Antiviral drugs for influenza are an adjunct to influenza vaccine for controlling and preventing influenza. However, these agents are not a substitute for vaccination. Four licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir.
Amantadine and rimantadine are chemically related antiviral drugs known as adamantanes with activity against influenza A viruses but not influenza B viruses. Amantadine was approved in 1966 for chemoprophylaxis of influenza A (H2N2) infection and was later approved in 1976 for treatment and chemoprophylaxis of influenza type A virus infections among adults and children aged >1 year. Rimantadine was approved in 1993 for treatment and chemoprophylaxis of influenza A infection among adults and prophylaxis among children. Although rimantadine is approved only for chemoprophylaxis of influenza A infection among children, certain specialists in the management of influenza consider it appropriate for treatment of influenza A among children (230).
Zanamivir and oseltamivir are chemically related antiviral drugs known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for treating uncomplicated influenza infections. Zanamivir is approved for treating persons aged >7 years, and oseltamivir is approved for treatment for persons aged >1 year. In 2000, oseltamivir was approved for chemoprophylaxis of influenza among persons aged >13 years.
The four drugs differ in pharmacokinetics, side effects, routes of administration, approved age groups, dosages, and costs. An overview of the indications, use, administration, and known primary side effects of these medications is presented in the following sections. Information contained in this report might not represent FDA approval or approved labeling for the antiviral agents described. Package inserts should be consulted for additional information.
Appropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. Early diagnosis of influenza can reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because certain bacterial infections can produce symptoms similar to influenza, bacterial infections should be considered and appropriately treated, if suspected. In addition, bacterial infections can occur as a complication of influenza.
Influenza surveillance information and diagnostic testing can aid clinical judgment and help guide treatment decisions. 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 (29,33,34). Influenza surveillance by state and local health departments and CDC can provide information regarding the presence of influenza viruses in the community. Surveillance can also identify the predominant circulating types, subtypes, and strains of influenza.
Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing, polymerase chain reaction (PCR) and immunofluorescence (24). Sensitivity and specificity of any test for influenza might vary by the laboratory that performs the test, the type of test used, and the type of specimen tested. Among respiratory specimens for viral isolation or rapid detection, nasopharyngeal specimens are typically more effective than throat swab specimens (231). As with any diagnostic test, results should be evaluated in the context of other clinical information available to health-care providers.
Commercial rapid diagnostic tests are available that can be used by laboratories in outpatient settings to detect influenza viruses within 30 minutes (24,232). 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. The types of specimens acceptable for use (i.e., throat swab, nasal wash, or nasal swab) also vary by test. The specificity and, in particular, the sensitivity of rapid tests are lower than for viral culture and vary by test (233,234). Because of the lower sensitivity of the rapid tests, physicians should consider confirming negative tests with viral culture or other means. Further, when interpreting results of a rapid influenza test, physicians should consider the positive and negative predictive values of the test in the context of the level of influenza activity in their community. Package inserts and the laboratory performing the test should be consulted for more details regarding use of rapid diagnostic tests. Additional information concerning diagnostic testing is located at http://www.cdc.gov/flu/professionals/labdiagnosis.htm.
Despite the availability of rapid diagnostic tests, collecting clinical specimens for viral culture is critical, because only culture isolates can provide specific information regarding circulating influenza subtypes and strains. 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 the emergence of antiviral resistance and the emergence of novel influenza A subtypes that might pose a pandemic threat.
Treatment
When administered within 2 days of illness onset to otherwise healthy adults, amantadine and rimantadine can reduce the duration of uncomplicated influenza A illness, and zanamivir and oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day, compared with placebo (72,235--249). More clinical data are available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A infection than for treatment of influenza B infection (250--266). However, in vitro data and studies of treatment among mice and ferrets (267--274), in addition to clinical studies, have documented that zanamivir and oseltamivir have activity against influenza B viruses (241,245--247,275,276).
