiring mental alertness or coordination. Take throughout flu season or for at least 10 days following vaccination for effective prophylaxis. Take second dose of the day in early afternoon to decrease incidence of insomnia.

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