P&T News: October/November 2000

Treatment of Influenza Virus

Barbara A. Mutnick, R.Ph., M.H.P., Clinical Pharmacist, Department of Pharmaceutical Care
Peer Review Status: Internally Peer Reviewed: Adapted from the Recommendations of the Advisory Committee on Immunization Practices

For the 2000-2001 influenza season in the United States, lower than anticipated production yields for this year's influenza A(H3N2) vaccine component and other manufacturing problems are expected to lead to a substantial delay in the distribution of influenza vaccine and possibly fewer total doses of vaccine for distribution than last year.

Influenza antiviral drugs are useful for controlling influenza outbreaks in specific and circumscribed situations, such as nursing homes. In addition, long-term antiviral chemoprophylaxis of high-risk institutionalized residents or some persons at high risk for complications from influenza might be indicated if vaccine either is unavailable, ineffective (e.g., severely immunocompromised persons), or contraindicated. However, these drugs are not a substitute for influenza vaccine. Even if an influenza vaccine shortage develops, Centers for Disease Control and Prevention (CDC) and Advisory Committee on Immunization Practices (ACIP) do not support their routine and widespread use as chemoprophylaxis against influenza because this is an untested and expensive strategy that could result in large numbers of persons experiencing adverse effects. Outlined below are the CDC's recommendations for the use of antiviral agents for influenza.

Diagnosis

The appropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. The early diagnosis of influenza can help reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because some 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 as well as diagnostic testing (e.g., viral culture and rapid tests for influenza) can aid clinical judgment and help guide treatment decisions. Influenza surveillance by state and local health departments and CDC can provide information about the presence of influenza viruses in the community. Surveillance can also identify the predominant circulating types, subtypes, and strains of influenza.

Indications for Antiviral Use

Four currently licensed agents are available in the United States: amantadine (Symmetrel®, generic), rimantadine (Flumadine®), zanamivir (Relenza®), and oseltamivir (Tamiflu®). Amantadine and rimantadine are chemically related antiviral drugs with activity against influenza A viruses but not influenza B viruses. Amantadine was approved in 1966 for prophylaxis of influenza A (H2N2) infection and was later approved in 1976 for the treatment and prophylaxis of influenza type A virus infections in adults and children aged >1 year. Rimantadine was approved in 1993 for treatment and prophylaxis of infection in adults. Although rimantadine was approved only for prophylaxis of infection in children, many experts consider it appropriate for treatment among children. Zanamivir and oseltamivir are neuraminidase inhibitors with activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for the treatment of uncomplicated influenza infections, but neither has yet been approved for prophylaxis. Zanamivir was approved for treatment in persons aged > 12 years, and oseltamivir was approved for treatment in persons > 18 years.

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. More clinical data are available concerning the effectiveness of zanamivir and oseltamivir for treatment of influenza A infection than for treatment of influenza B infection. However, in vitro data and data from studies of treatment in mice and ferrets document that zanamivir and oseltamivir have activity against influenza B viruses.

None of the four antiviral agents has been demonstrated to be effective 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 based principally on studies of patients with uncomplicated influenza. Data are limited and inconclusive concerning the effectiveness of amantadine, rimantadine, and zanamivir for treatment of influenza in persons at high risk for serious complications of influenza, and no published data are available concerning the effectiveness of oseltamivir for treatment of influenza in high-risk populations. Studies of the efficacy of any of the four drugs for treatment in children are limited. To reduce the emergence of antiviral drug-resistant viruses, amantadine or rimantadine therapy for persons with influenza-like illness should be discontinued as soon as clinically warranted, generally after 3 to 5 days of treatment or within 24 to 48 hours after the disappearance of signs and symptoms. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days.

Prophylaxis
Chemoprophylactic drugs are not a substitute for vaccination, although they are important adjuncts in the prevention and control of influenza. Both amantadine and rimantadine are indicated for the prophylaxis of influenza A infection but are not effective against influenza B. Both drugs are approximately 70% to 90% effective in preventing illness from influenza A infection. When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection and the development of protective antibody against circulating influenza viruses. Therefore, some 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. Both drugs have been studied extensively in nursing home populations as a component of influenza outbreak control programs.

Zanamivir and oseltamivir have not been approved for prophylaxis, but recent community studies suggest that both drugs are similarly effective in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%). Experience with prophylactic use of these agents in institutional settings or among patients with chronic medical conditions is limited. Use of zanamivir has not been found to impair the immunologic response to influenza vaccine.

When determining the timing and duration for administering amantadine or rimantadine 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, amantadine or rimantadine prophylaxis should be taken only during the period of peak influenza activity in a community.

Side Effects and Adverse Reactions

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, the incidence of CNS side effects (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine than among those taking rimantadine. In a six-week study of prophylaxis among healthy adults, approximately 6% of participants taking rimantadine at a dosage of 200 mg/day experienced at least one CNS symptom, compared with approximately 13% of those taking the same dosage of amantadine and 4% of those taking placebo. A study of elderly persons also demonstrated fewer CNS side effects associated with rimantadine compared with amantadine. Gastrointestinal side effects (e.g., nausea and anorexia) occur in approximately 1% to 3% of persons taking either drug, compared with 1% of persons receiving the placebo.

