RIMANTADINE HYDROCHLORIDE

Rimantadine hydrochloride, USP is a synthetic antiviral drug available as a 100 mg film-coated tablet. Each film-coated tablet contains 100 mg of rimantadine hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, type A and FD&C Yellow No. 6 Aluminium Lake. Film coating material, Opadry (YS-1-19025-A), contains hypromellose and polyethylene glycol. Rimantadine hydrochloride, USP is a white to off-white crystalline powder which is freely soluble in water (50 mg/mL at 20°C). Chemically, rimantadine hydrochloride, USP is tricyclo [3.3.1.1 3.7 ]-decane-1-methanamine, α-methyl-, hydrochloride, with a molecular formula of C 12 H 21 N•HCl, a molecular weight of 215.77 and the following structural formula: 1

Rimantadine hydrochloride tablet is indicated for the prophylaxis and treatment of illness caused by various strains of influenza A virus in adults (17 years and older). Rimantadine hydrochloride tablet is indicated for prophylaxis against influenza A virus in children (1 year to 16 years of age). Prophylaxis In controlled studies of children (1 year to 16 years of age), healthy adults (17 years and older), and elderly patients (65 years of age and older), rimantadine hydrochloride has been shown to be safe and effective in preventing signs and symptoms of infection caused by various strains of influenza A virus. Since rimantadine hydrochloride does not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically-related viruses. Following vaccination during an influenza outbreak, rimantadine hydrochloride prophylaxis should be considered for the 2 to 4 week time period required to develop an antibody response. However, the safety and effectiveness of rimantadine hydrochloride prophylaxis have not been demonstrated for longer than 6 weeks. Treatment Rimantadine hydrochloride therapy should be considered for adults (17 years and older) who develop an influenza-like illness during known or suspected influenza A infection in the community. When administered within 48 hours after onset of signs and symptoms of infection caused by influenza A virus strains, rimantadine hydrochloride has been shown to reduce the duration of fever and systemic symptoms. The following points should be considered before initiating treatment or prophylaxis with rimantadine hydrochloride: Rimantadine hydrochloride 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 rimantadine hydrochloride.

For Prophylaxis in Adults and Children Adults (17 years and older) The recommended adult dose of rimantadine hydrochloride 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 (CrCl ≤ 10 mL/min) and in 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 duration ranged from 5 weeks to 6 weeks in pediatric subjects. In children 1 year to 9 years of age, rimantadine hydrochloride should be administered once a day, at a dose of 5 mg/kg but not exceeding 150 mg. For children 10 years of age or older, use the adult dose. (see Directions for Compounding of an Oral Suspension from Rimantadine Hydrochloride 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 rimantadine hydrochloride 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 rimantadine hydrochloride 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 (CrCl ≤ 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. Rimantadine hydrochloride 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) Rimantadine hydrochloride is not indicated for treatment of influenza in pediatric patients 16 years or younger. Directions for the Compounding of an Oral Suspension from Rimantadine Hydrochloride 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 rimantadine hydrochloride tablets, 100 mg using Ora-Sweet ® † . Other vehicles have not been studied. To make an oral suspension (10 mg/mL) from 100 mg rimantadine hydrochloride tablets, you will need the following: 100 mg tablets of rimantadine hydrochloride Ora-Sweet ® (a vehicle manufactured by Paddock Laboratories) a graduated cylinder a mortar and pestle an Amber Glass or Polyethylene terephthalate plastic (PET) bottle a funnel (optional) Compounding Procedures A 100 mg tablet of rimantadine hydrochloride is required for each 10 mL of compounded oral suspension to make a concentration of 10 mg/mL. A compounded oral suspension is stable for 14 days. Therefore, the maximum amount of oral suspension that can be dispensed to a patient should not exceed a 14 day supply. Step A: Guidance for how to determine the Number of Tablets and Total Volume needed to compound a 10 mg/mL oral suspension for each patient. 1. Verify the prescribed dose is correct. 2. Calculate the mg amount of rimantadine hydrochloride needed for the duration of therapy. (Daily Dose) × (Number of days) = (mg of rimantadine hydrochloride) For example, 75 mg/day × 10 days = 750 mg 3. Round up the mg of rimantadine hydrochloride 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 rimantadine hydrochloride) ÷ (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 rimantadine hydrochloride) ÷ (10 mg/mL) = (Total Volume) For example, 800 mg ÷ 10 mg/mL = 80 mL Step B: Once the total Number of Tablets and Volume are determined then follow the procedures below for compounding the oral suspension (10 mg/mL) from rimantadine hydrochloride tablets 100 mg Verify your calculations before you begin to compound an oral suspension. A 100 mg tablet of rimantadine hydrochloride is required for each 10 mL of compounded oral suspension to make a concentration of 10 mg/mL. 1. Place the required number of rimantadine hydrochloride 100 mg tablets into a clean mortar of sufficient size to contain the tablets and volume of vehicle, Ora-Sweet ® used in Step 3. 2. Grind the tablets and triturate to a fine powder using a pestle. Powder on the sides of the mortar or pestle should be removed using a spatula and incorporated into the trituration throughout the process. 3. Slowly add approximately one-third (1/3) of the total volume of vehicle to the mortar while triturating until a uniform suspension is achieved. 4. Transfer the suspension to an amber glass or a PET plastic bottle. Other types of bottles, such as non-PET plastic or uncolored bottles, have not been evaluated and should not be used. A funnel may be used to eliminate any spillage. 5. Slowly add the second one-third (1/3) of the total volume of vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the contents into the bottle. 6. Repeat the rinsing (Step 5) with the remaining one-third (1/3) of the vehicle, transferring the remaining contents to the fullest extent possible. Verify that the suspension is at the desired total volume or add additional vehicle if needed. 7. Close the bottle using a child-resistant cap. 8. Shake well to ensure homogeneous suspension. (Note: The active drug, rimantadine hydrochloride readily dissolves in the specified vehicle. The suspension is caused by some of the inert ingredients of rimantadine hydrochloride tablets 100 mg which are insoluble in this vehicle.) Labeling and Dispensing Information for the Compounded Oral Suspension 1. Include an ancillary label on the bottle indicating "Shake Gently Before Use". This compounded suspension should be gently shaken prior to administration to minimize the tendency for air entrapment with the Ora-Sweet ® preparation. The need to shake the compounded oral suspension gently prior to administration should be reviewed with the parent or guardian when the suspension is dispensed . 2. Provide an oral dosing device (a graduated oral syringe or spoon) that will measure the prescribed dose (in mL). If possible, mark or highlight the graduation corresponding to the appropriate dose on the oral syringe or spoon for each patient. 3. Include an Expiration Date label according to storage condition (see below) and a "Discard any Unused Portion" label to the bottle. Instruct the parent or guardian that any remaining material following completion of therapy or after the expiration date on the label must be discarded. STORAGE OF THE PHARMACY-COMPOUNDED SUSPENSION 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.

