Recommendations for Using Antiviral Agents for Seasonal Influenza

Annual vaccination is the primary strategy for preventing complications of influenza virus infections. Antiviral medications with activity against influenza viruses are useful adjuncts in the prevention of influenza, and effective when used early in the course of illness for treatment. Four influenza antiviral agents are licensed in the United States: amantadine, rimantadine, zanamivir, and oseltamivir. Influenza A virus resistance to amantadine and rimantadine can emerge rapidly during treatment. Because antiviral testing results indicated high levels of resistance (413416), neither amantadine nor rimantadine should be used for the treatment or chemoprophylaxis of influenza A in the United States during the 200708 influenza season. Surveillance demonstrating that susceptibility to these antiviral medications has been reestablished among circulating influenza A viruses will be needed before amantadine or rimantadine can be used for the treatment or chemoprophylaxis of influenza A. Oseltamivir or zanamivir can be prescribed if antiviral chemoprophylaxis or treatment of influenza is indicated. Oseltamivir is licensed for treatment of influenza in persons aged >1 year, and zanamivir is licensed for treating influenza in persons aged >7 years. Oseltamivir and zanamivir can be used for chemoprophylaxis of influenza; oseltamivir is licensed for use as chemoprophylaxis in persons aged >1 year, and zanamivir is licensed for use in persons aged >5 years.

During the 200708 influenza season, influenza A (H1N1) viruses with a mutation that confers resistance to oseltamivir were identified in the United States and other countries. As of June 27, 2008, in the United States, 111 (7.6%) of 1,464 influenza A viruses tested, and none of 305 influenza B viruses tested have been found to be resistant to oseltamivir. All of the resistant viruses identified in the United States and elsewhere are influenza A (H1N1) viruses. Of 1020 influenza A (H1N1) viruses isolated from patients in the United States, 111 (10.9%) exhibited a specific genetic mutation that confers oseltamivir resistance (417). Influenza A (H1N1) virus strains that are resistant to oseltamivir remain sensitive to zanamivir. Neuraminidase inhibitor medications continue to be the recommended agents for treatment and chemoprophylaxis of influenza in the United States. However, clinicians should be alert to changes in antiviral recommendations that might occur as additional antiviral resistance data becomes available during the 200809 influenza season (http://www.cdc.gov/flu/professionals/antivirals/index.htm).

Role of Laboratory Diagnosis

Influenza surveillance information and diagnostic testing can aid clinical judgment and help guide treatment decisions. However, only 69% of practitioners in one recent survey indicated that they test patients for influenza during the influenza season (418). The accuracy of clinical diagnosis of influenza on the basis of symptoms alone is limited because symptoms from illness caused by other pathogens can overlap considerably with influenza (26,39,40) (see Clinical Signs and Symptoms of Influenza).

Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing, reverse transcriptase-polymerase chain reaction (RT-PCR), and immunofluorescence assays (419). As with any diagnostic test, results should be evaluated in the context of other clinical and epidemiologic information available to health-care providers. Sensitivity and specificity of any test for influenza can vary by the laboratory that performs the test, the type of test used, the type of specimen tested, the quality of the specimen, and the timing of specimen collection in relation to illness onset. Among respiratory specimens for viral isolation or rapid detection of influenza viruses, nasopharyngeal and nasal specimens have higher yields than throat swab specimens (420). In addition, positive influenza tests have been reported up to 7 days after receipt of LAIV (421).

Commercial rapid diagnostic tests are available that can detect influenza viruses within 30 minutes (422,423). Certain tests are licensed for use in any outpatient setting, whereas others must be used in a moderately complex clinical laboratory. These rapid tests differ in the types of influenza viruses they can detect and whether they can distinguish between influenza types. Different tests can detect 1) only influenza A viruses; 2) both influenza A and B viruses, but not distinguish between the two types; or 3) both influenza A and B and distinguish between the two. None of the rapid influenza diagnostic tests specifically identifies any influenza A virus subtypes.

