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Special Alerts
CDC Recommendations for the Use of Antivirals for Influenza
January 2011
The Centers for Disease Control and Prevention (CDC) has issued recommendations for the use of antivirals for the control and prevention of influenza. Amantadine and rimantadine are not effective for the treatment or prevention of the currently circulating strains of influenza A virus. Oseltamivir or zanamivir should be used when an antiviral agent is needed. Based on information from the IDSA, rimantadine may be useful in order to control outbreaks in institutions under certain conditions: if influenza A virus subtyping is unavailable and oseltamivir resistant viruses are circulating, rimantadine may be used in combination with oseltamivir if zanamivir cannot be used (Harper 2009).
CDC recommendations may change as more information on antiviral susceptibilities and effectiveness becomes available. For the most recent recommendations and information from the CDC, please refer to Seasonal Influenza (Flu) "Antiviral Drugs, Information for Healthcare Professionals" at http://www.cdc.gov/flu/professionals/antivirals/index.htm.
Pronunciation
(ri MAN ta deen)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Prophylaxis (adults and children >1 year of age) and treatment (adults) of influenza A viral infection (per manufacturer labeling; also refer to current ACIP guidelines for recommendations during current flu season)
Note: In certain circumstances, the ACIP recommends use of rimantadine in combination with oseltamivir for the treatment or prophylaxis of influenza A infection when resistance to oseltamivir is suspected.
Pregnancy Risk Factor
C
Pregnancy Considerations
Animal data suggest embryotoxicity, maternal toxicity, and offspring mortality at doses 7-11 times the recommended human dose. There are no adequate and well-controlled studies in pregnant women.Influenza infection may be more severe in pregnant women. Untreated influenza infection is associated with an increased risk of adverse events to the fetus and an increased risk of complications or death to the mother. Oseltamivir and zanamivir are currently recommended for the treatment or prophylaxis influenza in pregnant women and women up to 2 weeks postpartum. Appropriate antiviral agents are currently recommended as an adjunct to vaccination and should not be used as a substitute for vaccination in pregnant women (consult current CDC guidelines). Healthcare providers are encouraged to refer women exposed to influenza vaccine, or who have taken an antiviral medication during pregnancy to the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) by contacting The Organization of Teratology Information Specialists (OTIS) at (877) 311-8972.
Lactation
Excretion in breast milk unknown/ not recommended
Breast-Feeding Considerations
Do not use in nursing mothers due to potential adverse effect in infants. The CDC recommends that women infected with the influenza virus follow general precautions (eg, frequent hand washing) to decrease viral transmission to the child. Mothers with influenza-like illnesses at delivery should consider avoiding close contact with the infant until they have received 48 hours of antiviral medication, fever has resolved, and cough and secretions can be controlled. These measures may help decrease (but not eliminate) the risk of transmitting influenza to the newborn during breast-feeding. During this time, breast milk can be expressed and bottle-fed to the infant by another person who is not infected. Protective measures, such as wearing a face mask, changing into a clean gown or clothing, and strict hand hygiene should be continued by the mother for ≥7 days after the onset of symptoms or until symptom-free for 24 hours. Infant care should be performed by a noninfected person when possible (consult current CDC guidelines).
Contraindications
Hypersensitivity to drugs of the adamantine class, including rimantadine and amantadine, or any component of the formulation
Warnings/Precautions
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Influenza A: Appropriate use: Consult current guidelines. Due to increased resistance, the ACIP has recommended that rimantadine and amantadine no longer be used for the treatment or prophylaxis of influenza A in the United States until susceptibility has been re-established. Rimantadine is not effective in the prevention or treatment of influenza B virus infections.
• Psychosis: Avoid use, if possible, in patients with uncontrolled psychosis or severe psychoneurosis.
• Renal impairment: Use with caution in patients with renal impairment.
• Seizures: Use with caution in patients with a history of seizure disorder; an increase in seizure incidence may occur. Discontinue if seizures occur.
Special populations:
• Elderly: The elderly are at higher risk for CNS (eg, dizziness, headache, weakness) and gastrointestinal (eg, nausea/vomiting, abdominal pain) adverse events; dosage adjustment is recommended in elderly patients >65 years of age.
Other warnings/precautions:
• Resistance: May develop during treatment; viruses exhibit cross-resistance between amantadine and rimantadine.
