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Mechanism of Action
US Drug Names
100 mg PO twice daily for 7 days. Initiation of treatment within 48 hours of illness confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, or progressive illness or hospitalized patients. The CDC recommends against use due to resistance.
100 mg PO twice daily for 7 days; however, a dose reduction to 100 mg PO once daily for 7 days is recommended in elderly nursing home patients. Initiation of treatment within 48 hours of illness confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, or progressive illness or hospitalized patients. The CDC recommends against use due to resistance.
100 mg PO twice daily. Safety and efficacy of prophylactic use beyond 6 weeks has not been determined. The CDC recommends against use due to resistance.
100 mg PO twice daily; however, a dose reduction to 100 mg PO once daily is recommended in elderly nursing home patients. Safety and efficacy of prophylactic use beyond 6 weeks has not been determined. The CDC recommends against use due to resistance.
5 mg/kg/dose PO once daily (Max: 150 mg/day). Safety and efficacy of prophylactic use beyond 6 weeks has not been determined. The CDC recommends against use due to resistance.
200 mg/day PO.
200 mg/day PO; 100 mg/day PO in elderly nursing home patients.
10 to 12 years: 200 mg/day PO.
1 to 9 years: 5 mg/kg/day PO or 150 mg/day PO, whichever is less.
Safety and efficacy have not been established.
The manufacturer recommends the adult dose be reduced to 100 mg PO once daily in patients with severe liver disease.
NOTE: Renal dosage adjustments are for adult patients.
CrCl 30 mL/minute or more: No dosage adjustment needed.
CrCl less than 30 mL/minute: Extend rimantadine dosing interval to every 24 hours (i.e., 100 mg PO once daily in adults).
Hemodialysis does not contribute to the removal of rimantadine.
Rimantadine is an oral antiviral agent indicated for the prophylaxis and treatment of seasonal influenza A virus infections in patients 17 years and older, and for prophylaxis only in children (age 1 to 16 years). Rimantadine is chemically and structurally related to amantadine, but rimantadine lacks the central nervous system effects seen with amantadine. These 2 drugs differ significantly in their pharmacokinetics, with rimantadine achieving higher concentrations in respiratory secretions. The pharmacokinetic properties of rimantadine may account for its more favorable side effect profile. The prophylactic efficacy of rimantadine is comparable to that of amantadine when these agents are administered in equivalent dosages of 200 mg/day. Both drugs provide therapeutic benefit if administered early in cases of uncomplicated influenza. However, antivirals should not be used as substitutes for influenza virus vaccination, which remains the main option for reducing the impact of seasonal influenza. The Centers for Disease Control and Prevention (CDC) and the Infectious Diseases Society of America (IDSA) recommend that adamantanes not be used for the treatment or prophylaxis of currently circulating influenza A viruses due to high resistance among H3N2 and H1N1 strains. 
For storage information, see the specific product information within the How Supplied section.
Compounding Oral Suspension from Tablets (Final Concentration = 10 mg/mL):
NOTE: These directions are provided by the manufacturer for use only during emergency situations, for patients who have difficulty swallowing tablets, or when lower doses are needed.
Gastrointestinal (GI) complaints were among the most common adverse events associated with the use of rimantadine during clinical trials. When compared with placebo, more patients who received rimantadine experienced episodes of nausea (2.8% vs. 1.6%), vomiting (1.7% vs. 0.6%), anorexia (1.6% vs. 0.8%), xerostomia or dry mouth (1.5% vs. 0.6%), and abdominal pain (1.4% vs. 0.8%). Other, less frequent, GI adverse events included diarrhea (0.3% to 1%), dyspepsia (0.3% to 1%), ageusia (less than 0.3%), and dysgeusia (less than 0.3%). At normal adult doses, GI symptoms, especially nausea, vomiting and abdominal pain, occur twice as frequently in elderly patients versus younger adults. Since GI adverse reactions appear to be dose-related, a lower rimantadine dose is recommended for patients 65 years or older. Additional GI adverse events (e.g., constipation, dysphagia, and stomatitis) were reported in clinical studies using higher than recommended doses of rimantadine. In the majority of cases, these GI symptoms rapidly resolved following treatment discontinuation. 
Neurologic complaints were among the most common adverse events associated with the use of rimantadine during clinical trials. When compared with placebo, patients receiving rimantadine experienced more episodes of insomnia (2.1% to 3.4% vs. 0.7% to 0.9%), dizziness (0.7% to 1.9% vs. 1.1%), nervousness or anxiety (1.3% to 2.1% vs. 0.6% to 0.7%), concentration impairment (2.1% vs. 1.4%), headache (1.4% vs. 1.3%), asthenia (1.4% vs. 0.5%), and fatigue (1% vs. 0.9%). Other, less frequent, neurologic adverse events observed in rimantadine recipients included agitation (0.3% to 1%), ataxia (0.3% to 1%), depression (0.7%), and drowsiness (0.3% to 1%). Cases of convulsions or seizures, confusion, euphoria, gait abnormalities, hallucinations, hyperkinesis, and tremor were rarely reported (less than 0.3%) in patients receiving rimantadine treatment. In elderly patients, CNS reactions including dizziness, headache, anxiety, asthenia, and fatigue, occurred up to two-times more often in patients treated with rimantadine versus placebo. Additionally, the incidence of neurologic adverse events (e.g., rigors, agitation, and hypoesthesia) were significantly increased in clinical trials that employed higher than recommended doses of rimantadine. Health care providers are advised to comply with approved dosing regimens. 