The types of specimens acceptable for use (i.e., throat, nasopharyngeal, or nasal aspirates, swabs, or washes) also vary by test, but all perform best when collected as close to illness onset as possible. The specificity and, in particular, the sensitivity of rapid tests are lower than for viral culture and vary by test (419,422424). Rapid tests for influenza have high specificity (>90%), but are only moderately sensitive (<70%). A recent study found sensitivity to be as low as 42% in clinical practice (425). Rapid tests appear to have higher sensitivity when used in young children, compared with adults, possibly because young children with influenza typically shed higher concentrations of influenza viruses than adults (426). Since RT-PCR has high sensitivity to detect influenza virus infection compared to viral culture, rapid tests have lower sensitivity than viral culture when compared to RT-PCR.

The limitations of rapid diagnostic tests must be understood in order to properly interpret results. Positive rapid influenza test results are generally reliable when community influenza activity is high and are useful in deciding whether to initiate antiviral treatment. Negative rapid test results are less helpful in making treatment decisions for individual patients when influenza activity in a community is high. Because of the lower sensitivity of the rapid tests, physicians should consider confirming negative tests with viral culture or other means because of the possibility of false-negative rapid test results, especially during periods of peak community influenza activity. The positive predictive value of rapid tests will be lower during periods of low influenza activity, and clinicians should consider the positive and negative predictive values of the test in the context of the level of influenza activity in their community when interpreting results (424). When local influenza activity is high, persons with severe respiratory symptoms or persons with acute respiratory illness who are at higher risk for influenza complications should still be considered for influenza antiviral treatment despite a negative rapid influenza test unless illness can be attributed to another cause. However, because certain bacterial infections can produce symptoms similar to influenza, if bacterial infections are suspected, they should be considered and treated appropriately. In addition, secondary invasive bacterial infections can be a severe complication of influenza. Package inserts and the laboratory performing the test should be consulted for more details regarding use of rapid diagnostic tests. Additional updated information concerning diagnostic testing is available at http://www.cdc.gov/flu/professionals/labdiagnosis.htm.

Despite the availability of rapid diagnostic tests, clinical specimens collected in virus surveillance systems for viral culture are critical for surveillance purposes. Only culture isolates of influenza viruses can provide specific information regarding circulating strains and subtypes of influenza viruses and data on antiviral resistance. This information is needed to compare current circulating influenza strains with vaccine strains, to guide decisions regarding influenza treatment and chemoprophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor antiviral resistance and the emergence of novel human influenza A virus subtypes that might pose a pandemic threat. Influenza surveillance by state and local health departments and CDC can provide information regarding the circulation of influenza viruses in the community, which can help inform decisions about the likelihood that a compatible clinical syndrome is indeed influenza.

Antiviral Agents for Influenza

Zanamivir and oseltamivir are chemically related antiviral medications known as neuraminidase inhibitors that have activity against both influenza A and B viruses. The two medications differ in pharmacokinetics, adverse events, routes of administration, approved age groups, dosages, and costs. An overview of the indications, use, administration, and known primary adverse events of these medications is presented in the following sections. Package inserts should be consulted for additional information. Detailed information about amantadine and rimantadine (adamantanes) is available in previous ACIP influenza recommendations (427).

Indications for Use of Antivirals

Treatment

Initiation of antiviral treatment within 2 days of illness onset is recommended, although the benefit of treatment is greater as the time after illness onset is reduced. Certain persons have a high priority for treatment (Box 3); however, treatment does not need to be limited to these persons. In clinical trials conducted in outpatient settings, the benefit of antiviral treatment for uncomplicated influenza was minimal unless treatment was initiated within 48 hours after illness onset. However, no data are available on the benefit for severe influenza when antiviral treatment is initiated >2 days after illness onset. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days.

Evidence for the efficacy of these antiviral drugs is based primarily on studies of outpatients with uncomplicated influenza. When administered within 2 days of illness onset to otherwise healthy children or adults, zanamivir or oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day compared with placebo (143,428442). Minimal or no benefit was reported when antiviral treatment is initiated >2 days after onset of uncomplicated influenza. Data on whether viral shedding is reduced are inconsistent. The duration of viral shedding was reduced in one study that employed experimental infection; however, other studies have not demonstrated reduction in the duration of viral shedding. A recent review that examined neuraminidase inhibitor effect on reducing ILI concluded that neuraminidase inhibitors were not effective in the control of seasonal influenza (443). However, lower or no effectiveness using a nonspecific (compared with laboratory-confirmed influenza) clinical endpoint such as ILI would be expected (444).