Adverse Reactions
1% to 10%:
Central nervous system: Insomnia (2% to 3%), concentration impaired (≤2%), dizziness (1% to 2%), nervousness (1% to 2%), fatigue (1%), headache (1%)
Gastrointestinal: Nausea (3%), anorexia (2%), vomiting (2%), xerostomia (2%), abdominal pain (1%)
Neuromuscular & skeletal: Weakness (1%)
<1%: Agitation, ataxia, bronchospasm, cardiac failure, confusion, convulsions, cough, depression, diarrhea, dyspepsia, dyspnea, euphoria, gait abnormality, hallucinations, heart block, hyperkinesias, hypertension, lactation, palpitation, pallor, parosmia, pedal edema, rash, somnolence, syncope, tachycardia, taste alteration, tinnitus, tremor
Drug Interactions
Influenza Virus Vaccine (Live/Attenuated): Antiviral Agents (Influenza A and B) may diminish the therapeutic effect of Influenza Virus Vaccine (Live/Attenuated). Management: Avoid anti-influenza antivirals during the period beginning 48 hours prior to and ending 2 weeks after vaccine administration. Persons receiving these agents within 2 weeks of the live intranasal spray vaccine should receive a repeat vaccine dose. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Food does not affect rate or extent of absorption
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Exerts its inhibitory effect on three antigenic subtypes of influenza A virus (H1N1, H2N2, H3N2) early in the viral replicative cycle, possibly inhibiting the uncoating process; it has no activity against influenza B virus and is two- to eightfold more active than amantadine
Pharmacodynamics/Kinetics
Onset of action: Antiviral activity: No data exist establishing a correlation between plasma concentration and antiviral effect
Protein Binding: ~40%, primarily to albumin
Metabolism: Extensively hepatic
Half-life elimination: 25.4 hours; prolonged in elderly, severe liver and severe renal impairment
Time to peak: 6 hours
Excretion: Urine (<25% as unchanged drug)
Clearance: Hemodialysis does not contribute to clearance
Dosage
Oral:
Prophylaxis:
Children
1-9 years: 5 mg/kg/day in 1-2 divided doses; maximum: 150 mg/day
≥10 years and <40 kg: 5 mg/kg/day in 2 divided doses (CDC, 2011)
Children ≥10 years (and ≥40 kg) and Adults: 100 mg twice daily
Elderly: 100 mg daily in the elderly (≥65 years), including elderly nursing home patients
Note: Prophylaxis (institutional outbreak): In order to control outbreaks in institutions, if influenza A virus subtyping is unavailable and oseltamivir resistant viruses are circulating, rimantadine may be used in combination with oseltamivir if zanamivir cannot be used. Treatment should continue for ≥2 weeks and until ~10 days after illness onset in the last patient (CDC, 2011; Harper 2009).
Treatment:
Children ≥17 years and Adults: 100 mg twice daily
Elderly: 100 mg daily in the elderly (≥ 65 years) or nursing home patients
Dosage adjustment in renal impairment:
Clcr ≥30 mL/minute: Dose adjustment not required
Clcr <30 mL/minute: 100 mg daily
Dosage adjustment in hepatic impairment: Severe dysfunction: 100 mg daily
Administration: Oral
Initiation of rimantadine within 48 hours of the onset of influenza A illness halves the duration of illness and significantly reduces the duration of viral shedding and increased peripheral airways resistance. Continue therapy for 5-7 days after symptoms begin; discontinue as soon as clinically warranted to reduce the emergence of antiviral drug resistant viruses
Monitoring Parameters
Monitor for CNS or GI effects in elderly or patients with renal or hepatic impairment
Patient Education
May cause dizziness, insomnia, fatigue, nervousness, or gastrointestinal upset. Report rash, palpitations, severe nausea or vomiting, or persistent CNS changes (eg, confusion, insomnia, anxiety, restlessness, irritability, hallucinations).
