Updated Treatment for Influenza A and B

Am Fam Physician. 2000 Dec 1;62(11):2467-2476.

Influenza causes significant morbidity and mortality and is responsible for considerable medical expenditures. Vaccination is the most effective public health measure to combat this illness. Amantadine and rimantadine are older antiviral agents that have been important adjuncts in the prevention and treatment of influenza A outbreaks. Zanamivir and oseltamivir are newer agents indicated for the treatment of both influenza A and B. For antiviral agents to be effective, they must be used within 48 hours of the onset of influenza symptoms. Antiviral agents reduce the duration of fever and illness by one to two and one-half days and also reduce the severity of some symptoms. Use of amantadine or rimantadine is appropriate if influenza virus A is known to be the predominant agent in a particular year or location. Data need to be evaluated on the development of resistance and use of the newer antiviral agents in geriatric patients, high-risk patients and children. For optimal use of antiviral agents, patients with influenza symptoms must present early, and family physicians must accurately and rapidly diagnose the illness.

Influenza is a significant public health burden. In 1997, influenza and pneumonia were the sixth leading causes of death in the United States.1 Over the past 25 years, approximately 20,000 deaths per year have been attributed to influenza in this country alone. The economic cost of influenza is estimated at $3 to $5 billion annually.2,3

The prevention of influenza is best accomplished with a broad-based immunization program. Patients at highest risk should be given priority to receive influenza vaccine (Table 1). 4

Treatment of influenza with antiviral agents complements, but is not a substitute for, an extensive and effective vaccination program. Currently available antiviral agents include amantadine (Symmetrel) and rimantadine (Flumadine), which are active against influenza virus A, and two newer products, zanamivir (Relenza) and oseltamivir (Tamiflu), which have activity against influenza viral types A and B.

TABLE 1

Recommendations for the Administration of Influenza Vaccine: Categories and Specific Indications

Age

Persons six months or older with an underlying medical condition (e.g., cardiac, pulmonary) who are at increased risk for complications of influenza or who required regular medical follow-up or hospitalization during the preceding year (see medical conditions below)

Persons 50 years or older

Any person six months or older to reduce the chance of influenza infection

Occupations

Physicians, nurses and other personnel in hospital and outpatient care settings, including emergency response workers

Employees of health care facilities (e.g., nursing homes, chronic care facilities) who have contact with residents

Persons who provide home care to people in high-risk groups

Medical conditions

Alcoholism and alcoholic cirrhosis

Long-term aspirin therapy in children and teenagers (6 months to 18 years of age) who may be at risk for Reye's syndrome after influenza virus infection

Chronic cardiovascular disorders in adults and children

Hemoglobinopathies

Immunocompromised conditions (e.g., congenital immunodeficiency, malignancy, human immunodeficiency virus infection, organ transplantation, immunosuppressive therapy)*

Chronic metabolic diseases (e.g., diabetes)

Chronic pulmonary diseases, including asthma and chronic obstructive pulmonary disease

Chronic renal dysfunction

Pregnancy beyond 14 weeks of gestation during the influenza season

Pregnancy in women with medical conditions that increase their risk for complications from influenza, regardless of trimester

Persons who can transmit influenza to high-risk individuals

Household members (including children) in close contact with persons who are at high risk for influenza

Residents of nursing homes and other chronic care facilities, regardless of age, who have chronic medical conditions


*—Vaccination ideally should occur about two weeks before chemotherapy or immunosuppressive therapy is started. If a patient is vaccinated during or within two weeks before the initiation of immunosuppressive therapy, influenza vaccine should be given again about three months after treatment ends.

Information from Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2000;49(RR-3):1–38.

TABLE 1   Recommendations for the Administration of Influenza Vaccine: Categories and Specific Indications

View Table

TABLE 1

Recommendations for the Administration of Influenza Vaccine: Categories and Specific Indications

Age

Persons six months or older with an underlying medical condition (e.g., cardiac, pulmonary) who are at increased risk for complications of influenza or who required regular medical follow-up or hospitalization during the preceding year (see medical conditions below)

Persons 50 years or older

Any person six months or older to reduce the chance of influenza infection

Occupations

Physicians, nurses and other personnel in hospital and outpatient care settings, including emergency response workers

Employees of health care facilities (e.g., nursing homes, chronic care facilities) who have contact with residents

Persons who provide home care to people in high-risk groups

Medical conditions

Alcoholism and alcoholic cirrhosis

Long-term aspirin therapy in children and teenagers (6 months to 18 years of age) who may be at risk for Reye's syndrome after influenza virus infection

Chronic cardiovascular disorders in adults and children

Hemoglobinopathies

Immunocompromised conditions (e.g., congenital immunodeficiency, malignancy, human immunodeficiency virus infection, organ transplantation, immunosuppressive therapy)*