Data are limited regarding the effectiveness of the four antiviral agents in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Evidence for the effectiveness of these four antiviral drugs is principally based on studies of patients with uncomplicated influenza (277). Data are limited and inconclusive concerning the effectiveness of amantadine, rimantadine, zanamivir, and oseltamivir for treatment of influenza among persons at high risk for serious complications of influenza (27,235,237,238,240,241,248,250--254). One study assessing oseltamivir treatment primarily among adults reported a reduction in complications necessitating antibiotic therapy compared with placebo (255). Fewer studies of the efficacy of influenza antivirals have been conducted among pediatric populations (235,238,244,245,251, 256,257). One study of oseltamivir treatment documented a decreased incidence of otitis media among children (245). Inadequate data exist regarding the safety and efficacy of any of the influenza antiviral drugs for use among children aged <1 year (234).
To reduce the emergence of antiviral drug-resistant viruses, amantadine or rimantadine therapy for persons with influenza A illness should be discontinued as soon as clinically warranted, typically after 3--5 days of treatment or within 24--48 hours after the disappearance of signs and symptoms. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days.
Chemoprophylaxis
Chemoprophylactic drugs are not a substitute for vaccination, although they are critical adjuncts in preventing and controlling influenza. Both amantadine and rimantadine are indicated for chemoprophylaxis of influenza A infection, but not influenza B. Both drugs are approximately 70%--90% effective in preventing illness from influenza A infection (72,235,251). When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection and development of protective antibody against circulating influenza viruses. Therefore, certain persons who take these drugs will develop protective immune responses to circulating influenza viruses. Amantadine and rimantadine do not interfere with the antibody response to the vaccine (235). Both drugs have been studied extensively among nursing home populations as a component of influenza outbreak-control programs, which can limit the spread of influenza within chronic care institutions (235,250,258--260).
Among the neuraminidase inhibitor antivirals, zanamivir and oseltamivir, only oseltamivir has been approved for prophylaxis, but community studies of healthy adults indicate that both drugs are similarly effective in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%) (261,262,278). Both antiviral agents have also been reported to prevent influenza illness among persons administered chemoprophylaxis after a household member was diagnosed with influenza (263,275,278). Experience with prophylactic use of these agents in institutional settings or among patients with chronic medical conditions is limited in comparison with the adamantanes (247,253, 254,264--266). One 6-week study of oseltamivir prophylaxis among nursing home residents reported a 92% reduction in influenza illness (247,279). Use of zanamivir has not been reported to impair the immunologic response to influenza vaccine (246,280). Data are not available regarding the efficacy of any of the four antiviral agents in preventing influenza among severely immunocompromised persons.
When determining the timing and duration for administering influenza antiviral medications for prophylaxis, factors related to cost, compliance, and potential side effects should be considered. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost-effective, one study of amantadine or rimantadine prophylaxis reported that the drugs should be taken only during the period of peak influenza activity in a community (281).
Persons at High Risk Who Are Vaccinated After Influenza Activity Has Begun. Persons at high risk for complications of influenza still can be vaccinated after an outbreak of influenza has begun in a community. However, development of antibodies in adults after vaccination takes approximately 2 weeks (222,223). When influenza vaccine is administered while influenza viruses are circulating, chemoprophylaxis should be considered for persons at high risk during the time from vaccination until immunity has developed. Children aged <9 years who receive influenza vaccine for the first time can require 6 weeks of prophylaxis (i.e., prophylaxis for 4 weeks after the first dose of vaccine and an additional 2 weeks of prophylaxis after the second dose).
Persons Who Provide Care to Those at High Risk. To reduce the spread of virus to persons at high risk during community or institutional outbreaks, chemoprophylaxis during peak influenza activity can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact include employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by a variant strain of influenza that might not be controlled by the vaccine, chemoprophylaxis should 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 expected to have an inadequate antibody response to influenza vaccine. This category includes persons infected with HIV, chiefly 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 peak influenza activity might be appropriate for persons at high risk who should not be vaccinated. Chemoprophylaxis can also be offered to persons who wish to avoid influenza illness. Health-care providers and patients should make this decision on an individual basis.
