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.

MICROBIOLOGY: 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 18 nM to 93 μgM) 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).

RESISTANCE: 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 5 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: Cross-resistance among the adamantanes rimantadine and amantadine has been observed. Resistance to rimantadine confers cross-resistance to amantadine and vice-versa. 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).

PHARMACOKINETICS: Although the pharmacokinetic profile of Flumadine has been described, no pharmacodynamic data establishing a correlation between plasma concentration and its antiviral effect are available.

Flumadine is absorbed after oral administration. The mean ± SD peak plasma concentration after a single 100 mg dose of Flumadine 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 half-life in this population was 25.4 ± 6.3 hours (range: 13 to 65 hours). The single dose elimination half-life 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 6 healthy subjects who were sex, age and weight matched to 6 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 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 > 80 mL/min). There were no clinically relevant differences in rimantadine Cmax, Cmin, and AUC0-τ between subjects with mild or moderate renal impairment compared to healthy subjects. In subjects with severe renal impairment, rimantadine Cmax, Cmin, and AUC0-τ on Day 14 increased by 75%, 82%, and 81%, respectively, compared with 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 8 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.

Indications and Usage for Flumadine

• Flumadine 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 Flumadine.

In 1,027 patients treated with Flumadine in controlled clinical trials at the recommended dose of 200 mg daily, the most frequently reported adverse events involved the gastrointestinal and nervous systems.

Incidence >1 %: Adverse events reported most frequently (1-3%) at the recommended dose in controlled clinical trials are shown in the table below.

Less frequent adverse events (0.3 to 1%) at the recommended dose in controlled clinical trials were:
Gastrointestinal System: diarrhea, dyspepsia; Nervous System: impairment of concentration, ataxia, somnolence, agitation, depression; Skin and Appendages: rash; Hearing and Vestibular: tinnitus;Respiratory: dyspnea. 

Additional adverse events (less than 0.3%) reported at recommended doses in controlled clinical trials were: Nervous System: gait abnormality, euphoria, hyperkinesia, tremor, hallucination, confusion, convulsions; Respiratory: bronchospasm, cough; Cardiovascular: pallor, palpitation, hypertension, cerebrovascular disorder, cardiac failure, pedal edema, heart block, tachycardia, syncope; Reproduction: non-puerperal lactation; Special Senses: taste loss/change, parosmia. Rates of adverse events, particularly those involving the gastrointestinal and nervous systems, increased significantly in controlled studies using higher than recommended doses of Flumadine. In most cases, symptoms resolved rapidly with discontinuation of treatment. In addition to the adverse events reported above, the following were also reported at higher than recommended doses: increased lacrimation, increased micturition frequency, fever, rigors, agitation, constipation, diaphoresis, dysphagia, stomatitis, hypesthesia and eye pain.

Adverse Reactions in Trials of Rimantadine and Amantadine: In a six-week prophylaxis study of 436 healthy adults comparing rimantadine with amantadine and placebo, the following adverse reactions were reported with an incidence >1 %.

As with any overdose, supportive therapy should be administered as indicated. Overdoses of a related drug, amantadine, have been reported with adverse reactions consisting of agitation, hallucinations, cardiac arrhythmia and death. The administration of intravenous physostigmine (a cholinergic agent) at doses of 1 to 2 mg in adults (Ref. 7) and 0.5 mg in children (Ref. 8) repeated as needed as long as the dose did not exceed 2 mg/hour has been reported anecdotally to be beneficial in patients with central nervous system effects from overdoses of amantadine.

Flumadine Dosage and Administration

FOR PROPHYLAXIS IN ADULTS AND CHILDREN:
Adults( 17 years and older):
The recommended adult dose of Flumadine is 100 mg twice a day. Study durations ranged from 11 days to 6 weeks in adult and elderly patients. In patients with severe hepatic dysfunction, severe renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10 mL/min) and elderly nursing home patients, a dose reduction to 100 mg daily is recommended. Because of the potential for accumulation of rimantadine metabolites during multiple dosing, patients with hepatic or renal impairment should be monitored for adverse effects.

Children (1 year to 16 years of age):

• Study durations ranged from 5 weeks to 6 weeks in pediatric patients.
• In children 1 year to 9 years of age, Flumadine should be administered once a day, at a dose of 5 mg/kg but not exceeding 150 mg.
• For children 10 to 16 years of age, use the adult dose.

(see Directions for Compounding of an Oral Suspension from Flumadine Tablets to prepare an oral suspension for administration to children and patients with difficulty swallowing tablets).

Children(Birth to 11 months):
The safety and efficacy of Flumadine for prophylaxis of influenza in pediatric patients younger than 1 year of age have not been established.

FOR TREATMENT IN ADULTS
Adults(17 years and older):
The recommended adult dose of Flumadine is 100 mg twice a day for 7 days. In patients with severe hepatic dysfunction, severe renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10 mL/ min) and elderly nursing home patients, a dose reduction to 100 mg daily is recommended. Because of the potential for accumulation of rimantadine metabolites during multiple dosing, patients with hepatic or renal impairment should be monitored for adverse effects. Flumadine therapy should be initiated as soon as possible, preferably within 48 hours after onset of signs and symptoms of influenza A infection. Therapy should be continued for approximately seven days from the initial onset of symptoms.

Children (16 years of age and younger):
Flumadine is not indicated for treatment of influenza in pediatric patients 16 years or younger.

Directions for the Compounding of an Oral Suspension from Flumadine Tablets (Final Concentration = 10 mg/mL)1

These directions are provided for use only during emergency situations, for patients who have difficulty swallowing tablets or where lower doses are needed. The pharmacist may compound a suspension (10 mg/mL) from Flumadine (rimantadine HCl) Tablets, 100 mg using Ora-Sweet®.1 Other vehicles have not been studied.

To make an oral suspension (10 mg/mL) from 100 mg Flumadine tablets, you will need the following:

• 100 mg tablets of Flumadine
• Ora-Sweet® (a vehicle manufactured by Paddock Laboratories)
• a graduated cylinder
• a mortar and pestle
• an Amber Glass or PET Plastic bottle
• a funnel (optional)

Ora-Sweet® is a registered trademark of Paddock Laboratories

Compounding Procedures:

1. Verify the prescribed dose is correct.
2. Calculate the mg amount of Flumadine needed for the duration of therapy. (Daily Dose) × (Number of days) = (mg of Flumadine) For example, 75 mg/day × 10 days = 750 mg
3. Round up the mg of Flumadine amount to the next 100 mg designation. For example, Round up 750 mg to 800 mg
4. Calculate the Number of 100 mg tablets that are required for the compounded oral suspension. (Rounded mg of Flumadine) ÷ (100 mg/tablet) = (Number of tablets) For example, 800 mg ÷ 100 mg/tablet = 8 tablets
5. Calculate the Total Volume of compounded oral suspension (10 mg/mL) (Rounded mg of Flumadine) ÷ (10 mg/mL) = (Total Volume) For example, 800 mg ÷ 10 mg/mL = 80 mL

Room Temperature: Stable for 14 days when stored in ambient room temperature conditions. Other storage conditions have not been studied.

Note: The storage conditions are based on stability studies of compounded oral suspensions, using the above mentioned vehicle, which was placed in amber glass and PET plastic bottles at 25°C (77°F). Stability studies have not been conducted with other vehicles or bottle types.

How is Flumadine Supplied

Flumadine® tablets (rimantadine hydrochloride tablets) are supplied as 100 mg tablets (orange, oval-shaped, film-coated) in bottles of 100 (NDC 49708- 521-88). Imprint on tablets: (Front) Flumadine 100; (Back) FOREST.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]