Data are limited about the effectiveness of zanamivir and oseltamivir in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases), or for preventing influenza among persons at high risk for serious complications of influenza. In a study that combined data from 10 clinical trials, the risk for pneumonia among those participants with laboratory-confirmed influenza receiving oseltamivir was approximately 50% lower than among those persons receiving a placebo and 34% lower among patients at risk for complications (p<0.05 for both comparisons) (445). Although a similar significant reduction also was determined for hospital admissions among the overall group, the 50% reduction in hospitalizations reported in the small subset of high-risk participants was not statistically significant. One randomized controlled trial documented a decreased incidence of otitis media among children treated with oseltamivir (437). Another randomized controlled study conducted among influenza-infected children with asthma demonstrated significantly greater improvement in lung function and fewer asthma exacerbations among oseltamivir-treated children compared with those who received placebo but did not determine a difference in symptom duration (446). Inadequate data exist regarding the efficacy of any of the influenza antiviral drugs for use among children aged <1 year, and none are FDA-licensed for use in this age group.

Two observational studies suggest that oseltamivir reduces severe clinical outcomes in patients hospitalized with influenza. A large prospective observational study assessed clinical outcomes among 327 hospitalized adults with laboratory-confirmed influenza whose health-care provider chose to use oseltamivir treatment compared to untreated influenza patients. The average age of adults in this study was 77 years, and 71% began treatment >48 hours after illness onset. In the multivariate analysis, oseltamivir treatment was associated with a significantly decreased risk for death within 15 days of hospitalization (odds ratio = 0.21; CI = 0.060.80). Benefit was observed even among those starting treatment >48 hours after symptom onset. However, oseltamivir treatment did not significantly reduce the duration of hospitalization or 30 day mortality after hospitalization. An additional 185 hospitalized children with laboratory confirmed influenza were identified during this study, but none received antiviral treatment and no assessment of outcomes based on receipt of antiviral treatment could be made (95). A retrospective cohort study of 99 hospitalized persons with laboratory-confirmed influenza administered who received oseltamivir that was conducted in Hong Kong reported that persons who received oseltamivir treatment >48 hours from illness onset had a median length of stay of 6 days compared to 4 days for persons who received oseltamivir within 48 hours of symptom onset (p<0.0001) (447). However, additional data on the impact of antiviral treatment on severe outcomes are needed.

More clinical data are available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A virus infection than for treatment of influenza B virus infection. Data from human clinical studies have indicated that zanamivir and oseltamivir have activity against influenza B viruses (437,448451). However, an observational study among Japanese children with culture-confirmed influenza and treated with oseltamivir demonstrated that children with influenza A virus infection resolved fever and stopped shedding virus more quickly than children with influenza B, suggesting that oseltamivir might be less effective for the treatment of influenza B (452).

The Infectious Diseases Society of America and the American Thoracic Society have recommended that persons with community-acquired pneumonia and laboratory-confirmed influenza should receive either oseltamivir or zanamivir if treatment can be initiated within 48 hours of symptom onset. Patients who present >48 hours after illness onset are potential candidates for treatment if they have influenza pneumonia or to reduce viral shedding while hospitalized (453). The American Academy of Pediatrics recommends antiviral treatment of any child with influenza who is also at high risk of influenza complications, regardless of vaccination status, and any otherwise healthy child with moderate-to-severe influenza infection who might benefit from the decrease in duration of clinical symptoms documented to occur with therapy (454).

