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Special Alerts
CDC Updated Interim Recommendations for the Use of Antivirals During 2009-2010 Influenza Season - Updated November 2009
The Centers for Disease Control and Prevention (CDC) has issued interim recommendations for the use of antivirals for the treatment and prevention of influenza during the 2009-2010 season. These recommendations apply to seasonal influenza and the 2009 H1N1 influenza (formerly known as novel influenza A [H1N1]). Antiviral doses and schedules for treatment or chemoprophylaxis of 2009 H1N1 influenza are the same as those recommended for seasonal influenza. Additionally, the U.S. Food and Drug Administration (FDA) has issued a temporary Emergency Use Authorization to allow the use of oseltamivir in children <1 year of age. The following is a summary of the updated interim recommendations:
(1) Treatment with oseltamivir or zanamivir is recommended in any patient hospitalized with suspected or confirmed influenza.
(2) Empiric treatment with oseltamivir or zanamivir should be considered for patients who are at higher risk for influenza-related complications (eg, children <2 years of age, adults ?65 years, pregnant women and women up to 2 weeks postpartum [including after pregnancy loss], immunosuppressed patients [of any age], patients <19 years of age receiving long-term aspirin therapy, persons [of any age] with disorders that may alter respiratory function or increase risk for aspiration [eg, cognitive dysfunction, seizure disorders, spinal cord injuries] and persons [of any age] with chronic health conditions such as pulmonary, cardiovascular, renal, hepatic, hematologic, neurologic, neuromuscular, or metabolic disorders). Morbidly obese (BMI ? 40) and obese persons may be at increased risk for hospitalization and death due to 2009 H1N1 influenza infection (studies pending). This patient population frequently has other underlying conditions that increases their risk of influenza complications. Carefully evaluate morbidly obese and obese patients for underlying conditions and empirically treat as indicated.
(3) Any suspected influenza patient (regardless of age or previous health) with warning signs/symptoms of severe disease (eg, dyspnea, tachypnea, unexplained oxygen desaturation) consistent with an acute lower respiratory tract illness or clinical deterioration should promptly receive empiric antiviral therapy. Antibiotic therapy may be considered due to the potential for concurrent bacterial coinfections (usually Staphylococcus or Streptococcus sp). The risk of developing severe disease is likely to be the highest in infants and children.
(4) Treatment (when indicated) should be started without delay (within 48 hours of illness onset). Early initiation is more likely to provide benefit; treatment initiated >48 hours of illness onset has shown some benefit in hospitalized patients.
(5) Healthcare providers should not wait for laboratory confirmation of influenza prior to initiating empiric antiviral therapy. Therapy should be started as soon as possible regardless of the diagnostic test used (eg, rapid influenza test or real-time reverse transcriptase-polymerase chain reaction [rRT-PCR] assay). A negative rapid influenza diagnostic test result does not rule out infection and patients should still be considered for treatment.
(6) Early recognition of illness and treatment (when indicated) is preferred over chemoprophylaxis for healthy vaccinated persons.
(7) Treatment or prophylaxis is generally not required in patients with suspected influenza who present with uncomplicated febrile illness or are not at higher risk for complications.
(8) Prophylaxis should be reserved for persons at high risk for influenza-related complications who have had close contact with someone likely to be infected. Alternately, the CDC emphasizes that early antiviral treatment is also an option. Close contacts (with risk factors for complications) or healthcare personnel with occupational exposures can be counseled as to the early signs and symptoms of influenza and advised to immediately contact their healthcare provider if signs or symptoms develop. This approach (signs and symptom education/prompt treatment) is also recommended by the CDC in vaccinated patients after a suspected exposure.
(9) Postexposure antiviral chemoprophylaxis with oseltamivir or zanamivir may be considered in the following populations after an exposure or close contact of a person with suspected, probable, or confirmed influenza during that person's infectious period ("infectious period" is defined as 1 day before through 24 hours after fever ends):
- Persons at higher risk of influenza complications and who are close contacts of a person with confirmed, probable, or suspected influenza
- Healthcare and public health workers or first responders
(10) Chemoprophylaxis is generally not recommended if more than 48 hours has lapsed since last exposure to the infectious person, and is not indicated if the exposure did not occur during the infectious period. Chemoprophylaxis is not recommended in healthy children or adults after a potential exposure in the community, school, camp, or other setting.
(11) Currently circulating 2009 H1N1 viruses are susceptible to oseltamivir and zanamivir, but resistant to amantadine and rimantadine. Oseltamivir-resistant 2009 H1N1 viruses have been identified, most commonly observed during chemoprophylaxis or in immunocompromised patients receiving treatment for influenza. Conversely, regular seasonal influenza A (H1N1) is commonly resistant to oseltamivir, but is typically susceptible to rimantadine and amantadine. At present, oseltamivir or zanamivir is appropriate for the treatment of 2009 H1N1 influenza. If oseltamivir-resistant seasonal H1N1 viruses become more common or are identified in community outbreaks, zanamivir (or a combination of oseltamivir and rimantadine or amantadine) should be considered for empiric treatment of suspected oseltamivir-resistant seasonal human influenza A (H1N1) virus infection.
CDC recommendations are changing frequently 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/h1n1flu/guidance/
http://www.cdc.gov/h1n1flu/recommendations.htm (updated by CDC October 16, 2009)
http://www.cdc.gov/h1n1flu/recommendations_pediatric_supplement.htm
Note: The information below is a portion of a previous notice posted in May 2009.
