Influenza epidemics occur each winter in the United States and account for significant morbidity and mortality. Although most influenza deaths occur among older adults, school-age children have the highest attack rates, approaching 50 per 100 individuals.1 Furthermore, peak school absenteeism occurs early in each influenza season as one of the first markers of epidemic influenza.
Based on this and other epidemiologie observations, it is believed that children serve as a reservoir for influenza infection for the entire community. In addition, infants and children bear significant morbidity due to influenza. In the first year of a community-wide surveillance study in Houston, 45% of febrile respiratory illnesses requiring medical attention occurred in children younger than 5 years.2 During the second year, influenza virus surpassed respiratory syncytial virus as a cause of lower respiratory tract disease necessitating pediatrie admission and was associated with a 7% mortality rate.
Taken together, these data suggest that both prevention and treatment of influenza in children are worthwhile goals. There are currently four anti-influenza agents approved for use. Amantadme has been available for the treatment and prophylaxis of influenza since 1976, and rimantadine was licensed in the early 1990s. Despite their availability and low cost drawbacks have prevented wide use of these drugs in pediatrics. Two new agents, zanamivir and oseltamivir, have recently become available and offer the potential for widespread and effective use in adults and children.
Amantadme was first approved for the prophylaxis of influenza A infections in 1966. Ten years later, it was also approved for the treatment of all influenza A infections in adults and in children older than 1 year. Amantadine exerts its antiviral effect by interfering with the uncoating of viral RNA inside infected cells, thereby preventing viral replication. This mechanism is via inhibition of the pH-activated ion channel function of the influenza A virus M2 protein. Amantadine is active against influenza A only. It has no activity against influenza B virus.
Most studies evaluating the effectiveness of amantadme for the prophylaxis and treatment of influenza A virus infections have been conducted in healthy adolescents and adults.3'4 A doubleblind, prospective trial of amantadine for prophylaxis against community-acquired influenza in more than 400 volunteers found a beneficial effect on both the frequency of influenza illness and the evidence of infection.3 Efficacy rates were 91% and 74% against documented influenza illness and laboratory-confirmed infections, respectively.3 Amantadine also reduces the signs and symptoms of influenza illness in patients treated within 48 hours of onset.4 In general, patients treated with amantadine improved subjectively and became afebrile approximately 1 day sooner than control subjects treated with placebo.4
Recommended Dally Dosages of Anti-Influenza Agents
Amantadine is well absorbed following oral administration, with peak plasma concentrations 2 to 4 hours after a single dose. The half-life is between 12 and 18 hours, allowing single or twice daily dosing (Table 1). Significant levels of drug penetrate into nasal secretions, saliva, breast milk, and cerebrospinal fluid. More than 90% is excreted unchanged by the kidneys, necessitating close monitoring and dosage adjustment in patients with renal disease based on creatinine clearance.
Advantages and Disadvantages
Despite the documented efficacy in prophylaxis and treatment and a favorable pharmacokinetic profile, amantadine has important drawbacks. The most common side effects involve the central nervous system (CNS) and include nervousness, anxiety, difficulty concentrating, and lightheadedness. In the prophylaxis trial noted previously, 13% of healthy young adults reported CNS side effects and 22% dropped out of the study due to adverse effects.3 Although the CNS complaints are usually mild and self-limited, even with continued dosing, more serious CNS side effects can occur, including delirium, agitation, and seizures.5 At particular risk are those with underlying seizure disorders or psychiatric illness, those with impaired renal function, and the elderly (who have elevated plasma levels of amantadme). Amantadme dosing should be carefully evaluated in these groups. Administration with antihistamines or anticholinergic medications also increases the risk of CNS toxicity and should be avoided.
Also, amantadine is active against influenza A only. The use of amantadine beyond a few days is associated with the rapid and predictable development of viral resistance. This results from mutations in the viral M2 protein and has occurred as soon as 3 days after starting amantadine in up to 30% of patients.5'6 Amantadineresistant isolates of influenza A are genetically stable, can be transmitted to susceptible contacts, are equivalent in pathogenicity to wild type isolates, and can be shed for prolonged periods in immunocompromised patients taking this drug.