Chemoprophylaxis

Chemoprophylactic drugs are not a substitute for vaccination, although they are critical adjuncts in preventing and controlling influenza. Certain persons are at higher priority for chemoprophylaxis (Box 4); however, chemoprophylaxis does not need to be limited to these persons. In community studies of healthy adults, both oseltamivir and zanamivir had similar efficacy in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%) (455,456). Both antiviral agents also have prevented influenza illness among persons administered chemoprophylaxis after a household member had influenza diagnosed (efficacy: zanamivir, 72%82%; oseltamivir, 68%89%) (455459). Studies have demonstrated moderate to excellent efficacy for prevention of influenza among patients in institutional settings (460465). For example, a 6-week study of oseltamivir chemoprophylaxis among nursing home residents demonstrated a 92% reduction in influenza illness (464). A 4-week study among community-dwelling persons at higher risk for influenza complications (median age: 60 years) demonstrated that zanamivir had an 83% effectiveness in preventing symptomatic laboratory-confirmed influenza (465). The efficacy of antiviral agents in preventing influenza among severely immunocompromised persons is unknown. A small nonrandomized study conducted in a stem cell transplant unit suggested that oseltamivir can prevent progression to pneumonia among influenza-infected patients (466).

When determining the timing and duration for administering influenza antiviral medications for chemoprophylaxis, factors related to cost, compliance, and potential adverse events should be considered. To be maximally effective as chemoprophylaxis, the drug must be taken each day for the duration of influenza activity in the community. Additional clinical guidelines on the use of antiviral medications to prevent influenza are available (453,454).

Persons at High Risk Who Are Vaccinated After Influenza Activity Has Begun

Development of antibodies in adults after vaccination takes approximately 2 weeks (369,370). Therefore, when influenza vaccine is administered after influenza activity in a community has begun, chemoprophylaxis should be considered for persons at higher risk for influenza complications during the time from vaccination until immunity has developed. Children aged <9 years who receive influenza vaccination for the first time might require as much as 6 weeks of chemoprophylaxis (i.e., chemoprophylaxis until 2 weeks after the second dose when immunity after vaccination would be expected). Persons at higher risk for complications of influenza still can benefit from vaccination after community influenza activity has begun because influenza viruses might still be circulating at the time vaccine-induced immunity is achieved.

Persons Who Provide Care to Those at High Risk

To reduce the spread of virus to persons at high risk, chemoprophylaxis during peak influenza activity can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact might include employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by a strain of influenza that might not be covered by the vaccine, chemoprophylaxis can be considered for all such persons, regardless of their vaccination status.

Persons Who Have Immune Deficiencies

Chemoprophylaxis can be considered for persons at high risk who are more likely to have an inadequate antibody response to influenza vaccine. This category includes persons infected with HIV, particularly those with advanced HIV disease. No published data are available concerning possible efficacy of chemoprophylaxis among persons with HIV infection or interactions with other drugs used to manage HIV infection. Such patients should be monitored closely if chemoprophylaxis is administered.

Other Persons

Chemoprophylaxis throughout the influenza season or during increases in influenza activity within the community might be appropriate for persons at high risk for whom vaccination is contraindicated, or for whom vaccination is likely to be ineffective. Health-care providers and patients should make decisions regarding whether to begin chemoprophylaxis and how long to continue it on an individual basis.

Antiviral Drug-Resistant Strains of Influenza

Oseltamivir and Zanamivir (Neuraminidase Inhibitors)

Among 2,287 isolates obtained from multiple countries during 19992002 as part of a global viral surveillance system, eight (0.3%) had a more than ten fold decrease in susceptibility to oseltamivir, and two (25%) of these eight also were resistant to zanamivir (467). In Japan, where more oseltamivir is used than in any other country, resistance to oseltamivir was identified in three (0.4%) A (H3N2) viruses in 200304, no A (H3N2) viruses in 200405, and no A (H3N2) viruses in 200506 influenza seasons. In 200506, four (2.2%) A (H1N1) viruses were identified to have oseltamivir resistance with a specific genetic marker (468). Neuraminidase inhibitor resistance remained low in the United States through the 200607 influenza season (CDC, unpublished data, 2007).

In 200708, increased resistance to oseltamivir was reported among A (H1N1) viruses in many countries (469,470). Persons infected with oseltamivir resistant A (H1N1) viruses had not previously received oseltamivir treatment and were not known to have been exposed to a person undergoing oseltamivir treatment (469,470). In the United States, approximately 10% of influenza A (H1N1) viruses, no A (H3N2) viruses, and no influenza B viruses were resistant to oseltamivir during the 200708 influenza season, and the overall percentage of influenza A and B viruses resistant to oseltamivir in the United States was <5%. No viruses resistant to zanamivir were identified (417). Oseltamivir or zanamivir continue to be the antiviral agents recommended for the prevention and treatment of influenza (418). Although recommendations for use of antiviral medications have not changed, enhanced surveillance for detection of oseltamivir-resistant viruses is ongoing and will enable continued monitoring of changing trends over time.