Chronic metabolic diseases (e.g., diabetes)

Chronic pulmonary diseases, including asthma and chronic obstructive pulmonary disease

Chronic renal dysfunction

Pregnancy beyond 14 weeks of gestation during the influenza season

Pregnancy in women with medical conditions that increase their risk for complications from influenza, regardless of trimester

Persons who can transmit influenza to high-risk individuals

Household members (including children) in close contact with persons who are at high risk for influenza

Residents of nursing homes and other chronic care facilities, regardless of age, who have chronic medical conditions


*—Vaccination ideally should occur about two weeks before chemotherapy or immunosuppressive therapy is started. If a patient is vaccinated during or within two weeks before the initiation of immunosuppressive therapy, influenza vaccine should be given again about three months after treatment ends.

Information from Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2000;49(RR-3):1–38.

Diagnosis of Influenza

Influenza must be distinguished from infection with the many viruses that cause the common cold, as both conditions occur primarily in the upper respiratory tract (Table 2).5,6 Bacterial infections can mimic influenza or occur as a complication of influenza virus infection. Antiviral agents have no effect on bacterial infections and do not prevent their complications.

TABLE 2

Comparing the Symptoms of Influenza and the Common Cold

Symptoms Influenza Common cold

Onset

Abrupt

More gradual

Fever

Common: 37.7 to 40°C (100 to 104°F)

Uncommon or an increase of only about 0.5°C (1°F)

Myalgia

Severe, common

Uncommon

Arthralgia

Severe, common

Uncommon

Anorexia

Common

Uncommon

Headache

Severe, common

Mild, uncommon

Cough (dry)

Common, severe

Mild to moderate

Malaise

Severe

Mild

Fatigue, weakness

More common, lasting 2 to 3 weeks

Very mild, short lasting

Chest discomfort

Common, severe

Mild to moderate

Stuffy nose

Occasional

Common

Sneezing

Occasional

Common

Sore throat

Occasional

Common


Information from Dolin R. Infectious disease. In: Fauci AS, et al., eds. Harrison's Principles of internal medicine. 14th ed. New York: McGraw-Hill, Health Professions Division, 1998:1112–6, and Is it a cold or the flu? Retrieved October 9, 2000, from: http://www.niaid.nih.gov/publications/cold/sick.htm.

TABLE 2   Comparing the Symptoms of Influenza and the Common Cold

View Table

TABLE 2

Comparing the Symptoms of Influenza and the Common Cold

Symptoms Influenza Common cold

Onset

Abrupt

More gradual

Fever

Common: 37.7 to 40°C (100 to 104°F)

Uncommon or an increase of only about 0.5°C (1°F)

Myalgia

Severe, common

Uncommon

Arthralgia

Severe, common

Uncommon

Anorexia

Common

Uncommon

Headache

Severe, common

Mild, uncommon

Cough (dry)

Common, severe

Mild to moderate

Malaise

Severe

Mild

Fatigue, weakness

More common, lasting 2 to 3 weeks

Very mild, short lasting

Chest discomfort

Common, severe

Mild to moderate

Stuffy nose

Occasional

Common

Sneezing

Occasional

Common

Sore throat

Occasional

Common


Information from Dolin R. Infectious disease. In: Fauci AS, et al., eds. Harrison's Principles of internal medicine. 14th ed. New York: McGraw-Hill, Health Professions Division, 1998:1112–6, and Is it a cold or the flu? Retrieved October 9, 2000, from: http://www.niaid.nih.gov/publications/cold/sick.htm.

A history consistent with influenza symptoms and a knowledge of the presence of influenza in the community increase the likelihood of accurate diagnosis. Various Web sites provide up-to-date information on influenza in specific cities, states and regions (Table 3). In addition, several rapid tests are available to confirm the diagnosis of influenza A or B and may be helpful in some situations. Using these aids, physicians can monitor the influenza type and its prevalence in their area, diagnose influenza more accurately and consider treatment options more carefully. In 1999–2000, for example, the peaks of widespread influenza A activity varied based on location. Because influenza B activity was not widespread, use of the less expensive antiviral agents (amantadine and rimantadine) would have been appropriate.

