Flumadine

Generic Name: Rimantadine Hydrochloride
Class: Adamantanes
VA Class: AM800
Chemical Name: α-Methyl tricyclo[3.3.1.13,7]decane-1-methanamine hydrochloride
Molecular Formula: C12H21N•HCl
CAS Number: 1501-84-4

Introduction

Antiviral; adamantane derivative.1 3 10 15 16 40 42

Uses for Flumadine

Treatment of Seasonal Influenza A Virus Infections

Symptomatic treatment of uncomplicated illness caused by susceptible influenza A virus.1 2 3 5 11 15 16 33 37 61

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for treatment of seasonal influenza.116 137 149 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve,116 144 and emergence of rimantadine-resistant influenza virus may decrease effectiveness of the drug.1

Beginning in the 2005–2006 influenza season, most influenza A (H3N2) strains circulating in the US were resistant to adamantanes (amantadine, rimantadine),29 77 116 121 and resistance to the drugs among seasonal influenza A (H3N2) isolates has remained high during subsequent influenza seasons.29 117 162 In addition, the 2009 pandemic influenza A (H1N1) virus was resistant to amantadine and rimantadine,52 117 151 162 and this strain is expected to continue to circulate during the 2010–2011 influenza season.144 162

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Amantadine and rimantadine have little or no activity against influenza B.1 11 15 16 35 42

CDC recommends that adamantanes (amantadine, rimantadine) not be used for the treatment of influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.77

CDC issues recommendations concerning the use of antiviral agents for the treatment of influenza, and these recommendations are updated as needed during each influenza season.144 Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at .

Prevention of Seasonal Influenza A Virus Infections

Prophylaxis of influenza infection caused by susceptible influenza A when timely vaccination with influenza virus vaccine is not feasible, contraindicated, or not available.1 3 4 7 8 16 47

Annual vaccination with seasonal influenza virus vaccine, as recommended by the US Public Health Service Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications.1 29 116 144 149 161 Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza in certain individuals.1 29 116 144 149 161

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for the prophylaxis of influenza.116 137 149 The most appropriate antiviral for prevention of influenza is selected based on information regarding the likelihood that the influenza strain is susceptible and the known adverse effects of the drug.137 144 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve,137 144 and emergence of rimantadine-resistant influenza virus may decrease effectiveness of the drug.1

CDC recommends that adamantanes (amantadine, rimantadine) not be used for prevention of influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.77

CDC issues recommendations concerning the use of antiviral agents for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.144 Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at .

Avian Influenza A Virus Infections

May be used for treatment or prophylaxis of avian influenza A virus infections in certain situations.94 104

The WHO recommends use of a neuraminidase inhibitor (i.e., oseltamivir) for the treatment of avian influenza A infections.94 104

Concomitant use of a neuraminidase inhibitor (i.e., oseltamivir) and an adamantane (amantadine, rimantadine) can be considered in a patient with pneumonic disease or clinical progression if local surveillance data indicate the H5N1 virus is known or likely to be susceptible to an adamantane.104

Should not be used alone for treatment of avian influenza A if a neuraminidase inhibitor is available.94 104

Flumadine Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1 14

Dosages <150 mg daily can be given as a single dose; dosages of 200 mg daily can be given in 2 divided doses.1 23 Dividing dosages >100 mg daily into 2 doses may minimize adverse effects.63

Dosage

Available as rimantadine hydrochloride; dosage expressed in terms of rimantadine hydrochloride.1

Pediatric Patients

Treatment of Seasonal Influenza A Virus Infections
Oral

Children ≥13 years of age: 100 mg twice daily.29

Initiate rimantadine treatment as soon as possible, preferably within 24–48 hours after onset of symptoms and continue for up to 5 days or 24–48 hours after symptoms disappear.1

Prevention of Seasonal Influenza A Virus Infections
Oral

Children 1–9 years of age: 5 mg/kg (maximum 150 mg) once daily.1 29

Children ≥10 years of age: 100 mg twice daily.1 AAP recommends 5 mg/kg daily in 2 divided doses in those weighing <40 kg or 100 mg twice daily in those weighing ≥40 kg.29

