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Clinical Update: Controlling influenza: Guidelines for using antiviral agents

The Journal of Respiratory DiseasesThe Journal of Respiratory Diseases Vol 6 No 1
Volume 6
Issue 1

The influenza vaccine has been used for many years to control outbreaks of influenza, and its role in reducing morbidity and mortality is widely appreciated among health care professionals and patients alike. The panic that occurred in 2004 after announcements of a vaccine shortage bears testimony to the importance placed on this approach to influenza prevention and control.

The influenza vaccine has been used for many years to control outbreaks of influenza, and its role in reducing morbidity and mortality is widely appreciated among health care professionals and patients alike. The panic that occurred in 2004 after announcements of a vaccine shortage bears testimony to the importance placed on this approach to influenza prevention and control.

With all the attention that the influenza vaccine garners, it might be easy to overlook other interventions--antiviral drugs, for instance--that can help reduce the incidence of influenza. The antiviral drugs available for use in the United States are amantadine, rimantadine, oseltamivir, and zanamivir. Although these agents are not a substitute for the influenza vaccine, they are a valuable adjunct to vaccination.

The Advisory Committee on Immunization Practices (ACIP) has released guidelines concerning the use of these antiviral drugs.1 This Clinical Update summarizes the highlights.


The antiviral agents are indicated as an adjunct to the influenza vaccine for preventing and controlling influenza infection (Table 1). Amantadine and rimantadine (known as adamantines) are active against influenza A virus only. When given within 2 days of the onset of symptoms to otherwise healthy persons, amantadine and rimantadine can shorten the duration of illness.1,2

Zanamivir and oseltamivir, newer agents known as neuraminidase inhibitors, are effective against influenza A and B viruses (Figure). The neuraminidase inhibitors shorten the duration of influenza illness by about 1 day when given to otherwise healthy persons.3-10

Data on the impact of the antiviral drugs in persons who are at risk for complications from influenza and in infants younger than 1 year are limited, and there is no information about antiviral efficacy in persons who are severely immunocompromised.


Amantadine and rimantadine are about 60% to 90% effective at preventing illness from influenza A virus.2,4 Prophylactic use of these antiviral drugs prevents overt illness while permitting a subclinical level of infection. This allows the patient's immune system to develop protective antibodies against circulating influenza virus. These agents do not interfere with the antibody response to the influenza vaccine.2

Zanamivir and oseltamivir also prevent full-blown influenza, with efficacy rates of 84% and 82%, respectively.3,11,12 In addition, they prevent influenza when administered prophylactically to persons who have a housemate with confirmed influenza (however, zanamivir is not approved for influenza chemoprophylaxis).12 Zanamivir does not impair the patient's immunologic response to the influenza vaccine.7

When deciding when and for how long to give antiviral agents, consider cost, compliance, and potential side effects. To be maximally effective, the drugs should be taken throughout the duration of influenza activity in the community. To be most cost-effective, however, they should be taken only during peak viral activity.13

Table 2 summarizes recommendations concerning prophylactic use of the antiviral agents in specific groups.

Dosage and duration of treatment

Table 3 summarizes recommendations for dosage and duration of treatment with the antiviral agents. Dosage recommendations vary according to patient age and coexisting medical conditions.

The ACIP recommends that treatment with amantadine or rimantadine be discontinued as soon as clinically warranted--usually after 3 to 5 days of treatment or within 24 to 48 hours after the disappearance of influenza symptoms and signs.1 For oseltamivir and zanamivir, the recommended duration of treatment is 5 days.

Side effects

Adverse reactions vary according to drug, dosage, and patient factors. Amantadine and rimantadine can have CNS and GI side effects; the incidence of CNS side effects is higher with amantadine.14,15 The side effects associated with these agents are usually mild and end soon after treatment stops; in some cases, side effects subside after the first week of treatment. Amantadine has anticholinergic effects and is best avoided in persons with untreated angle-closure glaucoma.1

Zanamivir can cause bronchospasm in some patients with asthma or chronic obstructive pulmonary disease.7 Therefore, this agent is not recommended for patients with underlying airway disease. Side effects reported with oseltamivir include nausea and vomiting.6,8

The effects of antiviral drugs on pregnant women and their fetuses have not been established. Therefore, the use of these drugs during pregnancy is indicated only when the potential benefits outweigh the risks to the mother and fetus.1

Drug interactions

Interactions between the antiviral agents and other medications appear to be fairly limited.1 No clinically significant interactions between rimantadine and other drugs have been identified. Similarly, no known drug interactions have been reported for zanamivir.