TABLE 3

Internet Resources for Influenza Prevention and Control

CDC Influenza Information: http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm

National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov

World Health Organization: http://www.who.int/health-topics/influenza.htm

FluNet: http://www.who.int/flunet

U.S. Department of Health and Human Services: http://www.dhhs.gov

American Lung Association: http://www.lungusa.org/diseases/c&fguide/lungcolds_flu.html

National Foundation for Infectious Disease: http://www.nfid.org/library/influenza

Consumer health information from sources such as John Hopkins and Harvard Medical School: http://www.intelihealth.com

ZymeTx, Inc.: http://www.fluwatch.com

TABLE 3   Internet Resources for Influenza Prevention and Control

View Table

TABLE 3

Internet Resources for Influenza Prevention and Control

CDC Influenza Information: http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm

National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov

World Health Organization: http://www.who.int/health-topics/influenza.htm

FluNet: http://www.who.int/flunet

U.S. Department of Health and Human Services: http://www.dhhs.gov

American Lung Association: http://www.lungusa.org/diseases/c&fguide/lungcolds_flu.html

National Foundation for Infectious Disease: http://www.nfid.org/library/influenza

Consumer health information from sources such as John Hopkins and Harvard Medical School: http://www.intelihealth.com

ZymeTx, Inc.: http://www.fluwatch.com

Amantadine and Symmetrel

Amantadine was the first antiviral agent approved by the U.S. Food and Drug Administration (FDA) for the prophylaxis (1966) and treatment (1976) of influenza A in adults and in children one year and older. In 1993, the FDA approved rimantadine for the prevention and treatment of influenza A in adults, but for prophylaxis only in children more than one year of age.4

The mechanism by which amantadine and rimantadine exert their antiviral effect is not clearly understood. These antiviral agents are thought to inhibit the M2 ion channel (present only on influenza virus A), thereby preventing viral uncoating.7

Amantadine and rimantadine are inexpensive and effective. However, use is limited by their lack of activity against influenza virus B.4  The advantages and disadvantages of these antiviral agents are listed in Table 4,4  and their similarities and differences are presented in Table 5.4  Age-based dosages are provided in Table 6.4

TABLE 4

Advantages and Disadvantages of Amantadine (Symmetrel) and Rimantadine (Flumadine)

Advantages

Indicated for prophylaxis in adults and in children more than 1 year of age

Amantadine can be used as treatment in children 1 year and older.

Various formulations (tablet, capsule, syrup)

Reduce duration of uncomplicated illness

Less costly than newer antiviral agents

Disadvantages

Effective only against influenza virus A

Central nervous system and gastrointestinal side effects

Dosage reductions necessary in patients with hepatic or renal insufficiency

Effective only when given within 48 hours of onset of symptoms

Higher risk of drug resistance


Information from Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2000;49(RR-3):1–38.

TABLE 4   Advantages and Disadvantages of Amantadine (Symmetrel) and Rimantadine (Flumadine)

View Table

TABLE 4

Advantages and Disadvantages of Amantadine (Symmetrel) and Rimantadine (Flumadine)

Advantages

Indicated for prophylaxis in adults and in children more than 1 year of age

Amantadine can be used as treatment in children 1 year and older.

Various formulations (tablet, capsule, syrup)

Reduce duration of uncomplicated illness

Less costly than newer antiviral agents

Disadvantages

Effective only against influenza virus A

Central nervous system and gastrointestinal side effects

Dosage reductions necessary in patients with hepatic or renal insufficiency

Effective only when given within 48 hours of onset of symptoms

Higher risk of drug resistance


Information from Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2000;49(RR-3):1–38.

TABLE 5

Comparison of Amantadine (Symmetrel) and Rimantadine (Flumadine)

Characteristic Amantadine Rimantadine

Metabolism and elimination

Renal clearance by filtration and tubular secretion

Hepatic metabolism and renal excretion

Side effects

Commonly has CNS and gastrointestinal side effects

Less likely to have CNS and gastrointestinal side effects

Drug interactions

CNS stimulants, antihistamines, anticholinergic agents

Not clinically significant

Pregnancy category and breast-feeding recommendation

C; not recommended for use in breast-feeding mothers

C; not recommended for use in breast-feeding mothers

Cost for 5-day treatment course*

$9.82 (3.48 to 6.74)

$18.87


CNS = central nervous system.

*—Estimated cost to the pharmacist based on average wholesale prices for treatment in adults as provided in Red book. Montvale, N.J.: Medical Economics Data, 2000. Cost to the patient will be higher, depending on prescription filling fee.

Information from Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2000;49(RR-3):1–38.

TABLE 5   Comparison of Amantadine (Symmetrel) and Rimantadine (Flumadine)

View Table

TABLE 5

Comparison of Amantadine (Symmetrel) and Rimantadine (Flumadine)

Characteristic Amantadine Rimantadine

Metabolism and elimination

Renal clearance by filtration and tubular secretion

Hepatic metabolism and renal excretion

Side effects

Commonly has CNS and gastrointestinal side effects

Less likely to have CNS and gastrointestinal side effects

Drug interactions

CNS stimulants, antihistamines, anticholinergic agents

Not clinically significant

Pregnancy category and breast-feeding recommendation

C; not recommended for use in breast-feeding mothers

C; not recommended for use in breast-feeding mothers

Cost for 5-day treatment course*

$9.82 (3.48 to 6.74)

$18.87


CNS = central nervous system.