Recommendations for Use
Because of these drawbacks, the use of amantadine has been limited. The American Academy of Pediatrics Committee on Infectious Diseases recommends consideration for use for only three groups of pediatrie patients7: (I) children with underlying chronic medical conditions that may predispose them to complicated influenza illness (eg, cardiac, respiratory, or immune system dysfunction); (2) all children with severe influenza illness; and (3) patients with special family or social situations whereby a more rapid improvement in symptoms or decrease in viral shedding would be highly beneficial (eg, children with examinations or athletic competitions or in households with elderly, debilitated individuals, or those with immunodeficiency).
Treatment should be given within 48 hours of the first symptoms and discontinued as soon as clinically possible to avoid emergence and spread of resistant virus. The usual course of therapy is 3 to 5 days or 24 to 48 hours after the symptoms have diminished, whichever is shorter.
Short-term amantadine prophylaxis is recommended (for 2 weeks) for high-risk children immunized after the start of influenza season to protect them until vaccine immunity develops. Amantadine prophylaxis is also indicated for the entire influenza season in individuals with immunodeficiency who may not respond to vaccination, high-risk patients who cannot receive vaccine due to allergy, and unimmunized caretakers of high-risk patients, and in addition to vaccine for any child for whom the prevention of influenza is highly desirable.
Rimantadine is a structural analogue of amantadine and shares a common mechanism of action via inhibition of influenza A virus M2 protein. Also like amantadine, rimantadine is active against influenza A only and has no activity against influenza B. Rimantadine was approved in 1993 for prophylaxis and treatment of influenza A virus infections in adults. Although rimantadine was licensed only for prophylaxis of influenza A infections in children older than 1 year, many pediatrie experts also use it therapeutically.
Similar to amantadine, rimantadine has been superior to placebo in the prophylaxis of both influenza illness and infection in healthy adolescents and young adults, with efficacy rates of 85% and 66%, respectively.3 A study of children receiving rimantadine prophylaxis found a 90% reduction in laboratory-documented influenza infection.8 In treatment trials of adolescents and adults with influenza, rimantadine is essentially equivalent to amantadine, providing a 1-day benefit in relief of the signs and symptoms of influenza A illness.4 A randomized, double-blind trial in children with influenza illness demonstrated that rimantadine was associated with significant improvements in fever, cough, and malaise within 48 hours compared with acetaminophen.6
Advantages and Disadvantages
Although rimantadine is generally similar to amantadine, the two have important differences in pharmacokinetics, adverse effects, and cost. Rimantadine is well absorbed following oral dosing and highly metabolized by the liver prior to renal excretion. Thus, dosage adjustments of rimantadine are required only with severe liver dysfunction or renal disease (creatinine clearance < 10 mL/min). In addition, rimantadine has significantly less CNS toxicity, probably due to its lower plasma concentrations. In the prophylaxis trial reported earlier, subjects receiving rimantadine and those receiving placebo reported similar rates of adverse CNS and gastrointestinal effects (6%).3 Despite this, seizures have been reported occasionally among patients with preexisting seizure disorders who are not taking anticonvulsant medications, suggesting a need for caution in this group.5 Unlike amantadine, significant drug interactions have not been reported with rimantadine, making it easier to use with other medications. Rimantadine is somewhat more expensive, costing $16.80 for a 7day supply compared with $2.10 for amantadine (G. Gibson, personal communication, May 2000; Table 2).
Select Characteristics of Anti-Influenza Agents
Recommendations foi Use
The recommended uses of rimantadine and amantadine in children are the same, as are the rates of emergence and transmission of resistant isolates. The two drugs share cross-resistance, which may further limit their use.