Development of viral resistance to zanamivir or oseltamivir during treatment has also been identified but does not appear to be frequent (450,471474). One limited study reported that oseltamivir-resistant influenza A viruses were isolated from nine (18%) of 50 Japanese children during treatment with oseltamivir (475). Transmission of neuraminidase inhibitor-resistant influenza B viruses acquired from persons treated with oseltamivir is rare but has been documented (476). No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of post-treatment isolates tested is limited (451,477). Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported (451). Prolonged shedding of oseltamivir- or zanamivir-resistant virus by severely immunocompromised patients, even after cessation of oseltamivir treatment, has been reported (478,479).

Amantadine and Rimantadine (Adamantanes)

Adamantane resistance among circulating influenza A viruses increased rapidly worldwide over the past several years, and these medications are no longer recommended for influenza prevention or treatment, although in some limited circumstances use of adamantanes in combination with a neuraminidase inhibitor medication might be considered (see Prevention and Treatment of Influenza when Oseltamivir Resistance is Suspected). The proportion of influenza A viral isolates submitted from throughout the world to the World Health Organization Collaborating Center for Surveillance, Epidemiology, and Control of Influenza at CDC that were adamantane-resistant increased from 0.4% during 19941995 to 12.3% during 20032004 (480). During the 200506 influenza season, CDC determined that 193 (92%) of 209 influenza A (H3N2) viruses isolated from patients in 26 states demonstrated a change at amino acid 31 in the M2 gene that confers resistance to adamantanes (413,414). Preliminary data from the 200708 influenza season indicates that resistance to adamantanes remains high among influenza A isolates, with approximately 99% of tested influenza A(H3N2) isolates and approximately 10% of influenza A(H1N1) isolates resistant to adamantanes (CDC, unpublished data, 2008). Amantadine or rimantidine should not be used alone for the treatment or prevention of influenza in the United States until evidence of susceptibility to these antiviral medications has been reestablished among circulating influenza A viruses. Adamantanes are not effective in the prevention or treatment of influenza B virus infections.

Prevention and Treatment of Influenza when Oseltamivir Resistance is Suspected

Testing for antiviral resistance in influenza viruses is not available in clinical settings. Because the proportion of influenza viruses that are resistant to oseltamivir remains <5% in the United States, oseltamivir or zanamivir remain the medications recommended for prevention and treatment of influenza. Influenza caused by oseltamivir-resistant viruses appears to be indistinguishable from illness caused by oseltamivir-sensitive viruses (469). When local viral surveillance data indicates that oseltamivir-resistant viruses are widespread in the community, clinicians have several options. Consultation with local health authorities to aid in decision-making is recommended as a first step. Persons who are candidates for receiving chemoprophylaxis as part of an outbreak known to be caused by oseltamivir-resistant viruses or who are being treated for influenza illness in communities where oseltamivir-resistant viruses are known to be circulating widely can receive zanamivir. However, zanamivir is not licensed for chemoprophylaxis indications in children aged <5 years, and is not licensed for treatment in children aged <7 years (451). In addition, zanamivir is not recommended for use in persons with chronic cardiopulmonary conditions, and can be difficult to administer to critically ill patients because of the inhalation mechanism of delivery. In these circumstances, a combination of oseltamivir and either rimantadine or amantadine can be considered, because influenza A (H1N1) viruses characterized to date that were resistant to oseltamivir have usually been susceptible to adamantane medications (CDC, unpublished data, 2008). However, adamantanes should not be used for chemoprophylaxis or treatment of influenza A unless they are part of a regimen that also includes a neuraminidase inhibitor, because viral surveillance data has documented that adamantane resistance among influenza A viruses is common. Influenza B viruses are not sensitive to adamantane drugs.