Geriatric Considerations
Refer to current CDC guidelines for appropriate use. Adverse CNS and GI effects occur frequently if dosage is not adjusted. Monitor GI effects in the elderly or patients with renal or hepatic impairment. Dosing must be individualized (100 mg 1-2 times/day). It is recommended that nursing home patients receive 100 mg/day.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Infectious Diseases Comment
The Centers for Disease Control and Prevention (CDC) has issued interim recommendations for the use of antivirals for the control and prevention of influenza during the 2010-2011 season. Amantadine and rimantadine are not effective for the treatment or prevention of the currently circulating strains of influenza A virus. Oseltamivir or zanamivir should be used when an antiviral agent is needed. In order to control outbreaks in institutions, if influenza A virus subtyping is unavailable and oseltamivir resistant viruses are circulating, rimantadine may be used in combination with oseltamivir if zanamivir cannot be used. CDC recommendation may change as more information on antiviral susceptibilities and effectiveness becomes available. For the most recent recommendations and information from the CDC, please refer to: http://www.cdc.gov/flu/professionals/antivirals/index.htm
Mental Health: Effects on Mental Status
May cause dizziness, anxiety, confusion, insomnia, restlessness, irritability, or hallucinations
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Recommendations for antiviral susceptibility and effectiveness may change. Validate with the CDC recommendations for use prior to prescribing. Use caution with hepatic or renal impairment, seizure disorders, uncontrolled psychoses, or severe psychoneurosis. Monitor for hypotension, CNS changes (confusion, anxiety, agitation), gastrointestinal upset, and anticholinergic effects (dry mouth, urinary retention, mydriases).
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 100 mg
Tablet, oral, as hydrochloride: 100 mg
Flumadine®: 100 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Flumadine)
100 mg (14): $43.99
Extemporaneously Prepared
Rimantadine 10 mg/mL Suspension:
To prepare suspension, 10 mL of Ora-Sweet® will be required for every 100 mg tablet of rimantadine. (Do not prepare more than a 14-day supply).
- Calculate the total dose needed (daily dose x number of days = mg of rimantadine needed) and round the final mg of rimantadine needed up to the next 100 mg (eg, 750 mg would be 800 mg, or eight 100 mg tablets).
- Calculate the total volume of Ora-Sweet® by taking the rounded mg of rimantadine and dividing by 10 mg/mL (eg, 800 mg divided by 10 mg/mL = 80 mL).
- Grind required number of tablets in mortar and triturate to a fine powder. Slowly add 1/3 of the total volume of Ora-Sweet® to the mortar and triturate until a uniform suspension is achieved.
- Transfer to an amber glass or PET plastic bottle. Slowly add another 1/3 of the total volume of Ora-Sweet® to the mortar, rinsing the mortar, then transferring the contents into the bottle. Repeat using the final 1/3 of Ora-Sweet®. Add additional vehicle to bottle, if needed, to achieve the total calculated volume.
- Shake well to ensure homogeneous suspension. Some inert ingredients in the tablet may be insoluble.
- Label: Shake gently prior to each use.
- Suspension is stable for 14 days when stored at room temperature (25°C/77°F).
References
Bentley DW, Karki SD, and Betts RF, “Rimantadine and Seizures,” Ann Intern Med, 1989, 110(4):323-4.
Centers for Disease Control and Prevention (CDC), "Influenza Division, National Center for Immunization and Respiratory Diseases. Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza --- Recommendations of the Advisory Committee on Immunization Practices (ACIP)," MMWR Surveill Summ, 2011, 60(1):1-28.
Centers for Disease Control and Prevention, "Interim Guidance: Considerations Regarding 2009 Novel H1N1 Flu Virus in Intrapartum and Postpartum Hospital Settings," Available at http://www.cdc.gov/h1n1flu/guidance/obstetric.htm
Dolin R, Reichman RC, Madore HP, et al, “A Controlled Trial of Amantadine and Rimantadine in the Prophylaxis of Influenza A Infection,” N Engl J Med, 1982, 307(10):580-4.
Douglas RG Jr, “Prophylaxis and Treatment of Influenza,” N Engl J Med, 1990, 322(7):443-50.
“Drugs for Non-HIV Viral Infections,” Med Lett Drugs Ther, 1994, 36(919):27.
Guay DR, “Amantadine and Rimantadine Prophylaxis of Influenza A in Nursing Homes,” Drugs Aging, 1994, 5(1):8-19.
Harper SA, Bradley JS, Englund JA, et al, "Expert Panel of the Infectious Diseases Society of America. Seasonal Influenza in Adults and Children -- Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America," Clin Infect Dis, 2009, 48(8):1003-32.
Keating MR, “Antiviral Agents,” Mayo Clin Proc, 1992, 67(2):160-78.
Patriarca PA, Kater NA, Kendal AP, et al, “Safety of Prolonged Administration of Rimantadine Hydrochloride in the Prophylaxis of Influenza A Virus Infections in Nursing Homes,” Antimicrob Agents Chemother, 1984, 26(1):101-3.
Wintermeyer SM and Nahata MC, “Rimantadine: A Clinical Perspective,” Ann Pharmacother, 1995, 29(3):299-310.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
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