*—Estimated cost to the pharmacist based on average wholesale prices for treatment in adults as provided in Red book. Montvale, N.J.: Medical Economics Data, 2000. Cost to the patient will be higher, depending on prescription filling fee.

Information from Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2000;49(RR-3):1–38.

TABLE 6

Dosages of Amantadine (Symmetrel) and Rimantadine (Flumadine)

Indication Patient age (years) Amantadine* Rimantadine

Treatment

1 to 9

5 mg per kg per day, up to 150 mg given in two divided doses‡

NA

10 to 13

100 mg twice daily§

NA

14 to 64

100 mg twice daily

100 mg twice daily

≥65

≤100 mg twice daily

100 or 200 mg per day∥

Prophylaxis

1 to 9

5 mg per kg per day, up to 150 mg given in two divided doses‡

5 mg per kg per day, up to 150 mg given in two divided doses‡

10 to 13

100 mg twice daily§

100 mg twice daily§

14 to 64

100 mg twice daily

100 mg twice daily

≥65

≤100 mg twice daily

100 or 200 mg twice daily∥


NA = not applicable.

*—Consult drug package insert for dosage recommendations when administering amantadine to patients with a creatinine clearance of 50 mL per minute per 1.73 m2 or less.

†—A reduction in dosage to 100 mg per day of rimantadine is recommended in patients who have severe hepatic dysfunction or a creatinine clearance of 10 mL per minute or less. Other patients with less severe hepatic or renal dysfunction who are taking 100 mg per day of rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued if necessary.

—5 mg per kg of amantadine or rimantadine syrup = 1 teaspoon per 10 kg (22 lb).

§—Children 10 years and older who weigh less than 40 kg (88 lb) should be given amantadine or rimantadine in a dosage of 5 mg per kg per day.

∥—Elderly nursing home residents should be given rimantadine in a dosage of only 100 mg per day. A dosage reduction to 100 mg per day should be considered in all patients 65 years and older if they have side effects when taking rimantadine in a dosage of 200 mg per day.

Adapted from Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbid Mortal Wkly Rep 2000;49(RR-03):1–38.

TABLE 6   Dosages of Amantadine (Symmetrel) and Rimantadine (Flumadine)

View Table

TABLE 6

Dosages of Amantadine (Symmetrel) and Rimantadine (Flumadine)

Indication Patient age (years) Amantadine* Rimantadine

Treatment

1 to 9

5 mg per kg per day, up to 150 mg given in two divided doses‡

NA

10 to 13

100 mg twice daily§

NA

14 to 64

100 mg twice daily

100 mg twice daily

≥65

≤100 mg twice daily

100 or 200 mg per day∥

Prophylaxis

1 to 9

5 mg per kg per day, up to 150 mg given in two divided doses‡

5 mg per kg per day, up to 150 mg given in two divided doses‡

10 to 13

100 mg twice daily§

100 mg twice daily§

14 to 64

100 mg twice daily

100 mg twice daily

≥65

≤100 mg twice daily

100 or 200 mg twice daily∥


NA = not applicable.

*—Consult drug package insert for dosage recommendations when administering amantadine to patients with a creatinine clearance of 50 mL per minute per 1.73 m2 or less.

†—A reduction in dosage to 100 mg per day of rimantadine is recommended in patients who have severe hepatic dysfunction or a creatinine clearance of 10 mL per minute or less. Other patients with less severe hepatic or renal dysfunction who are taking 100 mg per day of rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued if necessary.

—5 mg per kg of amantadine or rimantadine syrup = 1 teaspoon per 10 kg (22 lb).

§—Children 10 years and older who weigh less than 40 kg (88 lb) should be given amantadine or rimantadine in a dosage of 5 mg per kg per day.

∥—Elderly nursing home residents should be given rimantadine in a dosage of only 100 mg per day. A dosage reduction to 100 mg per day should be considered in all patients 65 years and older if they have side effects when taking rimantadine in a dosage of 200 mg per day.

Adapted from Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbid Mortal Wkly Rep 2000;49(RR-03):1–38.

Neuraminidase Inhibitors

In 1999, the FDA approved zanamivir and oseltamivir for the treatment of uncomplicated acute influenza A or B in patients who have been symptomatic for less than 48 hours.8,9 There is some evidence that these agents are also effective for prophylaxis, although they are not yet approved for this indication.

