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Rimantadine (Systemic)


VA CLASSIFICATION
Primary: AM890

Commonly used brand name(s): Flumadine.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antiviral (systemic)—

Indications

Accepted

Influenza A (prophylaxis and treatment)—Rimantadine is indicated for the prophylaxis of respiratory tract infections caused by influenza A virus in adults and children, and the treatment of respiratory tract infections caused by influenza A virus in adults. {01} {11} {14}

—Influenza A virus strains that are resistant to amantadine or rimantadine are cross-resistant to the other medication. {08} {09}

—Although rimantadine is structurally similar to amantadine, differing only in the 10-carbon ring side chain, rimantadine, unlike amantadine, is not effective in the control of Parkinson's disease. {12}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    215.77 {01}

Mechanism of action/Effect:

Rimantadine is thought to exert its inhibitory effect early in the viral replicative cycle, possibly by blocking or greatly reducing the uncoating of viral RNA within host cells. {01} {07} Genetic studies suggest that a single amino acid change on the transmembrane portion of the M2 protein can completely eliminate influenza A virus' susceptibility to rimantadine. {01} {09}

Absorption:

Well absorbed; tablets and syrup are absorbed equally well after oral administration. {01} {03} {04}

Distribution:


Vol D:

Adults: 17 to 25 L/kg. {04} {10}

Children: Mean of 289 L. {03}


Concentrations in the nasal mucus average 50% higher than those in plasma. {07}


Protein binding:

Moderate (approximately 40%). {01}

Biotransformation:

Extensively metabolized in the liver {01} {03}; glucuronidation and hydroxylation are the major metabolic pathways. {04} {10}

Half-life:

Young adults (22 to 44 years old)—25 to 30 hours. {01} {02} {03} {10}

Older adults (71 to 79 years old) and patients with chronic liver disease—Approximately 32 hours. {01} {10}

Children (4 to 8 years old)—13 to 38 hours. {03}

Time to peak concentration:

1 to 4 hours. {17} {18}

Peak serum concentration:


Steady state {02}:

100 mg once a day: Approximately 181 nanograms per mL.

100 mg twice a day: Approximately 416 nanograms per mL.


Rimantadine concentrations in elderly nursing home patients were found to be nearly 3 times those of younger adults. {05} {19}


Elimination:
    Renal; > 90% recovered in the urine within 72 hours, mostly as metabolites. {04} Less than 25% excreted in urine as unchanged drug. {01} {10}
    In dialysis—Hemodialysis has a negligible effect on the clearance of rimantadine. {01} {04}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients who are hypersensitive to amantadine may also be hypersensitive to rimantadine. {01}

Carcinogenicity

Carcinogenicity studies in animals have not been performed. {01}

Mutagenicity

No mutagenic effects were seen when rimantadine was evaluated in several standard mutagenicity assays. {01}

Pregnancy/Reproduction
Fertility—
A study in male and female rats given doses of up to 60 mg per kg of body weight (mg/kg) per day (3 times the maximum human dose based on body surface area comparisons) showed no impairment of fertility. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done.

Rimantadine crosses the placenta in mice. It has been shown to be embryotoxic in rats when given at a dose of 200 mg/kg per day (11 times the maximum human dose based on body surface area comparisons), and has caused fetal resorption. Maternal toxicity included ataxia, tremors, seizures, and significantly reduced weight gain. Rimantadine was not embryotoxic when given to rabbits in doses of up to 50 mg/kg per day (5 times the maximum human dose based on body surface area comparisons). However, there was evidence of a change in the ratio of fetuses with 12 ribs to fetuses with 13 ribs; normally the ratio is 50:50 in a litter, but the ratio was 80:20 after rimantadine treatment. {01}

FDA Pregnancy Category C.