Control of Influenza Outbreaks in Institutions

Use of antiviral drugs for treatment and chemoprophylaxis of influenza is a key component of influenza outbreak control in institutions. In addition to antiviral medications, other outbreak-control measures include instituting droplet precautions and establishing cohorts of patients with confirmed or suspected influenza, re-offering influenza vaccinations to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients (481483). Both adamantanes and neuraminidase inhibitors have been successfully used to control outbreaks caused by antiviral susceptible strains when antivirals are combined with other infection control measures. (460,462,464,484488).

When confirmed or suspected outbreaks of influenza occur in institutions that house persons at high risk, chemoprophylaxis with a neuraminidase inhibitor medication should be started as early as possible to reduce the spread of the virus (489,490). In these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice can substantially expedite administration of antiviral medications. Specimens should be collected from ill cases for viral culture to assess antiviral resistance and provide data on the outbreak viruses. Chemoprophylaxis should be administered to all eligible residents, regardless of whether they received influenza vaccinations during the previous fall, and should continue for a minimum of 2 weeks. If surveillance indicates that new cases continue to occur, chemoprophylaxis should be continued until approximately 710 days after illness onset in the last patient (489). Chemoprophylaxis also can be offered to unvaccinated staff members who provide care to persons at high risk. Chemoprophylaxis should be considered for all employees, regardless of their vaccination status, if indications exist that the outbreak is caused by a strain of influenza virus that is not well-matched by the vaccine. Such indications might include multiple documented breakthrough influenza-virus infections among vaccinated persons, studies indicating low vaccine effectiveness, or circulation in the surrounding community of suspected index case(s) of strains not contained in the vaccine.

In addition to use in nursing homes, chemoprophylaxis also can be considered for controlling influenza outbreaks in other closed or semiclosed settings (e.g., dormitories, correctional facilities, or other settings in which persons live in close proximity). To limit the potential transmission of drug-resistant virus during outbreaks in institutions, whether in chronic or acute-care settings or other closed settings, measures should be taken to reduce contact between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis.

Dosage

Dosage recommendations vary by age group and medical conditions (Table 4).

Adults

Zanamivir is licensed 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).

Oseltamivir is licensed for treatment of adults with uncomplicated acute illness caused by influenza A or B virus and for chemoprophylaxis of influenza among adults. Dosages and schedules for adults are listed (Table 4).

Children

Zanamivir is licensed for treatment of influenza among children aged >7 years. The recommended dosage of zanamivir for treatment of influenza is 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart). Zanamivir is licensed for chemoprophylaxis of influenza among children aged >5 years; the chemoprophylaxis dosage of zanamivir for children aged >5 years is 10 mg (2 inhalations) once a day.

Oseltamivir is licensed for treatment and chemoprophylaxis among children aged >1 year. Recommended treatment dosages vary by the weight of the child: 30 mg twice a day for children who weigh <15 kg, 45 mg twice a day for children who weigh >1523 kg, 60 mg twice a day for those who weigh >2340 kg, and 75 mg twice a day for those who weigh >40 kg. Dosages for chemoprophylaxis are the same for each weight group, but doses are administered only once per day rather than twice.

Persons Aged >65 Years

No reduction in dosage for oseltamivir or zanamivir is recommended on the basis of age alone.

Persons with Impaired Renal Function

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 (450). 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 (491,492). 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 (451).

Serum concentrations of oseltamivir carboxylate, the active metabolite of oseltamivir, increase with declining renal function (450). For patients with creatinine clearance of 1030 mL per minute (450), a reduction of the treatment dosage of oseltamivir to 75 mg once daily and in the chemoprophylaxis dosage to 75 mg every other day is recommended. No treatment or chemoprophylaxis dosing recommendations are available for patients undergoing routine renal dialysis treatment.

Persons with Liver Disease

Use of zanamivir or oseltamivir has not been studied among persons with hepatic dysfunction.

Persons with Seizure Disorders

Seizure events have been reported during postmarketing use of zanamivir and oseltamivir, although no epidemiologic studies have reported any increased risk for seizures with either zanamivir or oseltamivir use.

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 (493).

Route

Oseltamivir is administered orally in capsule or oral suspension form. Zanamivir is available as a dry powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Patients should be instructed about the correct use of this device.