Zanamivir and oseltamivir are neuraminidase inhibitors. Neuraminidase is a viral-surface glycoprotein that is necessary for the replication of influenza viruses A and B. Neuraminidase activity permits the viruses to spread to other cells.10 Neuraminidase inhibitors prevent viruses from budding (releasing) and spreading. They may also reduce the spread of influenza viruses throughout the respiratory tract and allow upper respiratory tract mucus to inactivate the viruses more easily.11 They do not interfere with the antibody response to vaccine.4,12  The advantages and disadvantages of neuraminidase inhibitors are presented in Table 7. Zanamivir and oseltamivir are compared in Table 8.8,9

TABLE 7

Advantages and Disadvantages of Neuraminidase Inhibitors

Advantages

Effective against influenza virus A and B

Reduced duration and severity of selected symptoms

No central nervous system side effects

Decreased incidence of influenza complications and antibiotic use

Lower risk for emergence of drug resistance

Disadvantages

Effective only when treatment is initiated within 48 hours of the onset of symptoms

Lack of data on use in geriatric, high-risk and pediatric patients

No data on use in patients with renal or hepatic dysfunction Cost

Zanamivir (Relenza) not indicated in children less than 7 years of age; oseltamivir (Tamiflu) not indicated in children less than 18 years of age

Zanamivir generally not recommended in patients with underlying airway disease (asthma, chronic obstructive pulmonary disease); may cause allergic-like reactions

Patient education required for use of inhaler in zanamivir therapy

Not approved for prophylaxis

Less clinical experience with these agents

TABLE 7   Advantages and Disadvantages of Neuraminidase Inhibitors

View Table

TABLE 7

Advantages and Disadvantages of Neuraminidase Inhibitors

Advantages

Effective against influenza virus A and B

Reduced duration and severity of selected symptoms

No central nervous system side effects

Decreased incidence of influenza complications and antibiotic use

Lower risk for emergence of drug resistance

Disadvantages

Effective only when treatment is initiated within 48 hours of the onset of symptoms

Lack of data on use in geriatric, high-risk and pediatric patients

No data on use in patients with renal or hepatic dysfunction Cost

Zanamivir (Relenza) not indicated in children less than 7 years of age; oseltamivir (Tamiflu) not indicated in children less than 18 years of age

Zanamivir generally not recommended in patients with underlying airway disease (asthma, chronic obstructive pulmonary disease); may cause allergic-like reactions

Patient education required for use of inhaler in zanamivir therapy

Not approved for prophylaxis

Less clinical experience with these agents

TABLE 8

Comparison of Zanamivir (Relenza) and Oseltamivir (Tamiflu)

Characteristic Zanamivir* Oseltamivir*

Age limit for use

7 years and older

18 years and older

Route of administration

Oral (inhalation)

Oral (capsule)

Dosage

10 mg twice daily†

75 mg twice daily

Precautions and warnings

Not generally recommended in patients with asthma, COPD or other underlying airway disease; may cause bronchospasm and allergic-like reactions

A dosage reduction is recommended for patients with a creatinine clearance of less than 30 mL per minute (0.50 mL per second).

Metabolism and elimination

Renally excreted as unchanged drug Not a substrate or inhibitor of cytochrome P450 isoenzymes

Converted to oseltamivir carboxylate primarily by hepatic esterases Not a substrate or inhibitor of cytochrome P450 isoenzymes

Side effects

Nasal and throat irritation, cough, headache; bronchospasm and decreased expiratory flow rate in patients with asthma or COPD

Nausea and vomiting, which may be reduced by administration with food

Drug interactions

Unlikely, but has not been studied completely

Unlikely, but has not been studied completely

Pregnancy category

C

C

Cost for five-day treatment course‡

$44.40

$53


COPD = chronic obstructive pulmonary disease.

*—Neither zanamivir nor oseltamivir is approved for prophylaxis.

—Zanamivir is administered using a plastic device that is included in the medication package. Patients should be instructed on proper use of the device. Two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) are administered twice daily (approximately 12 hours apart) for five days. Two doses should be taken on the first day of treatment whenever possible, provided that there is at least two hours between doses. On subsequent days, doses should be taken about 12 hours apart (e.g., morning and evening) at approximately the same time each day.

—Estimated cost to the pharmacist based on average wholesale prices for treatment in adults as provided in Red book. Montvale, N.J.: Medical Economics Data, 2000. Cost to the patient will be higher, depending on prescription filling fee.

Information from Relenza (zanamivir for inhalation). Package insert. Research Triangle Park, N.C.: Glaxo Wellcome, Inc., April 2000, and Tamiflu (oseltamivir phosphate) capsules. Package insert. Nutley, N.J.: Roche Laboratories Inc., 1999.