Control of Influenza Outbreaks in Institutions
Using antiviral drugs for treatment and prophylaxis 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 (282--284) (for additional information regarding outbreak control in specific settings, see Additional Information Regarding Influenza Infection Control Among Specific Populations).
The majority of published reports concerning use of antiviral agents to control influenza outbreaks in institutions are based on studies of influenza A outbreaks among nursing home populations where amantadine or rimantadine were used (235,250,258--260,281). Less information is available concerning use of neuraminidase inhibitors in influenza A or B institutional outbreaks (253,254,266,279,285). When confirmed or suspected outbreaks of influenza occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. 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.
When outbreaks occur in institutions, chemoprophylaxis should be administered to all 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 1 week after the end of the outbreak. The dosage for each resident should be determined individually. Chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza that is not well-matched by the vaccine.
In addition to nursing homes, chemoprophylaxis also can be considered for controlling influenza outbreaks in other closed or semiclosed settings (e.g., dormitories or other settings where persons live in close proximity). For example, chemoprophylaxis with rimantadine has been used successfully to control an influenza A outbreak aboard a large cruise ship (167).
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 as much as possible between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis (see Antiviral Drug-Resistant Strains of Influenza).
Dosage recommendations vary by age group and medical conditions .
Children
Amantadine. Use of amantadine among children aged <1 year has not been adequately evaluated. The FDA-approved dosage for children aged 1--9 years for treatment and prophylaxis is 4.4--8.8 mg/kg body weight/day, not to exceed 150 mg/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 body weight/day (not to exceed 150 mg/day) to reduce the risk for toxicity. The approved dosage for children aged >10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg body weight/day, regardless of age, is advisable (252).
Rimantadine. Rimantadine is approved for prophylaxis among children aged >1 year and for treatment and prophylaxis among adults. Although rimantadine is approved only for prophylaxis of infection among children, certain specialists in the management of influenza consider it appropriate for treatment among children (230). Use of rimantadine among children aged <1 year has not been adequately evaluated. Rimantadine should be administered in 1 or 2 divided doses at a dosage of 5 mg/kg body weight/day, not to exceed 150 mg/day for children aged 1--9 years. The approved dosage for children aged >10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg body weight/day, regardless of age, is recommended (286).
Zanamivir. Zanamivir is approved for treatment among children aged >7 years. The recommended dosage of zanamivir for treatment of influenza is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) (246).
Oseltamivir. Oseltamivir is approved for treatment among persons aged >1 year and for chemoprophylaxis among persons aged >13 years. Recommended treatment dosages for children vary by the weight of the child: the dosage recommendation for children who weigh <15 kg is 30 mg twice a day; for children weighing >15--23 kg, the dosage is 45 mg twice a day; for those weighing >23--40 kg, the dosage is 60 mg twice a day; and for children weighing >40 kg, the dosage is 75 mg twice a day. The treatment dosage for persons aged >13 years is 75 mg twice daily. For children aged >13 years, the recommended dose for prophylaxis is 75 mg once a day (247).
Persons Aged >65 Years
Amantadine. The daily dosage of amantadine for persons aged >65 years should not exceed 100 mg for prophylaxis or treatment, because renal function declines with increasing age. For certain older persons, the dose should be further reduced.
Rimantadine. 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 (287). However, chronically ill older persons have had a higher incidence of CNS and gastrointestinal symptoms and serum concentrations 2--4 times higher than among healthy, younger persons when rimantadine has been administered at a dosage of 200 mg/day (235).
For prophylaxis among persons aged >65 years, the recommended dosage is 100 mg/day. For treatment of 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 (286).
Zanamivir and Oseltamivir. No reduction in dosage is recommended on the basis of age alone.
Persons with Impaired Renal Function
Amantadine. A reduction in dosage is recommended for patients with creatinine clearance <50 mL/min/1.73m2. 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 given 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 (288,289).
Rimantadine. A reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance <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 either the dosage should be reduced or the drug should be discontinued, if necessary. Hemodialysis contributes minimally to drug clearance (290).
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 observed (246,291). 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 (292,293). 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 (246).