Individualize duration of prophylaxis. For maximum effectiveness, must be taken every day during influenza activity in the community. Manufacturer states that safety and efficacy for >6 weeks not established.1

Adults

Treatment of Seasonal Influenza A Virus Infections
Oral

100 mg twice daily.1 28

Initiate rimantadine treatment as soon as possible, preferably within 24–48 hours after onset of symptoms and continue for up to 5 days or 24–48 hours after symptoms disappear.1

Prevention of Seasonal Influenza A Virus Infections
Oral

100 mg twice daily.1 28

Duration of antiviral prophylaxis should be individualized. For maximum effectiveness, the antiviral agent must be taken every day during influenza activity in the community. Manufacturer states that safety and efficacy for >6 weeks not established.1

For prophylaxis in conjunction with influenza virus vaccine (see Specific Drugs under Interactions), rimantadine should be administered for 2 weeks after vaccine administration.1

Prescribing Limits

Pediatric Patients

Prevention of Seasonal Influenza A Virus Infections
Oral

Children 1–9 years of age: Maximum 150 mg daily.1 29

Special Populations

Hepatic Impairment

Treatment or Prevention of Seasonal Influenza A Virus Infections

100 mg daily in patients with severe hepatic impairment.1

Renal Impairment

Treatment or Prevention of Seasonal Influenza A Virus Infections

100 mg daily in patients with severe renal impairment (Clcr ≤10 mL/minute).1 Further dosage adjustments may be needed.1

Geriatric Patients

≥65 years of age: 100 mg daily recommended by the manufacturer;1 ACIP and others recommend 100 mg daily in those who experienced adverse effects with the usual adult dosage.28

Geriatric individuals residing in nursing homes: 100 mg daily.1

Cautions for Flumadine

Contraindications

  • Known hypersensitivity to adamantane derivatives (rimantadine, amantadine) or any ingredient in the formulation.1

Warnings/Precautions

Warnings

CNS Effects

Patients with a history of seizure disorders should be observed closely for possible increased seizure activity.1 Discontinue if seizures occur.1

General Precautions

Other Viral or Bacterial Infections

Not effective for treatment or prophylaxis of viral respiratory tract illnesses other than those due to influenza A virus.1

Serious bacterial infections may present with influenza-like symptoms, coexist with influenza, or occur during influenza.25 73

Prescribing and Dispensing Errors.

Ensure accuracy of prescription; similar spelling of Flumadine (rimantadine) and flutamide may result in errors.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; adverse effects noted in the offspring of rats given the drug during the perinatal and postnatal period.1 Use not recommended.1

Pediatric Use

Used in children ≥1 year of age for prophylaxis of influenza A;1 has not been evaluated for prophylaxis in infants <1 year of age.1

Safety and efficacy for treatment of influenza A virus infection not established in children.1 Has been used for the treatment of influenza A infection in children 1–15 years of age; safety and efficacy similar to that in adults.37 59 61

Geriatric Use

Frequency and severity of adverse effects, including adverse CNS effects, in individuals >65 years of age receiving rimantadine hydrochloride 100 mg twice daily higher than in younger adults and children.1 47

Consider age-related decreases in renal function when selecting dosage.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Caution in patients with hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Caution in patients with renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea,1 3 9 37 47 53 insomnia,1 3 40 47 53 dizziness.1 3 19 25 40 47 53

Interactions for Flumadine

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

Slightly decreased rimantadine peak plasma concentrations and AUC1

Aspirin

Slightly decreased rimantadine peak plasma concentrations and AUC1

Cimetidine

Decreased rimantadine clearance with single dose of cimetidine1

Effect of long-term administration not evaluated1

Influenza virus vaccines

Influenza virus vaccine inactivated: Rimantadine does not interfere with the antibody response to the vaccine1