TABLE 8   Comparison of Zanamivir (Relenza) and Oseltamivir (Tamiflu)

View Table

TABLE 8

Comparison of Zanamivir (Relenza) and Oseltamivir (Tamiflu)

Characteristic Zanamivir* Oseltamivir*

Age limit for use

7 years and older

18 years and older

Route of administration

Oral (inhalation)

Oral (capsule)

Dosage

10 mg twice daily†

75 mg twice daily

Precautions and warnings

Not generally recommended in patients with asthma, COPD or other underlying airway disease; may cause bronchospasm and allergic-like reactions

A dosage reduction is recommended for patients with a creatinine clearance of less than 30 mL per minute (0.50 mL per second).

Metabolism and elimination

Renally excreted as unchanged drug Not a substrate or inhibitor of cytochrome P450 isoenzymes

Converted to oseltamivir carboxylate primarily by hepatic esterases Not a substrate or inhibitor of cytochrome P450 isoenzymes

Side effects

Nasal and throat irritation, cough, headache; bronchospasm and decreased expiratory flow rate in patients with asthma or COPD

Nausea and vomiting, which may be reduced by administration with food

Drug interactions

Unlikely, but has not been studied completely

Unlikely, but has not been studied completely

Pregnancy category

C

C

Cost for five-day treatment course‡

$44.40

$53


COPD = chronic obstructive pulmonary disease.

*—Neither zanamivir nor oseltamivir is approved for prophylaxis.

—Zanamivir is administered using a plastic device that is included in the medication package. Patients should be instructed on proper use of the device. Two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) are administered twice daily (approximately 12 hours apart) for five days. Two doses should be taken on the first day of treatment whenever possible, provided that there is at least two hours between doses. On subsequent days, doses should be taken about 12 hours apart (e.g., morning and evening) at approximately the same time each day.

—Estimated cost to the pharmacist based on average wholesale prices for treatment in adults as provided in Red book. Montvale, N.J.: Medical Economics Data, 2000. Cost to the patient will be higher, depending on prescription filling fee.

Information from Relenza (zanamivir for inhalation). Package insert. Research Triangle Park, N.C.: Glaxo Wellcome, Inc., April 2000, and Tamiflu (oseltamivir phosphate) capsules. Package insert. Nutley, N.J.: Roche Laboratories Inc., 1999.

ZANAMIVIR

Zanamivir is administered to the respiratory tract by oral inhalation. Patient education is required on proper use of the inhaler that delivers the drug, and instructions are included in the manufacturer's package insert. Zanamivir can cause bronchospasm and decreased pulmonary function in patients with asthma or chronic obstructive pulmonary disease (COPD) and is not generally recommended for use in these patients.

A randomized, double-blind, placebo-controlled trial13 conducted in 455 patients with influenza-like symptoms for less than 36 hours found that inhaled zanamivir shortened the duration of symptoms by one and one-half days in the intention-to-treat group (P = 0.011) as well as in influenza-positive populations (P = 0.004). Compared with placebo, zanamivir also reduced symptoms two days sooner in patients who were febrile (temperature greater than 37.8°C [100°F]) on enrollment (P < 0.001). In high-risk patients, zanamivir reduced symptoms a median of two and one-half days earlier than placebo (P = 0.048), with significantly fewer complications (P = 0.004) and less complication-associated antibiotic use (P = 0.025). This study also found that zanamivir-treated patients returned to normal activity two days earlier (P <0.001) and had less sleep disturbance (P = 0.047) than those who received placebo.

Fewer adverse events were reported in zanamivir-treated patients (37 percent) than in those who received placebo (43 percent).13 These events included bronchitis (3 percent in the treatment group versus 7 percent in the placebo group), cough (4 percent versus 6 percent), diarrhea (1 percent versus 4 percent) and nausea or vomiting (2 percent versus 4 percent). Sinusitis was more common in the treatment group (4 percent) than in the placebo group (1 percent). The authors of the study concluded that zanamivir was well tolerated and effective in reducing the duration and severity of influenza-associated symptoms.

Another randomized, double-blind, placebo-controlled trial14 assessed the efficacy of zanamivir, in a dosage of 10 mg once daily, for the prevention of influenza in healthy adults. This study found that zanamivir provided 67 percent protection against laboratory-confirmed clinical influenza compared with placebo (P<0.001) and had an efficacy of 84 percent for the prevention of laboratory-confirmed illness with fever (P = 0.001). During the four-week trial, the incidence of influenza infections was reduced by 31 percent in patients who received zanamivir compared with placebo (P = 0.03). Adverse events were comparable to those with placebo.