Pharmacokinetics

Zanamivir

In studies of healthy volunteers, approximately 7%21% of the orally inhaled zanamivir dose reached the lungs, and 70%87% was deposited in the oropharynx (451,494). Approximately 4%17% of the total amount of orally inhaled zanamivir is absorbed systemically. Systemically absorbed zanamivir has a half-life of 2.55.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (451,465).

Oseltamivir

Approximately 80% of orally administered oseltamivir is absorbed systemically (495). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxylate has a half-life of 610 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (450,496). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (468).

Adverse Events

When considering use of influenza antiviral medications (i.e., choice of antiviral drug, dosage, and duration of therapy), clinicians must consider the patient’s age, weight, and renal function (Table 4); presence of other medical conditions; indications for use (i.e., chemoprophylaxis or therapy); and the potential for interaction with other medications.

Zanamivir

Limited data are available about the safety or efficacy of zanamivir for persons with underlying respiratory disease or for persons with complications of acute influenza, and zanamivir is licensed only for use in persons without underlying respiratory or cardiac disease (497). In a study of zanamivir treatment of ILI among persons with asthma or chronic obstructive pulmonary disease in which study medication was administered after use of a B2-agonist, 13% of patients receiving zanamivir and 14% of patients who received placebo (inhaled powdered lactose vehicle) experienced a >20% decline in forced expiratory volume in 1 second (FEV1) after treatment (451,498). However, in a phase-I study of persons with mild or moderate asthma who did not have ILI, one of 13 patients experienced bronchospasm after administration of zanamivir (451). In addition, during postmarketing surveillance, cases of respiratory function deterioration after inhalation of zanamivir have been reported. Because of the risk for serious adverse events and because efficacy has not been demonstrated among this population, zanamivir is not recommended for treatment for patients with underlying airway disease (451). Allergic reactions, including oropharyngeal or facial edema, also have been reported during postmarketing surveillance (451,498).

In clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and for those receiving placebo (i.e., inhaled lactose vehicle alone) (428432,498). The most common adverse events reported by both groups were diarrhea, nausea, sinusitis, nasal signs and symptoms, bronchitis, cough, headache, dizziness, and ear, nose, and throat infections. Each of these symptoms was reported by <5% of persons in the clinical treatment studies combined (451). Zanamivir does not impair the immunologic response to TIV (499).

Oseltamivir

Nausea and vomiting were reported more frequently among adults receiving oseltamivir for treatment (nausea without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without vomiting, approximately 6%; vomiting, approximately 3%) (434,435,450,500). Among children treated with oseltamivir, 14% had vomiting, compared with 8.5% of placebo recipients. Overall, 1% discontinued the drug secondary to this side effect (437), and a limited number of adults who were enrolled in clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (450). Similar types and rates of adverse events were reported in studies of oseltamivir chemoprophylaxis (450). Nausea and vomiting might be less severe if oseltamivir is taken with food (450). No published studies have assessed whether oseltamivir impairs the immunologic response to TIV.

Transient neuropsychiatric events (self-injury or delirium) have been reported postmarketing among persons taking oseltamivir; the majority of reports were among adolescents and adults living in Japan (501). FDA advises that persons receiving oseltamivir be monitored closely for abnormal behavior (450).

Use During Pregnancy

Oseltamivir and zanamivir are both “Pregnancy Category C” medications, indicating that no clinical studies have been conducted to assess the safety of these medications for pregnant women. Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these two drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus; the manufacturers’ package inserts should be consulted (450,451). However, no adverse effects have been reported among women who received oseltamivir or zanamivir during pregnancy or among infants born to such women.

Drug Interactions

Clinical data are limited regarding drug interactions with zanamivir. However, no known drug interactions have been reported, and no clinically critical drug interactions have been predicted on the basis of in vitro and animal study data (450,451,502).

Limited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and oseltamivir carboxylate are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and probenecid resulted in reduced clearance of oseltamivir carboxylate by approximately 50% and a corresponding approximate twofold increase in the plasma levels of oseltamivir carboxylate (468).

No published data are available concerning the safety or efficacy of using combinations of any of these influenza antiviral drugs. Package inserts should be consulted for more detailed information about potential drug interactions.

 

 

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