Breast-feeding

It is not known whether rimantadine is distributed into breast milk. However, it is distributed into the milk of rats. Rimantadine concentrations in the milk of rats were twice those found in serum 2 to 3 hours after administration. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of rimantadine have not been performed in neonates and infants up to one year of age. However, use of rimantadine in children older than l year of age has not been shown to cause any pediatrics-specific problems that would limit its usefulness in children. {01}


Geriatrics


Elderly patients, particularly those in chronic care facilities, {19} are more likely than younger adults or children to experience adverse effects associated with rimantadine, primarily central nervous system (CNS) and gastrointestinal side effects. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen or{01}
Aspirin{01}    (concurrent use of acetaminophen or aspirin with rimantadine reduces the peak serum concentration of rimantadine by approximately 11%; the clinical significance is thought to be minimal at this time)


Cimetidine{01}    (concurrent use of a single dose of rimantadine with cimetidine reduces rimantadine clearance by 18% in healthy adults; the clinical significance is thought to be minimal at this time)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Epilepsy, history of, or other seizure disorders{01}{13}    (amantadine increases the risk of seizures; seizures have also been reported with rimantadine in 2 patients with a history of seizures who had previously been withdrawn from their anticonvulsants)


» Hepatic function impairment{01}    (a single-dose study done in patients with severe liver dysfunction showed a reduction in rimantadine clearance by 50% compared to healthy subjects)


Hypersensitivity to amantadine or rimantadine
» Renal function impairment, severe{01}{04}    (a single-dose study done in patients with end-stage renal failure showed a reduction in rimantadine clearance by 40%, and an increase in elimination half-life by 60%, compared to healthy subjects; a dosage reduction is recommended in patients with a creatinine clearance of £ 10 mL/min [0.17 mL/second])




Side/Adverse Effects

Note: Rimantadine has fewer CNS side effects than does amantadine. {07} {11} {12} {19} Elderly patients have a higher incidence of side effects, primarily CNS and gastrointestinal side effects, than do younger patients at conventional doses. {01} {19}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent {01} {05}
    
CNS effects (difficulty in concentrating; difficulty in sleeping; dizziness; headache; nervousness; unusual tiredness)
    
gastrointestinal disturbances (dryness of mouth; loss of appetite; nausea; stomach pain; vomiting)





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Rimantadine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to amantadine or rimantadine

Pregnancy—High doses were embryotoxic and maternotoxic in rats
Other medical problems, especially epilepsy or a history of seizures, liver function impairment and renal function impairment

Proper use of this medication
» Receiving a flu shot if recommended by your doctor

» Taking before exposure or as soon as possible after exposure

» Compliance with full course of therapy

» Importance of not missing doses and taking at evenly spaced times

Proper administration technique for oral liquid

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Caution if dizziness occurs

Checking with physician if no improvement within a few days


General Dosing Information
Chemoprophylactic administration should be started in anticipation of contact with, or as soon as possible after exposure to, persons having influenza A virus infections. Administration should be continued for at least 10 days following exposure. During an influenza epidemic, rimantadine should be given daily, usually for 6 to 8 weeks in most communities or until active immunity can be expected from administration of inactivated influenza A virus vaccine. {04} Rimantadine has been reported to be effective for post-exposure prophylaxis of household contacts {20}, but appeared to be less effective when used prophylactically in members of households in which index cases were being treated concurrently for influenza A. Failure was apparently due to transmission of drug-resistant strains of the virus. {08}

If administered concurrently with inactivated influenza A virus vaccine until protective antibodies develop, rimantadine should be continued chemoprophylactically for 2 to 3 weeks after the vaccine has been administered. {07} However, since the vaccine is only 70 to 80% effective {07}, continued administration of rimantadine may be beneficial in elderly or high-risk patients. If the vaccine is unavailable or contraindicated, rimantadine should be administered for up to 90 days in cases of possible repeated or unknown exposure. {16}

Treatment of influenza A virus infection with rimantadine should be started within 24 to 48 hours after the onset of symptoms {01} {07} {16} and should be continued for 5 to 7 days. Optimal duration of therapy has not been established. {19}


Oral Dosage Forms

RIMANTADINE HYDROCHLORIDE SYRUP

Usual adult and adolescent dose
Antiviral {01} {19}
Prophylaxis: Oral, 100 mg two times a day.

Treatment: Oral, 100 mg two times a day for approximately five to seven days from the inital onset of symptoms.


Note: In adults with impaired renal function (creatinine clearance £ 10 mL/minute [0.17 mL/second]) or severe hepatic dysfunction, and in elderly nursing home patients, a dose of 100 mg once a day is recommended. {01}
Although the manufacturer recommends twice-a-day dosing, once-a-day dosing has been well-tolerated and as effective because of the long elimination half-life of rimantadine. {14} {19}


Usual pediatric dose
Antiviral—Prophylaxis: {01}
Children up to 10 years of age: Oral, 5 mg per kg of body weight once a day. Maximum daily dose should not exceed 150 mg.