In yet another trial,15 patients with influenza symptoms received one of the following: intranasal zanamivir spray (6.4 mg) plus zanamivir inhalation (10 mg); zanamivir inhalation (10 mg) plus placebo spray; or placebo spray and placebo inhalation. The median duration of symptoms was reduced by one day in the patients who received zanamivir. When this antiviral agent was given within 30 hours to febrile, infected patients, symptoms were alleviated three days sooner than in those who received placebo (P ≤0.01).

In phase I clinical trials,8 bronchospasm occurred after zanamivir inhalation in one of 13 patients who had mild to moderate asthma. A subset of patients with asthma or COPD experienced a 20 percent decline of forced expiratory volume in one second (FEV1) or peak expiratory flow rate compared with those who were given placebo.

Since zanamivir was introduced, a warning has been added recommending against use of this agent in patients with underlying airway disease (asthma, COPD) because of the risk of serious adverse events (bronchospasm and decline in lung function) and lack of data to support efficacy in this patient population. If a patient without underlying airway disease should experience bronchospasm or a decline in respiratory function while using zanamivir, the drug should be discontinued immediately and, if necessary, hospitalization should be considered. If a physician chooses to use zanamivir in a patient with known airway disease, the patient should be made aware of the risks and should have a fast-acting bronchodilator available for use.8

OSELTAMIVIR

In contrast to zanamivir, oseltamivir is administered orally. Oseltamivir is a prodrug requiring conversion by hepatic esterases to its active form, oseltamivir carboxylate. Oseltamivir carboxylate does not undergo further metabolism and is eliminated entirely by renal excretion.

Although oseltamivir is only indicated for the treatment of influenza, data on prevention and treatment have been studied in experimental human influenza. In the prophylaxis arm of one study,16 influenza developed in 67 percent of patients who received placebo and in 38 percent of those who took oseltamivir (P = 0.16; efficacy: 61 percent). Viral shedding occurred in 50 percent of patients who were given placebo but in none who received oseltamivir (P<0.001; efficacy: 100 percent).

Infection-related respiratory illness developed in none of the oseltamivir-treated patients but occurred in 33 percent of those who received placebo (P<0.01). In the treatment arm of the study, the median duration of viral shedding was reduced in the patients who received oseltamivir. Viral shedding lasted 107 hours in the placebo group but only 58 hours in the treatment group (P = 0.003).

Symptom scores were also significantly lower in patients who were given oseltamivir compared with placebo (P = 0.05).16 Treated patients also had more rapid resolution of symptoms (53 hours for oseltamivir treatment versus 95 hours for placebo: P = 0.03). The treatment group also had a lower frequency of upper respiratory tract illness (18 percent for oseltamivir versus 54 percent for placebo), middle ear pressure abnormalities (28 percent versus 54 percent) and fever (14 percent versus 31 percent). Acetaminophen usage was also less in oseltamivir-treated patients (32 percent) than in those who were given placebo (69 percent).

Similar rates of adverse events were observed in the study.16 The exception was gastrointestinal complaints, which occurred more often with oseltamivir (18 percent) than with placebo (7 percent). Mild to moderate nausea after dosing was the primary side effect, occurring in 17 percent of oseltamivir-treated patients compared with 7 percent of placebo recipients; emesis was reported in 5 percent of oseltamivir-treated patients.

Another prevention trial17 concluded that oseltamivir, in a dosage of 75 mg once or twice daily for six weeks, was safe and effective. For culture-proven influenza, the protective effect of oseltamivir was 87 percent. The laboratory-confirmed infection rate was lower in the treatment group than in the placebo group (5.3 percent versus 10.6 percent, respectively: P < 0.001).

In this trial,17 nausea occurred more often in the oseltamivir-treated group (12.1 percent for once-daily treatment and 14.6 percent for twice-daily treatment) than in the placebo group (7.1 percent); vomiting was also more common in those who were given oseltamivir (2.5 percent for once-daily treatment and 2.7 percent for twice-daily treatment) compared with placebo (0.8 percent). However, the overall incidence of adverse events was similar in the three study groups (74 to 80 percent). Headache was the most common adverse event, with an incidence of 39 to 47 percent. Nearly 2 percent of patients in the placebo group withdrew from the study because of adverse events or intercurrent illness, compared with 1.5 percent of patients in the once-daily treatment group and 1.3 percent of those in the twice-daily treatment group. Discontinuation rates were similar for oseltamivir (3.1 percent) and placebo (4.0 percent).

A recently published trial18 evaluated the efficacy and safety of treatment with oseltamivir in a dosage of 75 mg taken once or twice daily. The duration of illness was reduced by 30 percent in patients treated with either dosage of oseltamivir compared with those who were given placebo (76.3 hours for once-daily treatment and 74.3 hours for twice-daily treatment versus 97 hours for placebo: P = 0.004). Based on symptom scores, illness severity in patients with acute influenza was reduced by 30 percent with once-daily treatment and by 38 percent with twice-daily treatment compared with placebo (P < 0.001).

