Am Fam Physician. 2000;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
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.
| 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 |
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.
| 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 |
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.
| 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
| 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 |
| 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 |
| 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∥ |
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
| 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 |
| 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 |
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.