Antimicrobial resistance can occur during therapy with rimantadine due to the development of viral mutations. Drug effectiveness may be diminished by resistance mutations or other factors such as viral virulence. Drug susceptibility patterns should be assessed when determining appropriateness of treatment with rimantadine. 
Rash developed in 0.3% to 1% of patients who received treatment with rimantadine during clinical trials. Additionally, in clinical trials that employed higher than recommended doses of rimantadine, episodes of diaphoresis and fever were observed. Health care providers are advised to comply with recommended dosing regimens. 
Although infrequent, adverse events of the respiratory system were reported during rimantadine clinical trials, including dyspnea (0.3% to 1%), bronchospasm (less than 0.3%), and increased cough (less than 0.3%). 
Adverse events of the cardiovascular system reported in less than 0.3% of patients receiving recommended doses of rimantadine in controlled clinical trials included pallor, palpitations, hypertension, cerebrovascular disorder, heart failure, pedal edema, heart block (AV block), sinus tachycardia, and syncope. 
Parosmia (less than 0.3%) and tinnitus (0.3% to 1%) were reported in patients receiving recommended doses of rimantadine in controlled clinical trials. Additionally, cases of ocular pain and increased lacrimation were noted in clinical trials that employed higher than recommended doses of rimantadine. Health care providers are advised to comply with recommended dosing regimens. 
Cases of non-puerperal lactation (galactorrhea) were noted in less than 0.3% of patients receiving treatment with recommended doses of rimantadine during controlled clinical trials. When higher than recommended doses were used in clinical trials, episodes of increased urinary frequency were reported. Health care providers are advised to comply with approved dosing regimens. 
Rimantadine is contraindicated in patients with a known rimantadine hypersensitivity, amantadine hypersensitivity, or hypersensitivity to any agent in the adamantane class.
Rimantadine should be used cautiously in patients with a history of seizure disorder. The manufacturer reports that during clinical trials a small number of patients with a history of seizures who were not receiving anticonvulsant therapy developed seizure-like activity while receiving rimantadine. Rimantadine should be discontinued if seizures develop.
Geriatric patients receiving either 200 or 400 mg/day of rimantadine experience considerably more central nervous system and GI adverse reactions than those patients receiving placebo. The side-effects appear to be dose related; therefore in patients 65 years or older, the recommended dose of rimantadine is 100 mg/day.
The safe and effective use of rimantadine in infants and neonates has not been determined. In children and adolescents ages 1 to 16 years, rimantadine may be used for prophylaxis against influenza A; however, safety and efficacy of treating symptomatic influenza has not been established in this population.
Rimantadine is primarily excreted unchanged in the urine. Dose reductions are advised for patients with renal failure or severe renal impairment (CrCl less than 30 mL/min). Monitor renal function closely and the dose adjusted accordingly.
Use caution when administering rimantadine to patients with hepatic disease. Severe hepatic impairment reduces the clearance of rimantadine, accumulation and toxicity can occur.
Rimantadine is classified as an FDA pregnancy risk category C drug. No adequate and well-controlled studies have been conducted in pregnant women. In animal studies, rimantadine 200 mg/kg/day (11-time the maximum recommended human dose (MRHD)) was embryotoxic in rats, causing increased fetal resorption. In rabbits receiving 50 mg/kg/day (0.1-times MRHD), no embryotoxic events were observed. According to the manufacturer, use during pregnancy should be avoided unless the potential benefits outweigh the possible risks to the fetus. 
It is unknown if rimantadine is excreted in human milk, and data regarding use during breast-feeding are limited; however, it is concentrated at amounts greater than maternal serum concentration in the milk of rats and adverse effects have been noted in rat offspring. Due to the potential for infant toxicities, the manufacturer advises against use in nursing mothers. Oseltamivir and zanamivir may be potential alternatives to consider during breast-feeding. However, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.  
A serious bacterial infection may begin with influenza-type symptoms or may coexist with or occur as complications of influenza. There are no data to suggest rimantadine is effective in preventing such complications or treating a viral infection other than influenza virus A.