The recent trial18 also found that once-daily treatment reduced the duration of cough by 43 percent and that twice-daily treatment reduced its duration by 27 percent. The duration of myalgias was reduced by 42 percent (16 hours in the treatment groups versus 28 hours in the placebo group). The duration of fever was reduced by 13 to 21 percent in the treatment group, and return to normal activity occurred two to three days earlier in treated patients than in the placebo group (P ≤ 0.05). Bronchitis, pneumonia, otitis media and sinusitis occurred in 15 percent of the patients who were given placebo, compared with 7 percent of those treated with oseltamivir (P = 0.03). Although oseltamivir was well tolerated, nausea and vomiting were reported more frequently in the two treatment groups (18.0 percent for 150 mg per day of oseltamivir and 14.1 percent for 75 mg per day: P = 0.002) than in the placebo group (7.4 percent for 75 mg per day of placebo and 3.4 percent for 150 mg per day of placebo: P < 0.001).

In a randomized trial that evaluated the resolution of illness in influenza-infected patients,19 duration of illness was reduced by 29 hours in patients who were given oseltamivir in a dosage of 75 mg per day (mean duration of illness: 87.4 hours) and by 35 hours in those who were given 150 mg per day (mean duration of illness: 81.8 hours). Compared with the mean duration of illness in the placebo groups (116.5 hours), the reductions in the treatment groups were statistically significant (75 mg per day of oseltamivir versus placebo: P = 0.02; 150 mg per day of oseltamivir versus placebo: P = 0.01). This study found that the earlier oseltamivir therapy was initiated, the sooner symptoms were reduced.

Final Comment

Zanamivir and oseltamivir appear to be safe and effective in the treatment of patients with acute influenza symptoms that have been present for less than 48 hours. Zanamivir generally should not be used in patients with an underlying airway disease such as asthma or COPD.

Clinical trials indicate that the neuraminidase inhibitors are effective in reducing the duration of influenza symptoms by one to one and one-half days if they are taken within 30 to 36 hours of symptom onset. Treatment with these agents reduces symptom severity, time to return to normal activity and the incidence of complications and antibiotic use. High-risk patients and those with a temperature greater than 37.8°C (100°F) seem to receive the most benefit from these antiviral agents.13,15,18,20,21 Further research should provide insight into the cost-effectiveness of treatment.

Although currently indicated only for the treatment of influenza, oseltamivir and zanamivir appear to be effective for prophylaxis. These antiviral agents do not reduce antibody response to the influenza vaccine, and they seem to result in less resistance compared with older agents.11,22 However, annual vaccination remains the best way to prevent influenza.

Data on the use of the newer antiviral agents in geriatric, high-risk and pediatric patients need to be reviewed, and the development of resistance needs to be evaluated. Trials to assess mortality, hospitalization rates and length of hospital stays should be considered.

Although the neuraminidase inhibitors reduce symptom severity and duration of illness, which may have potential public health benefit, cost and time to administration are important factors in determining the usefulness of these agents in the community setting. During isolated influenza A outbreaks, the older, less expensive antiviral agents provide both prophylaxis and treatment. Optimal use of both older and newer antiviral agents requires the prompt presentation of patients with influenza symptoms as well as fast, accurate diagnosis and prescribing by family physicians.

The Authors

NORMAN J. MONTALTO, D.O., is associate professor in the Department of Family Medicine at the Robert C. Byrd Health Sciences Center of West Virginia University/Charleston Division, Charleston Area Medical Center, Charleston, W.Va. After graduating from the College of Osteopathic Medicine and Health Sciences, Des Moines, Iowa, Dr. Montalto completed a rotating internship at Doctors' Hospital and a family medicine residency at Ohio State University, both in Columbus.

KIMBERLY D. GUM, PHARM.D., is a pharmacy resident at Charleston Area Medical Center. She earned her doctorate of pharmacy degree at West Virginia University/Charleston Division.

JEFFREY V. ASHLEY, M.D., is associate professor in the Department of Family Medicine at the Robert C. Byrd Health Sciences Center of West Virginia University/Charleston Division, Charleston Area Medical Center. Dr. Ashley graduated from West Virginia University School of Medicine, Morgantown, and completed a family practice residency at Charleston Area Medical Center. He is also a registered pharmacist.

Address correspondence to Norman J. Montalto, D.O., Department of Family Medicine, Robert C. Byrd Health Sciences Center of West Virginia University/Charleston Division, 1201 Washington St. East, Ste. 108, Charleston, W V 25301. Reprints are not available from the authors.

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Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.


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