The U.S. Food and Drug Administration (FDA) is recommending that all companies, U.S. states and localities, and other organizations consider keeping any oseltamivir (Tamiflu®) and zanamivir (Relenza®) that are nearing or are past the labeled expiration dates. These two medications are covered under the Emergency Use Authorization that the FDA has issued for the 2009 influenza (H1N1) outbreak. At present, the U.S. Department of Health and Human Services is evaluating options and may decide to utilize these stockpiled medications, if needed.
Any organization that decides to retain the soon-to-expire or expired zanamivir or oseltamivir should maintain the product(s) under the labeled storage requirements, and should contact the FDA's Emergency Operations Center (301-443-1240) with the amounts of antivirals in their stockpiles. The FDA is not directing this statement to individual patients with either of the antivirals in their home.
http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm154962.htm
Medication Safety Issues
Sound-alike/look-alike issues:
Rimantadine may be confused with amantadine, ranitidine, Rimactane®
Flumadine® may be confused with fludarabine, flunisolide, flutamide
Pronunciation
(ri MAN ta deen)
U.S. Brand Names
Index Terms
Generic Available
Yes: Tablet
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.
Lactation
Excretion in breast milk unknown/ not recommended
Breast-Feeding Considerations
Do not use in nursing mothers due to potential adverse effect in infants.
Contraindications
Hypersensitivity to drugs of the adamantine class, including rimantadine and amantadine, or any component of the formulation
Warnings/Precautions
Disease-related concerns:
• Eczema: Avoid use, if possible, in patients with recurrent and eczematoid dermatitis.
• 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.
• 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.
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%), anxiety (1%), 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, concentration impaired, 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 virus medications during the period beginning 48 hours prior to vaccine administration and ending 2 weeks after vaccine administration. This only applies to the live influenza virus vaccine. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Food does not affect rate or extent of absorption
Storage
Store at 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
Absorption: Tablet and syrup formulations are equally absorbed
Metabolism: Extensively hepatic
Half-life elimination: 25.4 hours; prolonged in elderly
Time to peak: 6 hours
Excretion: Urine (<25% as unchanged drug)
Clearance: Hemodialysis does not contribute to clearance
Dosage
Oral:
Prophylaxis:
Children 1-10 years: CDC recommendation: 5 mg/kg/day in 2 divided doses; maximum: 150 mg/day
Children >10 years and Adults: 100 mg twice daily
Elderly: 100 mg/day in nursing home patients or all elderly patients who may experience adverse effects using the adult dose
Treatment:
Adults: 100 mg twice daily
Elderly: 100 mg once daily in patients ?65 years
Dosage adjustment in renal impairment:
Clcr >10 mL/minute: Dose adjustment not required
Clcr ?10 mL/minute: 100 mg/day
Dosage adjustment in hepatic impairment: Severe dysfunction: 100 mg/day
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.
Monitoring Parameters
Monitor for CNS or GI effects in elderly or patients with renal or hepatic impairment
Patient Education
Do not take any new medication during therapy unless approved by prescriber. Take as directed. Complete full course of therapy even if feeling better. Take a missed dose as soon as possible. If almost time for next dose, skip the missed dose and return to your regular schedule. Do not take a double dose. May cause dizziness, insomnia, fatigue, nervousness (use caution when driving or engaged in potentially hazardous tasks until response to medication is known); gastrointestinal upset (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report rash, palpitations; severe nausea or vomiting; persistent CNS changes (eg, confusion, insomnia, anxiety, restlessness, irritability, hallucinations) or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
Geriatric Considerations
Rimantadine is no longer recommended for the treatment or chemoprophylaxis of influenza A infection. 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
Consult current guidelines for appropriate use. Due to increased resistance the ACIP recommends that amantadine and rimantadine no longer be used for the treatment or prophylaxis of influenza A in the United States. If an antiviral medication is needed, oseltamivir or zanamivir should be used. In some areas, resistance is developing against oseltamivir. If resistance is suspected, amantadine or rimantadine may be used in combination with oseltamivir for the treatment or prophylaxis of influenza A infection when zanamivir therapy is not indicated (such as in children of certain ages).Amantadine may still be used for its other approved indications, such as in the treatment of Parkinson's disease.
For additional information, refer to the ACIP guidelines on the following CDC website: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr57e717a1.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
Use caution with hepatic or renal impairment, seizure disorders, uncontrolled psychoses, or severe psychoneurosis. Assess effectiveness (resolution of infection) and adverse reactions (eg, hypotension, CNS changes [confusion, anxiety, agitation], gastrointestinal upset, anticholinergic effects [dry mouth, urinary retention, mydriases]). Teach patient appropriate use, possible side effects/interventions (eg, postural hypotension), and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Syrup, as hydrochloride:
Flumadine®: 50 mg/5 mL (240 mL) [raspberry flavor] [DSC]
Tablet, as hydrochloride: 100 mg
Flumadine®: 100 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Flumadine)
100 mg (14): $43.99
References
Bentley DW, Karki SD, and Betts RF, “Rimantadine and Seizures,” Ann Intern Med, 1989, 110(4):323-4.
Centers for Disease Control, “Prevention and Control of Influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP),” MMWR Recomm Rep, 2008, 56 (early release):1-60. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr57e717a1.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.
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 November 2009
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