Children 10 years of age and over: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


50 mg per 5 mL (Rx) [Flumadine (methylparaben) (propylparaben) (sodium saccharin)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Continue medicine for full time of treatment.


RIMANTADINE HYDROCHLORIDE TABLETS

Usual adult and adolescent dose
See Rimantadine Hydrochloride Syrup .

Usual pediatric dose
See Rimantadine Hydrochloride Syrup .

Strength(s) usually available
U.S.—


100 mg (Rx) [Flumadine]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Continue medicine for full time of treatment.



Developed: 03/29/94



References
  1. Flumadine package insert (Forest—US), Rev 9/93, Rec 11/93.
  1. Wills RJ, Farolino DA, Choma N, Keigher N. Rimantadine pharmacokinetics after single and multiple doses. Antimicrob Agents Chemother 1987; 31(5): 826-8.
  1. Anderson EL, Van Voris LP, Bartram J, Hoffman HE, Belshe RB. Pharmacokinetics of a single dose of rimantadine in young adults and children. Antimicrob Agents Chemother 1987; 31(7): 1140-2.
  1. Capparelli EV, Stevens RC, Chow MSS, Izard M, Wills RJ. Rimantadine pharmacokinetics in healthy subjects and patients with end-stage renal failure. Clin Pharmacol Ther 1988; 43(5): 536-41.
  1. Patriarca PA, Kater NA, Kendal AP, Bregman DJ, Smith JD, Sikes RK. Safety of prolonged administration of rimantadine hydrochloride in the prophylaxis of influenza A virus infections in nursing homes. Antimicrob Agents Chemother 1984; 26(1): 101-3.
  1. Hall CB, et al. Children with influenza A infection: treatment with rimantadine. Pediatrics 1987; 80(2): 275-82.
  1. Douglas RG. Prophylaxis and treatment of influenza. N Engl J Med 1990; 322(7): 443-50.
  1. Hayden FG, Belshe RB, Clover RD, Hay AJ, Oakes MG, Soo W. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med 1989; 321(25): 1696-702.
  1. Belshe RB, Smith MH, Hall CB, Betts R, Hay AJ. Genetic basis of resistance to rimantadine emerging during treatment of influenza virus infection. J Virol 1988; 62(5): 1508-12.
  1. Wills RJ, et al. Pharmacokinetics of rimantadine hydrochloride in patients with chronic liver disease. Clin Pharmacol Ther 1987; 42(4): 449-54.
  1. Dolin R, Reichman RC, Madore HP, Maynard R, Linton PN, Webber-Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 1982; 307(10): 580-4.
  1. Hayden FG, Gwaltney JM, Van de Castle RL, Adams KF, Giordani B. Comparative toxicity of amantadine hydrochloride and rimantadine hydrochloride in healthy adults. Antimicrob Agents Chemother 1981; 19(2): 226-33.
  1. Bentley DW, Karki SD, Betts RF. Rimantadine and seizures. Ann Intern Med 1989; 110(4): 323-4.
  1. Hayden FG, Monto AS. Oral rimantadine hydrochloride therapy of influenza A virus H3N2 subtype infection in adults. Antimicrob Agents Chemother 1986; 29(2): 339-41.
  1. Hayden FG, Sperber SJ, Belshe RB, Clover RD, Hay AJ, Pyke S. Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine. Antimicrob Agents Chemother 1991; 35(9): 1741-7.
  1. Reviewers' responses to monograph revision of 1/94.
  1. Hayden FG, Minocha A, Spyker DA, Hoffman HE. Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults. Antimicrob Agents Chemother 1985; 28(2): 216-21.
  1. Tominack RL, Wills RJ, Gustavson LE, Hayden FG. Multiple-dose pharmacokinetics of rimantadine in elderly adults. Antimicrob Agents Chemother 1988; 32(12): 1813-9.
  1. Panel comment, 2/94.
  1. Bricaire M, Hannoun C, Boissel JP. Prévention de la grippe A. Presse Méd. 1990; 19(2): 69-72.
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