Zanamivir was the first of a new class of antiviral agents for the treatment of influenza A and B virus infections in adolescents and adults. It was approved in 1999 and is a sialic acid analogue that specifically inhibits the viral neuraminidase enzyme. During infection, all strains of influenza A and B viral particles attach to host cell membranes via binding of their viral hemagglutinin to the terminal sialic acid (neuraminic acid) residues on membrane glycoproteins (Figure).9·10 Following penetration and uncoating, viral replication proceeds and newly formed viral particles bud from the surface of infected cells covered with host cell membrane to reinitiate the infectious cycle. Neuraminidase is an essential enzyme of influenza virus because it cleaves the cellular sialic acid residues from the envelope of newly formed particles to prevent viral clumping on the surface of infected cells. Without this, influenza loses infectivity. In addition, the active neuraminidase site is highly conserved ie, highly similar) among all strains of influenza A and B, making it an ideal target for an antiviral drug.
The efficacy of zanamivir has been studied in several large, controlled trials that included adolescents and young adults. These have demonstrated a consistent beneficial antiviral effect. In one study, patients given zanamivir reported improvement of all symptoms 1 day faster than those treated with placebo.11 This positive effect was evident by 3 days of treatment and was similar in patients infected with influenza A or B virus. No statistically significant differences existed between patients given zanamivir and control subjects if fever was not present at enrollment or if symptoms had been present for more than 30 hours.
Figure. Replication of influenza virus within the host cell. Amantadine and rimantadine interfere with viral uncoating, preventing release of viral RNA. Zanamivir and oseltamivir inhibit viral neuraminidase (NA) that influenza needs to cleave cell wall neuraminic or siafic acid (triangles) from newly formed virus particles. The hemagglutinin (HA) of influenza initiates infection by attaching to cell wall sialic acid. Thus, if residual sialic acid remains on new viral particles, its hemagglutinin will cause clumping and interfere with further replication. RNP = ribonucleoprotein. (Reprinted with permission from Cubareva LV, Kaiser L, Hayden FC. Influenza virus neuraminidase inhibitors. Lancet. 2000; 355:82 7-8 35. © by The Lancet Ltd., 2000.)
Several other studies have confirmed these findings. Patients with fever who were treated within 30 hours of illness onset had the maximal benefit, with symptoms shortened by up to 3 days.12 Two recently published trials of zanamivir included a subset of patients at high risk for severe or complicated influenza.11,12 Most had mild asthma, with smaller numbers having cardiac disease, immune deficiency, or metabolic disorders, or being elderly. Both studies demonstrated a 2- to 3-day shortening of symptoms with zanamivir, and high-risk patients were significantly less likely to have antibiotics prescribed or to be diagnosed with complications such as bronchitis or sinusitis compared with those receiving placebo.
Similar beneficial effects have recently been demonstrated in children. A large, double-blind, placebo-controlled trial in children 5 to 12 years old demonstrated that those receiving zanamivir experienced alleviation of symptoms a median of 1.25 days sooner than those treated with placebo.13 The children who received zanamivir were also able to resume normal activities sooner and were less likely to be diagnosed with a complication or receive antibiotics compared with control subjects.
A small study of experimental influenza in adults by Walker et al.14 found that treatment with zanamivir 1 day following viral inoculation was associated with a significant decrease in abnormal middle ear pressure and earache, suggesting a beneficial effect for otitis media. Additionally, early treatment was associated with an 85% efficacy against the development of febrile illness, with significantly decreased viral shedding and a 40% to 65% reduction in symptom scores.15
Preliminary studies have also examined the efficacy of zanamivir prophylaxis. Similar to amantadine and rimantadine, zanamivir was 84% to 95% effective in preventing febrile illness due to laboratory-documented influenza and 31% to 80% effective in preventing infection.15'16 Despite these initial promising results, zanamivir is not yet approved for the prophylaxis of influenza in adults or children.
Advantages and Disadvantages
Zanamivir is licensed for the treatment of influenza A and B infections in adults and in children 7 years or older who have had symptoms of influenza for less than 48 hours. The major advantages of zanamivir are its activity against both influenza A and B, a favorable pharmacokinetic and side effect profile, no known interaction with other medications, and antiviral activity against amantadine- and rimantadine-resistant strains.