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). 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 elderly persons who have been taking amantadine as prophylaxis at a dosage of 200 mg/day. Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects (Table 1). In acute overdosage of amantadine, CNS, renal, respiratory, and cardiac toxicity, including arrhythmias, have been reported. Because rimantadine has been marketed for a shorter period than amantadine, its safety in certain patient populations (e.g., chronically ill and elderly persons) has been evaluated less frequently.

When considering amantadine or rimantadine (i.e., choice of antiviral drug, dose, and duration of therapy), clinicians must take into account the patient's age, weight, and renal function (Table 1); the presence of other medical conditions; indications for the use of amantadine or rimantadine (i.e., prophylaxis or therapy); and the potential for interaction with other medications.

Zanamivir
Preliminary results of a study of zanamivir treatment of influenza-like illness among persons with asthma or chronic obstructive pulmonary disease indicated that more patients receiving zanamivir than placebo experienced a >20% decline in forced expiratory volume in 1 second (FEV1) or peak expiratory flow rates after treatment. Moreover, in a phase I study of persons with mild or moderate asthma who did not have influenza-like illness, one of 13 patients experienced bronchospasm following administration of zanamivir. In addition, during postmarketing surveillance, cases of respiratory function deterioration following inhalation of zanamivir have been reported among patients with underlying asthma or chronic obstructive pulmonary disease. 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 proper monitoring and supportive care, including the availability of short-acting bronchodilators. 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 develop difficulty breathing. No clear 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.

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). 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.

Oseltamivir
Nausea and vomiting were reported more frequently among persons receiving oseltamivir for treatment [nausea without vomiting (~ 10%); vomiting (~9%)] than among persons receiving placebo (nausea without vomiting, approximately 6%; vomiting, approximately 3%). However, few persons enrolled in the clinical treatment trials of oseltamivir discontinued treatment because of these symptoms. Nausea and vomiting might be less severe if oseltamivir is taken with food.

Use During Pregnancy

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. However, both amantadine and rimantadine have been shown in animal studies to be teratogenic and embryotoxic when administered at very high doses. 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.

Drug Interactions

Careful observation is advised when amantadine is administered concurrently with drugs that affect the CNS, especially CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs can increase the incidence of adverse CNS reactions. No clinically significant 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 important drug interactions have been predicted on the basis of in vitro data and data from studies of rats.

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.

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, the package inserts should be consulted.

Dosage

Dosage recommendations vary by age group and medical conditions (Table 1).

Table 1. Recommended daily dosage of influenza antiviral medications for treatment and prophylaxis
Anitviral agent	Age group
	1-9 years	10-13 years	14-64 years	> 65 years
Amantadine*
Treatment	5 mg/kg/day up to 150 mg(A) in two divided doses	100 mg twice daily(B)	100 mg twice daily	< 100 mg/day
Prophylaxis	5 mg/kg/day up to 150 mg(A) in two divided doses	100 mg twice daily(B)	100 mg twice daily	< 100 mg/day
Rimantadine(C)
Treatment	NA**	NA	100 mg twice daily	100 or 200 mg/day(D)
Prophylaxis	5 mg/kg/day up to 150 mg(A) in two divided doses	100 mg twice daily(B)	100 mg twice daily	100 or 200 mg/day(D)
Zanamivir
Treatment(E)	NA	10 mg(E) twice daily	10 mg twice daily	10 mg twice daily
Prophylaxis(F)	NA	NA	NA	NA
Oseltamivir
Treatment***	NA	NA	75 mg*** twice daily	75 mg twice daily
Prophylaxis(F)	NA	NA	NA	NA
* Consult the drug package insert for dosage recommendations for administering amantadine to persons with creatinine clearance < 50 ml/min/1.73m2. (A) 5 mg/kg of amantadine or rimantadine syrup = 1 tsp/22 lbs. (B) Children > 10 years of age who weigh <40 kg should be administered amantadine or rimantadine at a dosage of 5 mg/kg/day. (C) A reduction in dosage to 100 mg/day or rimantadine is recommended for persons who have severe hepatic dysfunction or those with creatinine clearance < 10 ml/min. Other persons with less severe hepatic or renal dysfunction taking 100 mg/day or rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary. ** NA = Not applicable. (D) Elderly nursing home residents should be administered only 100 mg/day or rimantadine. A reduction in dosage to 100 mg/day should be considered for all persons > 65 years of age if they experience possible side effects when taking 200 mg/day. (E) Zanamivir is approved for persons > 12 years of age and is administered as two 5-mg inhalations of medicated powder twice a day (i.e., 10 mg twice a day). The medication is administered via inhalation using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of proper use of the device. (F) Neither zanamivir nor oseltamivir are appropriate for prophylaxis. *** Oseltamivir is approved for persons > 18 years of age. A reduction in the dose of oseltamivir is recommended for persons with creatinine clearance < 30 ml/min.

Summary

These four antiviral drugs differ in terms of their pharmacokinetics, side effects, and costs. An overview of the indications, use, administration, and known primary side effects of these medications has been presented; however, readers should consult the package inserts for more information. A complete copy of the Recommendations of the Advisory Committee of Immunization Practices (ACIP) for Prevention and Control of Influenza can be found at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4903a1.htm.

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