Data for oseltamivir are limited, but there might be potential for interaction between this drug and others excreted by the anionic pathway of the kidneys. Amantadine must be given cautiously with other drugs that affect the CNS.1 Evidence indicates that concomitant administration of antihistamines or anticholinergics and amantadine can increase the incidence of adverse CNS reactions.2

Antiviral resistance

Resistance develops in about one third of persons treated with amantadine or rimantadine, and cross-resistance exists.16 Furthermore, resistant strains of influenza virus can replace susceptible strains within 2 to 3 days of treatment with an adamantine.17 However, amantadine-resistant and rimantadine-resistant viruses are not more virulent or transmissible than susceptible viruses, and screening for epidemic strains of influenza A virus has rarely detected adamantine-resistant viruses.17,18

Development of resistance to zanamivir and oseltamivir is uncommon.8,19,20 No transmission of viruses that are resistant to neuraminidase inhibitors has been documented thus far.

For more information about influenza surveillance, prevention, detection, and control, consult the following:

• CDC Voice Information System: 888-232-3228.

• CDC Fax Information Service: 888-232-3299.

• MMWR: www.cdc.gov/mmwr.

• Influenza vaccine information: 800-CDC-INFO (800-232-4636).



1. Harper SA, Fukuda K, Uyeki TM, et al; Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in

MMWR Morb Mortal Wkly Rep

. 2005;54:750].

MMWR Recomm Rep.

2.Tominack RL, Hayden FG. Rimantadine hydrochloride and amantadine hydrochloride use in influenza A virus infections.

Infect Dis Clin North Am.

3. Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections.

J Infect Dis.

1999; 180: 254-261.
4.Demicheli V, Jefferson T, Rivetti D, Deeks J. Prevention and early treatment of influenza in healthy adults.


5.Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. GG167 Influenza Study Group.

N Engl J Med.

6.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. US Oral Neuraminidase Study Group.


2000; 283: 1016-1024.
7.Relenza (zanamivir for inhalation) [package insert]. Research Triangle Park, NC: Glaxo Wellcome, Inc; 2001.
8. Tamiflu (oseltamivir phosphate) capsules [package insert]. Nutley, NJ: Roche Laboratories, Inc; 2001.
9. Cooper NJ, Sutton AJ, Abrams KR, et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials.


2003; 326: 1235.
10. Jefferson T, Demicheli V, Deeks J, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults.

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11. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.

N Engl J Med.

12. Monto AS, Pichichero ME, Blanckenberg SJ, et al. Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households.

J Infect Dis.

13. Patriarca PA, Arden NH, Koplan JP, Goodman RA. Prevention and control of type A influenza infections in nursing homes. Benefits and costs of four approaches using vaccination and amantadine.

Ann Intern Med.

14. Dolin R, Reichman RC, Madore HP, et al. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection.

N Engl J Med.

15. Soo W. Adverse effects of rimantadine: summary from clinical trials.

J Respir Dis.

16. Belshe RB, Smith MH, Hall CB, et al. Genetic basis of resistance to rimantadine emerging during treatment of influenza virus infection.

J Virol.

17. Hayden FG, Sperber SJ, Belshe RB, et al. Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine.

Antimicrob Agents Chemother.

18. Hayden FG, Hay AJ. Emergence and transmission of influenza A viruses resistant to amantadine and rimantadine.

Curr Top Microbiol Immunol.

19. Barnett JM, Cadman A, Gor D, et al. Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies.

Antimicrob Agents Chemother.

2000; 44: 78-87.
20. Jackson HC, Roberts N, Wang ZM, et al. Management of influenza: use of new antivirals and resistance in perspective.

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21. American Academy of Pediatrics. Influenza. In: Pickering LK, ed.

Red Book: 2003 Report of the Committee on Infectious Diseases.

26th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2003.

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