Oseltamivir. Serum concentrations of oseltamivir carboxylate (GS4071), the active metabolite of oseltamivir, increase with declining renal function (247,294). For patients with creatinine clearance of 10--30 mL/min (247), a reduction of the treatment dosage of oseltamivir to 75 mg once daily and in the prophylaxis dosage to 75 mg every other day is recommended. No treatment or prophylaxis dosing recommendations are available for patients undergoing routine renal dialysis treatment.
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 (295).
Rimantadine. A reduction in dosage to 100 mg/day is recommended for persons with severe hepatic dysfunction.
Zanamivir and Oseltamivir. Neither of these medications has been studied among persons with hepatic dysfunction.
Persons with Seizure Disorders
Amantadine. An increased incidence of seizures has been reported among patients with a history of seizure disorders who have received amantadine (296). 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 (297). The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated.
Zanamivir and Oseltamivir. 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.
Amantadine, rimantadine, and oseltamivir are administered orally. Amantadine and rimantadine are available in tablet or syrup form, and oseltamivir is available in capsule or oral suspension form (298,299). 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 will benefit from instruction and demonstration of correct use of this device (246).
Amantadine
Approximately 90% of amantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion (258,300--303). Thus, renal clearance of amantadine is reduced substantially among persons with renal insufficiency, and dosages might need to be decreased (see Dosage).
Rimantadine
Approximately 75% of rimantadine is metabolized by the liver (251). The safety and pharmacokinetics of rimantadine among persons with liver disease have been evaluated only after single-dose administration (251,304). In a study of persons with chronic liver disease (the majority with stabilized cirrhosis), no alterations in liver function were observed after a single dose. However, for persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease (286).
Rimantadine and its metabolites are excreted by the kidneys. The safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration (251,290). Further studies are needed to determine multiple-dose pharmacokinetics and the most appropriate dosages for patients with renal insufficiency. In a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that among healthy persons of the same age (290). Hemodialysis did not contribute to drug clearance. In studies of persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were higher than those among control patients without renal disease who were the same weight, age, and sex (286,305).
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 (246,306). Approximately 4%--17% of the total amount of orally inhaled zanamivir is systemically absorbed. Systemically absorbed zanamivir has a half-life of 2.5--5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (246,293).
Oseltamivir
Approximately 80% of orally administered oseltamivir is absorbed systemically (294). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxylate has a half-life of 6--10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (247,307). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (308).
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; presence of other medical conditions; indications for use (i.e., prophylaxis or therapy); and the potential for interaction with other medications.
Amantadine and Rimantadine
Both amantadine and rimantadine can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day. However, incidence of CNS side effects (e.g., nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine than among those taking rimantadine (308). In a 6-week study of prophylaxis among healthy adults, approximately 6% of participants taking rimantadine at a dosage of 200 mg/day experienced one or more CNS symptoms, compared with approximately 13% of those taking the same dosage of amantadine and 4% of those taking placebo (308). A study of older persons also demonstrated fewer CNS side effects associated with rimantadine compared with amantadine (287). Gastrointestinal side effects (e.g., nausea and anorexia) occur among approximately 1%--3% of persons taking either drug, compared with 1% of persons receiving the placebo (308).
Side effects associated with amantadine and rimantadine are usually mild and cease soon after discontinuing the drug. Side effects can diminish or disappear after the first week, despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures) (288,296). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among older persons who have been taking amantadine as prophylaxis at a dosage of 200 mg/day (258). Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects. In acute overdosage of amantadine, CNS, renal, respiratory, and cardiac toxicity, including arrhythmias, have been reported (288). Because rimantadine has been marketed for a shorter period than amantadine, its safety among certain patient populations (e.g., chronically ill and older persons) has been evaluated less frequently. Because amantadine has anticholinergic effects and might cause mydriasis, it should not be used among patients with untreated angle closure glaucoma (288).