Influenza virus vaccine live intranasal: Potential interference with antibody response to the live vaccine; no specific studies1 144

Influenza virus vaccine inactivated: May be used concomitantly with or at any interval before or after rimantadine1 144

Influenza virus vaccine live intranasal: Do not administer the live intranasal vaccine until at least 48 hours after rimantadine is discontinued; do not administer rimantadine until at least 2 weeks after administration of the live intranasal vaccine;1 144 repeat vaccination if influenza antiviral is given 2 days before to 14 days after the vaccine144

Flumadine Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract; peak plasma concentrations usually attained within 6 hours.1 14 40 49 51

Commercially available tablets and oral solution are bioequivalent.1 56 60

Food

Food does not appear to affect absorption.1 14

Distribution

Extent

Not fully characterized.1 Distributed into nasal secretions.40 51 54

Crosses the placenta in rats; distributed into milk in rats.1 Not known whether rimantadine crosses the placenta or is distributed into human milk.1

Plasma Protein Binding

40%.1 40

Elimination

Metabolism

Extensively metabolized in the liver.1 40 55

Elimination Route

Principally excreted in urine (74%) as metabolites and unchanged drug (25%).1 40 55

Not removed by hemodialysis.1

Half-life

25–38 hours in adults and children.1 40 49 51 54 60

Special Populations

No change in pharmacokinetics in patients with chronic liver disease (mainly stabilized cirrhosis).1 Clearance reduced and half-life increased twofold in patients with severe hepatic impairment.1

In patients with renal impairment, half-life prolonged and clearance decreased.1 20

Stability

Storage

Oral

Tablets

15–30°C.1

Oral Solution

15–30°C.1

Actions and Spectrum

  • Adamantane-derivative (a symmetric tricyclic amine);1 3 10 15 16 40 42 structurally related to amantadine.2 3 4 5 8 10 15 16 17 40 42

  • Has antiviral activity against some strains of influenza A, including some strains of H1N1, H2N2, and H3N2.1 4 5 11 12 16 42 45

  • Has little or no activity against influenza B.1 11 15 16 35 42

  • Worldwide incidence of influenza A viruses resistant to adamantanes (amantadine, rimantadine) has increased over the last several years.84 92 121

  • Beginning in the 2005–2006 influenza season, most influenza A (H3N2) strains circulating in the US were resistant to amantadine and rimantadine.77 121 Resistance to amantadine and rimantadine among seasonal influenza A (H3N2) isolates has remained high during subsequent influenza seasons.29 93 117 162

  • Although amantadine and rimantadine were active against most seasonal influenza A (H1N1) viruses circulating in the US during the 2008–2009 and 2009–2010 influenza seasons,133 139 162 the 2009 pandemic influenza A (H1N1) virus is resistant to amantadine and rimantadine.52 117 151 162

  • Some strains of avian influenza A (H5N1) have been susceptible to rimantadine;38 39 other strains, including influenza A (H5N1) isolated from patients in Asia during 2004 and 2005, have been resistant.76

  • Rimantadine inhibits viral replication by interfering with the influenza A virus M2 protein, an integral membrane protein.1 11 15 16 41 42 46

  • Strains of influenza A virus with reduced susceptibility to rimantadine have been produced in vitro and have emerged during therapy with the drug.1 6 8 9 10 11 12 24 25 41 42 43 46

  • Rimantadine-resistant influenza A viruses also are resistant to amantadine.9 10 16 25 41 42 43 46 48

Advice to Patients

  • Importance of not getting up suddenly from a sitting or lying position; notify clinician if dizziness or lightheadedness occur.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Rimantadine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

50 mg/5 mL

Flumadine Syrup

Forest

Tablets, film-coated

100 mg*

Flumadine

Forest

Rimantadine Hydrochloride Tablets

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Flumadine 100MG Tablets (CARACO): 14/$43.99 or 42/$109.97

Rimantadine HCl 100MG Tablets (GLOBAL PHARMACEUTICAL CORP): 30/$69.99 or 90/$195.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions December 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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