Although influenza isolates resistant to zanamivir have been generated in vitro by cell culture techniques, neuraminidase inhibitorresistant influenza isolates have rarely been recovered from immunocompromised hosts in vivo.9 Mutations in the conserved active site of the neuraminidase enzyme appear to mediate this resistance. Because neuraminidase function is critical to influenza virus, changes associated with viral resistance have also been associated with decreased viral infectivity and virulence in animal models. This suggests that resistant strains will be less pathogenic and transmissible than wild influenza. Based on these data, resistance of influenza to neuraminidase inhibitors is predicted to be infrequent and unlikely to interfere significantly with the clinical use of this class of compounds.
The drawbacks to zanamivir include cost, difficulty with administration, and its restricted use in children. The pharmacy cost of a 5-day supply of zanamivir is approximately $50, compared with $2.10 for a 7-day supply of amantadine (G. Gibson, personal communication, May 2000). Additionally, the diskhaler requires prior instruction and may be difficult for younger children or older adults. Finally, zanamivir is not approved for influenza prophylaxis at any age or for treatment of children younger than 7 years (a group with high attack rates).
Recommendations for Use
Zanamivir is not orally bioavailable and thus is marketed as a dry powder for inhalation. It is packaged with a diskhaler and given as two oral inhalations (10 mg) twice a day for 5 days.17 Approximately 10% to 20% of the active compound reaches the lungs, whereas the rest is deposited in the oropharynx. Five percent to 15% of the total dose is absorbed and excreted in the urine. No dosage adjustment is recommended for patients with renal failure.
In general, zanamivir is well tolerated. Equal numbers of patients in drug and placebo groups report adverse effects, of which upper respiratory tract and gastrointestinal complaints are most common.9 However, zanamivir is not generally recommended for patients with underlying respiratory disease because of post-licensure reports of wheezing and decreased pulmonary function (peak expiratory flow rates can drop more than 20%) in subjects receiving treatment. If such individuals use zanamivir, it is recommended that they have a fast-acting bronchodilator available and discontinue zanamivir if respiratory difficulty develops.9,17
In October 1999, oseltamivir was approved for the treatment of influenza A and B infections in adults with symptoms of illness for less than 48 hours. Similar to zanamivir, oseltamivir inhibits influenza virus neuraminidase.
In a few randomized, controlled trials, oseltamivir has been effective for the treatment and prophylaxis of influenza. Hayden et al.18 reported a significant reduction in the duration of viral shedding, time to resolution of symptoms, frequency of upper respiratory tract illness, and fever in subjects treated with oseltamivir 26 hours following influenza inoculation. These findings were confirmed in a large, randomized, controlled trial of treatment with oseltamivir for previously healthy adults with community-acquired influenza and fever.19 More than 600 patients were enrolled. Time to clinical improvement was shortened by 32 hours in the treatment group compared with the control group, a 30% reduction. Reduced fever was apparent after the first day of therapy. Secondary complications of influenza, such as pneumonia, bronchitis, sinusitis, and otitis media, were reduced by 50%, as was the use of physician-prescribed antibiotics. Preliminary data on the treatment of children 1 to 12 years old with influenza have also been encouraging.20 Duration of illness decreased by 1.5 days and otitis media by 43%. Oseltamivir has also been 74% efficacious in preventing laboratory-documented influenza illness in healthy adults.21
Advantages and Disadvantages
Similar to zanamivir, the benefits of oseltamivir over older anti-influenza drugs include activity against influenza A and B viruses, minima] drug toxicity, and the expectation of limited viral resistance. In addition, oseltamivir is available in tablet form with good oral bioavailability, and favorable pharmacokinetics allow twice daily administration. However, it is as costly as zanamivir and is not approved for use in children younger than 18 years.