Zanamivir
In a study of zanamivir treatment of influenza-like illness among persons with asthma or chronic obstructive pulmonary disease where 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 (246,248). However, in a phase-I study of persons with mild or moderate asthma who did not have influenza-like illness, 1 of 13 patients experienced bronchospasm after administration of zanamivir (246). In addition, during postmarketing surveillance, cases of respiratory function deterioration after inhalation of zanamivir have been reported. Certain patients had underlying airways disease (e.g., asthma or chronic obstructive pulmonary disease). Because of the risk for serious adverse events and because the efficacy has not been demonstrated among this population, zanamivir is not recommended for treatment for patients with underlying airway disease (246). If physicians decide to prescribe zanamivir to patients with underlying chronic respiratory disease after carefully considering potential risks and benefits, the drug should be used with caution under conditions of appropriate monitoring and supportive care, including the availability of short-acting bronchodilators (277). Patients with asthma or chronic obstructive pulmonary disease who use zanamivir are advised to 1) have a fast-acting inhaled bronchodilator available when inhaling zanamivir and 2) stop using zanamivir and contact their physician if they experience difficulty breathing (246). No definitive evidence is available regarding the safety or efficacy of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of acute influenza (277). Allergic reactions, including oropharyngeal or facial edema, have also been reported during postmarketing surveillance (246,253).
In clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and those receiving placebo (i.e., inhaled lactose vehicle alone) (236--241,253). 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 (246).
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%) (242,243,247,309). Among children treated with oseltamivir, 14.3% had vomiting, compared with 8.5% of placebo recipients. Overall, 1% discontinued the drug secondary to this side effect (245), whereas a limited number of adults who were enrolled in clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (247). Similar types and rates of adverse events were reported in studies of oseltamivir prophylaxis (247). Nausea and vomiting might be less severe if oseltamivir is taken with food (247,309).
No clinical studies have been conducted regarding the safety or efficacy of amantadine, rimantadine, zanamivir, or oseltamivir for pregnant women; only two cases of amantadine use for severe influenza illness during the third trimester have been reported (134,135). However, both amantadine and rimantadine have been demonstrated in animal studies to be teratogenic and embryotoxic when administered at substantially high doses (286,288). Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these four drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus (see manufacturers' package inserts) (246, 247,286,288).
Careful observation is advised when amantadine is administered concurrently with drugs that affect CNS, including CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs can increase the incidence of adverse CNS reactions (235). No clinically substantial interactions between rimantadine and other drugs have been identified.
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 data and data from studies using rats (246,310).
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 (247,307).
No published data are available concerning the safety or efficacy of using combinations of any of these four influenza antiviral drugs. For more detailed information concerning potential drug interactions for any of these influenza antiviral drugs, package inserts should be consulted.
Amantadine-resistant viruses are cross-resistant to rimantadine and vice versa (311). Drug-resistant viruses can appear in approximately one third of patients when either amantadine or rimantadine is used for therapy (257,312,313). During the course of amantadine or rimantadine therapy, resistant influenza strains can replace susceptible strains within 2--3 days of starting therapy (312,314). Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy (315,316); however, the frequency with which resistant viruses are transmitted and their effect on efforts to control influenza are unknown. Amantadine- and rimantadine-resistant viruses are not more virulent or transmissible than susceptible viruses (317). The screening of epidemic strains of influenza A has rarely detected amantadine- and rimantadine-resistant viruses (312,318,319).
Persons who have influenza A infection and who are treated with either amantadine or rimantadine can shed susceptible viruses early in the course of treatment and later shed drug-resistant viruses, including after 5--7 days of therapy (257). Such persons can benefit from therapy even when resistant viruses emerge.
Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (320--327), but induction of resistance requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (328,329). Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent (247,330--333). In clinical treatment studies using oseltamivir, 1.3% of posttreatment isolates from patients aged >13 years and 8.6% among patients aged 1--12 years had decreased susceptibility to oseltamivir (247). No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment isolates tested is limited (334) and the risk for emergence of zanamivir-resistant isolates cannot be quantified (246). Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported (331). Available diagnostic tests are not optimal for detecting clinical resistance to the neuraminidase inhibitor antiviral drugs, and additional tests are being developed (334,335). Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted (336).