Guidance on the Use of Influenza Antiviral Agents
This page contains excerpts from Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza – Recommendations of the Advisory Committee on Immunization Practices (ACIP). PDF Version [1 MB, 28 pages]. It provides guidance on the use of influenza antiviral agents, and is provided for historical context, but the text has not been updated from the ACIP document from which it was excerpted to include peramivir. Please see the current summary of recommendations for clinical practice regarding the use of influenza antiviral medications available at Influenza Antiviral Medications: Summary for Clinicians and a list of related references at Antiviral Guide References.
Dosage recommendations vary by age group, intended use (chemoprophylaxis or treatment), and medical conditions (See Table 2 in Summary for Clinicians).
Duration of Antiviral Treatment
The recommended duration of treatment is 5 days [105, 116, 156]. Longer treatment regimens might be necessary in severely ill hospitalized patients or persons with immunosuppression. Additional clinical guidelines on the use of antiviral medications to treat influenza are available and contain additional detail on treatment issues [51, 105, 198].
Zanamivir. Inhaled zanamivir is FDA-approved for treatment of adults with uncomplicated acute illness caused by influenza A or B virus, and for chemoprophylaxis of influenza among adults. Zanamivir is not recommended for persons with underlying airways disease (e.g., asthma or chronic obstructive pulmonary diseases) . Zanamivir is administered via an inhaler device in 5-mg blister doses per inhalation. The recommended dosage of zanamivir for treatment of influenza is 2 inhalations (1 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart). The chemoprophylaxis dosage of zanamivir is 10 mg (2 inhalations) once a day.
Oseltamivir. Oral oseltamivir is FDA-approved for treatment of adults with uncomplicated acute illness caused by influenza A or B virus and for chemoprophylaxis of influenza among adults . Oseltamivir is available for oral administration in 30 mg, 45 mg, and 75 mg capsules and liquid suspension. Dosage and schedule recommendations are listed in Table 2 in Summary for Clinicians.
Zanamivir. Zanamivir is FDA-approved for treatment of influenza among children aged 7 years and older. Standard duration of treatment is five days. Zanamivir is approved for chemoprophylaxis of influenza among children aged 5 years and older. Treatment and chemoprophylaxis dosing and frequency are the same for children as for adults.
Oseltamivir. Oseltamivir is FDA-approved for treatment of children aged 2 weeks and older and chemoprophylaxis of influenza among children aged 1 year and older (116). Although not part of the FDA-approved indications, use of oral oseltamivir for treatment of influenza in infants less than 14 days old, and for chemoprophylaxis in infants 3 months to 1 year of age, is recommended by the CDC and the American Academy of Pediatrics. The treatment dosing recommendation for oral oseltamivir for children younger than 1 year is 3mg/kg twice a day. Recommended treatment dosages for children 1 year and older vary by the weight of the child: 30 mg twice a day for children who weigh 15 kg or less, 45 mg twice a day for children who weigh more than 15 kg and up to 23 kg, 60 mg twice a day for those who weigh more than 23 kg and up to 40 kg, and 75 mg twice a day for those who weigh more than 40 kg (Table 2 in Summary for Clinicians) . Standard duration of treatment is five days. Dosages for chemoprophylaxis are the same for each weight group, but doses are administered only once per day rather than twice (Table 2 in Summary for Clinicians) .
On December 21, 2012, FDA approved oseltamivir for the treatment of influenza in people aged 2 weeks and older. During the influenza A(H1N1)pdm09 (2009 H1N1) pandemic, recommendations for oseltamivir dosing of children aged younger than 1 year were developed, on the basis of very limited pharmacokinetic data. The Emergency Use Authorization (EUA) issued during the 2009 H1N1 pandemic for this indication expired on June 23, 2010 , but recommendations on dosing for children aged younger than 1 year are available [28, 51, 200, 201]. CDC recommends that clinicians who treat children aged 3-11 months administer 3 mg/kg/dose orally twice per day for treatment, and 3 mg/kg/dose orally once per day for chemoprophylaxis. Infants aged younger than 3 months are recommended to receive 3 mg/kg/dose orally twice per day for treatment. However, chemoprophylaxis for infants aged younger than 3 months is not recommended unless the exposure situation is judged to be critical, because of a lack of data on use of oseltamivir on this age group. Lower doses should be considered for infants who are not receiving regular oral feedings or those who have substantially reduced renal function .
Weight-based dosing recommendations for full-term infants are thought to be inappropriate for premature infants, (i.e., might lead to excessively high plasma concentrations) who might have slower clearance of oseltamivir as a result of immature renal function [200–202]. Clinicians who are considering administering oseltamivir to infants should consult the Table below and the Summary for Clinicians for further details regarding current treatment recommendations.
