"Dec. 3, 2012 -- The U.S. flu season is here -- the earliest start since the "moderately severe" season of 2003.
Just as in 2003, the nasty H3N2 flu bug is causing most cases so far.
"This could be a bad flu year," warned CDC"...
Mechanism Of Action
The mechanism of action of rimantadine is not fully understood. Rimantadine appears to exert its inhibitory effect early in the viral replicative cycle, possibly inhibiting the uncoating of the virus. Genetic studies suggest that a virus protein specified by the virion M2 gene plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine.
Rimantadine inhibits the replication in cell culture of influenza A virus isolates from each of the three antigenic subtypes, i.e., H1N1, H2N2 and H3N2, that have been isolated from man. Rimantadine has little or no activity against influenza B virus (Ref. 1,2). Rimantadine does not appear to interfere with the immunogenicity of inactivated influenza A vaccine.
A quantitative relationship between the susceptibility in cell culture of influenza A virus to rimantadine and clinical response to therapy has not been established.
Susceptibility test results, expressed as the concentration of the drug required to inhibit virus replication by 50% or more in a cell culture system, vary greatly (from 19 nM to 93 μM) depending upon the assay protocol used, size of the virus inoculum, isolates of the influenza A virus strains tested, and the cell types used (Ref. 2).
Influenza A virus isolates resistant to rimantadine have been selected in cell culture and in vivo as a result of treatment. Rimantadine-resistant strains of influenza A virus have emerged among freshly isolated strains in closed settings where rimantadine has been used. Resistant viruses have been shown to be transmissible and to cause typical influenza illness. (Ref. 3, 9). Substitutions at any one of five amino acid positions in the transmembrane domain of M2 confer resistance to rimantadine. The most common substitution causing resistance among influenza A (H1N1) and A (H3N2) is S31N. Other less common substitutions that cause resistance include substitutions A30F, V27A, V30A, and L26F.
Rimantadine resistance has been observed in circulating seasonal influenza and pandemic isolates from individuals who have not received rimantadine. Swine-origin influenza A (H1N1) (S-OIV) viruses that were resistant to rimantadine have been shown to contain the S31N substitution. Existing primers used for detection of adamantine resistance in seasonal viruses do not work with all tested S-OIVs (Ref. 11). The CDC should be consulted for questions regarding resistance to rimantadine in circulating influenza strains.
Cross-resistance among the adamantanes, rimantadine and amantadine, has been observed. Resistance to rimantadine confers cross-resistance to amantadine and viceversa. Substitutions that confer resistance to rimantadine include (most frequently) M2 S31N, as well as the less common changes V27A, V30A, L26F and A30T (Ref. 10).
Although the pharmacokinetic profile of Flumadine (rimantadine) has been described, no pharmacodynamic data establishing a correlation between plasma concentration and its antiviral effect are available.
Flumadine (rimantadine) is absorbed after oral administration. The mean ± SD peak plasma concentration after a single 100 mg dose of Flumadine (rimantadine) was 74 ± 22 ng/mL (range: 45 to 138 ng/mL). The time to peak concentration was 6 ± 1 hours in healthy adults (age 20 to 44 years). The single dose elimination halflife in this population was 25.4 ± 6.3 hours (range: 13 to 65 hours). The single dose elimination halflife in a group of healthy 71 to 79 year-old subjects was 32 ± 16 hours (range: 20 to 65 hours).
After the administration of rimantadine 100 mg twice daily to healthy volunteers (age 18 to 70 years) for 10 days, area under the curve (AUC) values were approximately 30% greater than predicted from a single dose. Plasma trough levels at steady state ranged between 118 and 468 ng/mL. In these patients no age-related differences in pharmacokinetics were detected. However, in a comparison of three groups of healthy older subjects (age 50-60, 61-70 and 71-79 years), the 71 to 79 year-old group had average AUC values, peak concentrations and elimination half-life values at steady state that were 20 to 30% higher than the other two groups. Steady-state concentrations in elderly nursing home patients (age 68 to 102 years) were 2- to 4-fold higher than those seen in healthy young and elderly adults.
The pharmacokinetic profile of rimantadine in children has not been established.
Following oral administration, rimantadine is extensively metabolized in the liver with less than 25% of the dose excreted in the urine as unchanged drug. Three hydroxylated metabolites have been found in plasma. These metabolites, an additional conjugated metabolite and parent drug account for 74 ± 10% (n=4) of a single 200 mg dose of rimantadine excreted in urine over 72 hours.
In a group (n=14) of patients with chronic liver disease, the majority of whom were stabilized cirrhotics, the pharmacokinetics of rimantadine were not appreciably altered following a single 200 mg oral dose compared to six healthy subjects who were sex, age and weight matched to six of the patients with liver disease. After administration of a single 200 mg dose to patients (n=10) with severe hepatic dysfunction, AUC was approximately 3-fold larger, elimination half-life was approximately 2-fold longer and apparent clearance was about 50% lower when compared to historic data from healthy subjects.
Rimantadine pharmacokinetics were evaluated following administration of 100 mg Flumadine (rimantadine) twice daily for 14 days to subjects with mild (creatinine clearance [CrCl] 50-80 mL/min), moderate (CrCl 30-49 mL/min), and severe (CrCl 5-29 mL/min) renal impairment and to healthy subjects (CrCl > 80mL/min). There were no clinically relevant differences in rimantadine Cmax, Cmin, and AUC0-∞ between subjects with mild or moderate renal impairment compared to healthy subjects. In subjects with severe renal impairment, rimantadine Cmax, Cmin, and AUC0-infin; on Day 14 increased by 75%, 82%, and 81%, respectively, compared to healthy subjects. The rimantadine elimination half-life was slightly prolonged (increase of 18% or less) in subjects with mild and moderate renal impairment but increased by 49% in subjects with severe renal impairment compared to healthy subjects.
After a single 200 mg oral dose of rimantadine was given to eight hemodialysis patients (CrCl 0-10 mL/min), there was a 1.6-fold increase in the elimination half-life and a 40% decrease in apparent clearance compared to age-matched healthy subjects. Hemodialysis did not contribute to the clearance of rimantadine.
The in vitro human plasma protein binding of rimantadine is about 40% over typical plasma concentrations. Albumin is the major binding protein.
1. Belshe RB, Burk B, Newman F, et al. J Infect Dis. 1989;159(3):430-435.
2. Sim IS, Cerruti RL, Connell EV. J Respir Dis. 1989(Suppl):S46-S51.
3. Hayden FG, Belshe RB, Clover RD, et al. N Engl J Med. 1989;321(25):1696-1702.
10. Deyde VM, Xu X, Bright RA, et al. J Infect Dis. 2007;196(2):249-257.
11. CDC. MMWR Morb Mortal Wkly Rep. 2009;58(16):433-435.
Last reviewed on RxList: 4/26/2010
This monograph has been modified to include the generic and brand name in many instances.
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