Rimantadine hydrochloride tablet is contraindicated in patients with known hypersensitivity to drugs of the adamantane class, including rimantadine and amantadine.

In 1,027 patients treated with rimantadine hydrochloride 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 % to 3%) at the recommended dose in controlled clinical trials are shown in the table below. Rimantadine (n=1,027) Control (n=986) Nervous System Insomnia 2.1% 0.9% Dizziness 1.9% 1.1% Headache 1.4% 1.3% Nervousness 1.3% 0.6% Fatigue 1.0% 0.9% Gastrointestinal System Nausea 2.8% 1.6% Vomiting 1.7% 0.6% Anorexia 1.6% 0.8% Dry mouth 1.5% 0.6% Abdominal Pain 1.4% 0.8% Body as a Whole Asthenia 1.4% 0.5% 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 rimantadine hydrochloride. 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%. Rimantadine 200 mg/day (n=145) Placebo (n=143) Amantadine 200 mg/day (n=148) Nervous System Insomia 3.4% 0.7% 7.0% Nervousness 2.1% 0.7% 2.8% Impaired Concentration 2.1% 1.4% 2.1% Dizziness 0.7% 0.0% 2.1% Depression 0.7% 0.7% 3.5% Total % of subjects with adverse reactions 6.9% 4.1% 14.7% Total % of subjects withdrawn due to adverse reactions 6.9% 3.4% 14.0% Geriatric Use Approximately 200 patients over the age of 65 were evaluated for safety in controlled clinical trials with rimantadine hydrochloride. Geriatric subjects who received either 200 mg or 400 mg of rimantadine daily for 1 to 50 days experienced considerably more central nervous system and gastrointestinal adverse events than comparable geriatric subjects receiving placebo. Central nervous system events including dizziness, headache, anxiety, asthenia, and fatigue, occurred up to two times more often in subjects treated with rimantadine than in those treated with placebo. Gastrointestinal symptoms, particularly nausea, vomiting, and abdominal pain occurred at least twice as frequently in subjects receiving rimantadine than in those receiving placebo. The gastrointestinal symptoms appeared to be dose related. In patients over 65, the recommended dose is 100 mg, daily (see CLINCAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Acetaminophen: Rimantadine hydrochloride, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Co-administration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine hydrochloride, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. Cimetidine: When a single 100 mg dose of rimantadine hydrochloride was administered with steady-state cimetidine (300 mg four times a day), there were no statistically significant differences in rimantadine C max or AUC between rimantadine hydrochloride alone and rimantadine hydrochloride in the presence of cimetdine. Live Attenuated Influenza Vaccine (LAIV): The concurrent use of rimantadine hydrochloride with live attenuated intranasal influenza vaccine has not been evaluated. However, because of potential interference between these products, the live attenuated intranasal influenza vaccine should not be administered until 48 hours after cessation of rimantadine hydrochloride and rimantadine hydrochloride should not be administered until two weeks after the administration of live attenuated intranasal influenza vaccine unless medically indicated. The concern about potential interference arises principally from the potential for antiviral drugs to inhibit replication of live vaccine virus.