Amantadine. Amantadine is FDA-approved for treatment and chemoprophylaxis of influenza A virus infections among adults and children aged 1 year and older; however, because of resistance in circulating influenza A virus strains, amantadine is not currently recommended for antiviral treatment or chemoprophylaxis of influenza A. Use of amantadine among children aged younger than 1 year has not been evaluated adequately. The FDA-approved dosage for children aged 1–9 years for treatment and chemoprophylaxis is 4.4–8.8 mg/kg per day, not to exceed 150 mg per day. Although further studies are needed to determine the optimal dosage for children aged 1–9 years, physicians should consider prescribing only 5 mg/kg per day (not to exceed 150 mg per day) to reduce the risk for toxicity. The approved dosage for children aged 10 years and older is 200 mg per day (100 mg twice a day); for children weighing less than 40 kg, 5 mg/kg per day is the recommended dose, regardless of age .
Rimantadine. Rimantadine is FDA-approved for chemoprophylaxis of influenza A virus infections among children aged 1 year and older and for treatment and chemoprophylaxis of influenza A virus infections among adults; however, because of resistance in circulating influenza A virus strains, rimantadine is not currently recommended for antiviral treatment or chemoprophylaxis of influenza A. Although rimantadine is approved only for chemoprophylaxis of influenza A among children, certain specialists in the management of influenza consider it appropriate for treatment among children . Use of rimantadine among children aged younger than 1 year has not been evaluated adequately. Rimantadine should be administered in 1 or 2 divided doses at a dosage of 5 mg/kg per day, not to exceed 150 mg per day for children aged 1–9 years. The approved dosage for children aged 10 years and older is 200 mg per day (100 mg twice a day); however, for children weighing less than 40 kg, prescribing 5 mg/kg per day, regardless of age, is recommended .
Use of Medications for Symptomatic Relief in Children
Aspirin or aspirin-containing products (e.g. bismuth subsalicylate [Pepto Bismol]) should not be administered to any person aged 18 years and younger with suspected influenza because of the risk for Reye’s syndrome. For relief of fever, other antipyretic medications (e.g., acetaminophen or non-steroidal anti-inflammatory drugs) are recommended. Children aged younger than 4 years should not receive over-the-counter cold medications without a health care provider being consulted first .
Persons Aged 65 Years and Older
Oseltamivir and Zanamivir. No reduction in dosage for oseltamivir or zanamivir is recommended on the basis of age alone [116, 156].
Amantadine. Because of resistance in circulating influenza A virus strains, amantadine is not currently recommended for antiviral treatment or chemoprophylaxis of influenza A. The daily dosage of amantadine for persons aged 65 years and older should not exceed 100 mg for chemoprophylaxis or treatment of amantadine-susceptible influenza A viruses, because renal function declines with increasing age. For certain older persons, the dose should be reduced further [206, 207].
Rimantadine. Because of resistance in circulating influenza A virus strains, rimantadine is not currently recommended for antiviral treatment or chemoprophylaxis of influenza A. Among older persons, the incidence and severity of central nervous system (CNS) side effects are substantially lower among those taking rimantadine at a dosage of 100 mg/day than among those taking amantadine at dosages adjusted for estimated renal clearance . However, chronically ill older persons have had a higher incidence of CNS and gastrointestinal symptoms and serum concentrations two to four times higher than among healthy, younger persons when rimantadine has been administered at a dosage of 200 mg/day [204, 205, 208].
For chemoprophylaxis of rimantadine-susceptible influenza A viruses among persons aged 65 years and older, the recommended dosage is 100 mg/day. For treatment of amantadine-susceptible influenza A virus infection in older persons in the community, a reduction in dosage to 100 mg/day should be considered if they experience side effects when taking a dosage of 200 mg/day. For treatment of older nursing home residents, the dosage of rimantadine should be reduced to 100 mg/day .
Pregnant women with confirmed or suspected influenza are recommended to receive antiviral treatment, and treatment of fever with acetaminophen . Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Pregnant women are known to be at higher risk for complications from infection with seasonal influenza viruses [210, 211] and severe disease among pregnant women was reported during past pandemics [209, 212, 213]. Multiple studies have demonstrated that pregnant women are at higher risk for influenza complications from 2009 H1N1 virus infection [12, 24, 25, 68].