Rimantadine's exact mechanism of action is unknown. Rimantadine appears to block the uncoating of the virus particle and subsequent release of viral nucleic acid into the host cell. This process is thought to be caused by interference with fusion of the virion coat to vacuolar membranes, thereby producing a virustatic effect. Because uncoating is an early part of the viral replication cycle, rimantadine, if administered early, serves as an effective agent in preventing further viral shedding.
Studies suggest that a virus protein specified by the virion M2 gene plays a role in the susceptibility of the influenza A virus to inhibition by rimantadine. Substitutions at any of the 5 amino acid positions in the transmembrane domain of M2 confer resistance to rimantadine. The most common substitution causing resistance is S31N (H1N1 influenza A, including swine-origin influenza A, and H3N2 influenza). Less common substitutions that cause resistance include A30F, V27A, V30A, and L26F. Resistance to rimantadine confers cross-resistance to amantadine and vice-versa.
Influenza viruses are classified into 3 distinct types, influenza A, influenza B, and influenza C. Influenza A is further divided into subtypes based on their hemagglutinin (H or HA) and neuraminidase (N or NA) activity. At least 16 distinct HAs (H1 to H16) and 9 NAs (N1 to N9) have been described. Influenza infection may be attributed to either influenza A virus or influenza B virus. Influenza A virus subtypes include H1N1 and H3N2. In 2009, a novel influenza A H1N1 virus (previously referred to as swine influenza) was identified; this virus is included in season influenza A viruses. Human cases of influenza illness from the avian H5N1 virus (commonly known as avian flu) have been reported since 1997. Human infections with avian H7N9, H5N2, H5N8, H9N2, H7N7, and H7N3 viruses have also been described.
Rimantadine is administered orally. Protein binding is approximately 40% (albumin as the major binding protein), with extensive metabolism by the liver to 3 distinct hydroxylated metabolites and 1 conjugated metabolite. These metabolites and the parent drug account for 74 +/- 10% (n=4) of a single 200 mg oral dose of rimantadine excreted in the urine over 72 hours. The half-life of rimantadine is 25.4 +/- 6.3 hours (range: 13 to 65 hours). Urinary excretion of unchanged rimantadine accounts for less than 25% of the dose in healthy subjects.
Affected cytochrome P450 isoenzymes and drug transporters: none
The absorption of rimantadine is similar for both tablets and syrup. The mean peak plasma concentration after a single oral 100 mg dose is 74 +/- 22 ng/mL (range 45 to 138 ng/mL). The time to peak plasma concentration is 6 +/- 1 hours in healthy adults (age 20 to 44 years). After a 10-day course of 100 mg PO twice daily in healthy volunteers, systemic drug exposure (AUC) values were approximately 30% greater than predicted from a single dose. Plasma trough levels at steady state ranging between 118 and 468 ng/mL.
In a group (n=14) of patients with chronic liver disease, mainly patients with stabilized cirrhosis, the pharmacokinetics of rimantadine were not appreciably altered after a single 200 mg oral dose when compared to 6 healthy, matched subjects. After administration of a single 200 mg oral dose to patients (n=10) with severe hepatic dysfunction, the exposure (AUC) was approximately 3-fold larger, the elimination half-life was approximately 2-fold longer, and the apparent clearance was about 50% lower compared to historic data from healthy subjects.
Rimantadine is not appreciably removed by hemodialysis. The rimantadine dosage should be reduced in patients with severe renal disease, but supplemental doses in patients receiving hemodialysis are not required. Rimantadine pharmacokinetics were evaluated after the administration of 100 mg PO twice daily for 14 days in patients with mild renal impairment (CrCl 50 to 80 mL/min), moderate renal impairment (CrCl 30 to 49 mL/min), and severe renal impairment (CrCl 5 to 29 mL/min) and compared to healthy subjects (CrCl greater than 80 mL/min). There were no clinically relevant differences in the rimantadine peak concentration (Cmax), trough (Cmin), or exposure (AUC) in patients with mild or moderate renal impairment as compared to healthy subjects. In patients with severe renal impairment on day 14, the rimantadine Cmax increased by 75%, the Cmin increased by 82%, and the AUC increased by 81% as compared to healthy subjects. The elimination half-life in patients with mild or moderate renal impairment was slightly prolonged (up to 18%), but was increased by 49% in patients with severe renal impairment. After a single 200 mg oral dose of rimantadine was administered to 8 hemodialysis patients (CrCl 10 mL/min or less), 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; however, hemodialysis did not contribute to the clearance of rimantadine.
The pharmacokinetic profile of rimantadine in children has not been established.
The single-dose elimination half-life of rimantadine in a group of healthy 71 to 79 year old subjects was 32 +/- 16 hours (range: 20 to 65 hours). In a comparison of 3 groups of healthy older subjects (aged 50 to 60, 61 to 70, and 71 to 79 years), the 71 to 79 year old group had average exposure (AUC) values, peak concentrations, and elimination half-life values at steady-state that were 20% to 30% higher than the other 2 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.
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