Recommendations foi Use
Oseltamivir is the ethyl ester prodrug of the active compound oseltamivir carboxylate, and is converted to its active form in the liver following oral dosing. Approximately 80% of the prodrug is bioavailable as the active compound, with peak plasma concentrations achieved 3 to 4 hours following a single dose. The half-life is 6 to 10 hours with predominantly renal excretion. Therefore, dosing needs to be modified in patients with a creatinine clearance of less than 30 mL/min.9 Food does not interfere with absorption of oseltamivir and may actually reduce associated nausea and vomiting.17 In the treatment trial noted earlier, nausea and vomiting were the only adverse effects reported significantly more often among patients treated with the drug than among control subjects (17% vs 7.4%, respectively).19
Four licensed anti-influenza agents are currently available. Amantadme and rimantadine have demonstrated efficacy in the prophylaxis and treatment of influenza, but their use is restricted by activity limited to influenza A virus, significant toxicity, and die rapid and frequent development of resistance. Zanamivir and oseltamivir are new drugs that interfere with viral neuraminidase and alleviate symptoms of influenza 1 to 3 days faster than placebo. Neither is currently approved for prophylaxis, although a few studies suggest they also may be effective for the prevention of influenza illness and infection. The advantages of these newer neuraminidase inhibitors include activity against both influenza A and B viruses, low rates of mild adverse effects, and the infrequent development of viral resistance. However, these newer drugs are significantly more expensive than amantadme or rimantadine. Although vaccination remains the major weapon against influenza, the neuraminidase inhibitors have potential as beneficial additions to the armamentarium against the yearly onslaught of influenza.
1. Glezen WP, Taber LH Frank AL, Gruber WC, Piedra PA. Influenza virus infections in infants. Pediatr Infect Dis J. 1997;16:1065-1068.
2. Glezen WP, Couch RB. Interpandemic influenza in the Houston area, 1974-76. N Engi } Med. 1978;298:587-592.
3. Dolin R, Reichman RC, Madore HP, Maynard R, Linton PN, Webber-Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N EngifMed. 1982;307:580-584.
4. Van Voris LP, Betts RF, Hayden FG, Christmas WA, Douglas RG Jr. Successful treatment of naturally occurring influenza A/USSR/77 HlNl. JAMA. 1981;245:11281131.
5. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR. 1999;48(RR04):l-28.
6. Hall CB, Dolin R, Gala CL, et al. Children with influenza A infection: treatment with rimantadine. Pediatrics. 1987;80:275-282.
7. American Academy of Pediatrics. Influenza. In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases, 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000:351-359.
8. Clover RD, Crawford SA, Abell TD, Ramsey CN Jr, Glezen WP, Couch RB. Effectiveness of rimantadine prophylaxis of children within families. American Journal Diseases in Children. 1986;! 40:706-709.
9. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. 2000;355:827-835
10. Laver WG, Bischofberger N, Webster RG. Disarming flu viruses. Sei Am. 1999;280:78-87.
11. Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engi } Med. 1997;337:874-880.
12. The Management of Influenza in the Southern Hemisphere Trialists Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet. 1998;352: 1877-1 881.
13. Hedrick JA, Barzilai A, Behre U, et al. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis ]. 2000;19:410-417.
14. Walker JB, Hussey EK, Treanor JJ, Montalvo A, Hayden FG. Effects of the neuraminidase inhibitor zanamivir on otologie manifestations of experimental human influenza. J infect Dis. 1997; 175: 141 7-1422.
15. Hayden FG, Treanor JJ, Betts RF, Lobo M, Esinhart JD, Hussey EK. Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. JAMA. 1996;275:295-299.
16. Monto AS, Robinson DP, Herlocher ML, Hinson JM Jr, Elliott MJ, Crisp A. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA. 1999;282:31-35.
17. Centers for Disease Control and Prevention. Neuraminidase inhibitors for treatment of influenza A and B infections. MMWR. 1999;48(RR14):l-9. [Erratum appears in MMWR. 1999;48:1139.]
18. Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. }AMA. 1999;282: 1240-1 246.
19. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA. 2000;283:1016-1024.
20. Hoffmann-La Roche. Roche announces new data on recently approved Tamiflu, first pill to treat the most common strains of influenza (A & B) [press release]. Nutley, NJ: Hoffmann-La Roche; November 8, 1999,
21. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Erigí J Med. 1999;341 '.1336-1343.
Recommended Dally Dosages of Anti-Influenza Agents
Select Characteristics of Anti-Influenza Agents