Oseltamivir, zanamivir, rimantadine, and amantadine are “Pregnancy Category C” medications, indicating that data from clinical studies are not adequate to assess the safety of these medications for pregnant women [116, 156]. Although a few adverse events have been reported occasionally in pregnant women who took these medications, no causal relation between the use of these medications and these adverse events has been established [214, 215]. In addition, fever can cause adverse fetal outcomes, and reducing fever, whether directly by using antipyretics, or indirectly by reducing the duration and severity of symptoms with antiviral medications, might reduce this risk . One retrospective cohort study found no evidence of an association between oseltamivir use during pregnancy and a variety of adverse events, including preterm birth, premature rupture of membranes, increased duration of hospital stay for mother or neonate, malformations, or fetal weight .
Oseltamivir is preferred for treatment of pregnant women (Rasmussen, 2009; 2011). Pregnant women are recommended to receive the same antiviral dosing as nonpregnant persons .
As with others at high risk for influenza-related complications, treatment of pregnant women with suspected or confirmed influenza virus infection should begin as early as possible after onset of illness. Treatment should not be delayed while waiting for results of diagnostic testing [28, 51].
Persons with Impaired Renal Function
Zanamivir. Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir, decreases in renal clearance, increases in half-life, and increased systemic exposure to zanamivir were reported . However, a limited number of healthy volunteers who were administered high doses of intravenous zanamivir tolerated systemic levels of zanamivir that were substantially higher than those resulting from administration of zanamivir by oral inhalation at the recommended dose [173, 214]. On the basis of these considerations, the manufacturer recommends no dose adjustment for inhaled zanamivir for a 5-day course of treatment for patients with either mild-to-moderate or severe impairment in renal function .
Oseltamivir. Serum concentrations of oseltamivir carboxylate, the active metabolite of oseltamivir, increase with declining renal function . For patients with creatinine clearance of 10–30 mL per minute, a reduction of the treatment dosage of oseltamivir to 30 mg orally once daily for five days and in the chemoprophylaxis dosage to 30 mg every other day is recommended. Treatment or chemoprophylaxis dosing recommendations have been proposed for patients undergoing routine renal dialysis treatment but are based on limited pharmacokinetic data [217, 218].
Amantadine. When used for amantadine-susceptible influenza A virus infection, a reduction in dosage is recommended for patients with creatinine clearance less than 50 mL/min. Guidelines for amantadine dosage on the basis of creatinine clearance are located in the package insert. Because recommended dosages on the basis of creatinine clearance might provide only an approximation of the optimal dose for a specific patient, such persons should be observed carefully for adverse reactions. If necessary, further reduction in the dose or discontinuation of the drug might be indicated because of side effects. Hemodialysis contributes minimally to amantadine clearance .
Rimantadine. When used for rimantadine-susceptible influenza A virus infection, a reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance less than 10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including older persons, should be monitored for adverse effects, and, if necessary, either the dosage should be reduced or the drug should be discontinued. Hemodialysis contributes minimally to rimantadine clearance .
Persons with Liver Disease
Amantadine. No increase in adverse reactions to amantadine has been observed among persons with liver disease. Rare instances of reversible elevation of liver enzymes among patients receiving amantadine have been reported, although a specific relation between the drug and such changes has not been established .
Rimantadine. A reduction in dosage to 100 mg/day is recommended for persons with severe hepatic dysfunction .
Persons with Seizure Disorders
Zanamivir and oseltamivir. Seizure events have been reported during postmarketing use of zanamivir and oseltamivir [115, 156], although no epidemiologic studies have reported any increased risk for seizures with either zanamivir or oseltamivir use.
Amantadine. An increased incidence of seizures has been reported among patients with a history of seizure disorders who have received amantadine . Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine.
Rimantadine. Seizures (or seizure-like activity) have been reported among persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine . The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been evaluated adequately.
Persons with Immunosuppression
A recent retrospective case-control study demonstrated that oseltamivir was safe and well tolerated when used during the control of an influenza outbreak among hematopoietic stem cell transplant recipients living in a residential facility . Longer treatment regimens might be necessary in immunosuppressed persons who may have prolonged influenza viral replication. Such patients are at risk of developing antiviral-resistant virus. A higher dose of oral or enterically administered oseltamivir has been recommended by some experts (e.g., 150 mg twice daily in adults with normal renal function) for treatment of influenza in immunocompromised patients and in severely ill hospitalized patients. However, oral or enterically administered oseltamivir has been reported to be adequately absorbed in critically ill adults, with standard doses producing therapeutic blood levels (Ariano, 2010), and limited data suggest that higher dosing may not provide additional clinical benefit (Abdel-Ghafar, 2008; Ariano, 2010; Kumar, 2010; Lee, 2013; South East Asia Infectious Disease Clinical Research Network, 2013).