Introduction
Four prescription medications with antiviral activity against
influenza viruses are commercially available in the United
States (amantadine, rimantadine, oseltamivir, zanamivir).
The four drugs are classified into two categories, the adamantane
derivatives and the neuraminidase inhibitors, on the basis
of their chemical properties and activities against influenza
viruses.
Controlled clinical trials have demonstrated the efficacy
of all four antiviral medications in reducing symptom duration
when used for treatment of influenza infections. Three of
the antiviral drugs have been approved for use as chemoprophylaxis. Table
1 summarizes information about the use of antiviral medications
in the United States for influenza.
Neuraminidase Inhibitors (Zanamivir, Oseltamivir)
The neuraminidase inhibitors, zanamivir and oseltamivir,
are chemically related drugs that have activity against both
influenza A and B viruses.
- Zanamivir is an orally inhaled powdered drug that is
approved for treatment of influenza in persons aged 7 years
and older. Zanamivir is not approved for chemoprophylaxis
of influenza.
- Oseltamivir is an orally administered capsule or oral
suspension that is approved for treatment of influenza
in persons aged 1 year and older. Oseltamivir is also approved
for chemoprophylaxis of influenza in persons aged 13 years
and older.
How do the neuraminidase inhibitor drugs work?
Zanamivir and oseltamivir block the active site of the influenza
viral enzyme neuraminidase, which is common to both influenza
A and influenza B viruses. This effect results in viral aggregation
at the host cell surface and reduces the number of viruses
released from the infected cell.
How effective are the neuraminidase
inhibitor drugs?
Treatment
When used within 48 hours of illness onset, both drugs decrease
shedding and reduce the duration of influenza symptoms by
approximately 1 day compared with placebo. Summary results
from randomized, placebo-controlled, double-blinded studies
of oseltamivir showed a significant reduction in influenza-related
lower respiratory tract complications (pneumonia and bronchitis)
associated with antibiotic use and a significant reduction
in hospitalizations. These impacts occurred in both healthy
and high-risk adolescents and adults. No studies have assessed
the impact of antiviral drug therapy on mortality. For both
drugs, the recommended duration of treatment is 5 days.
Chemoprophylaxis
Oseltamivir, but not zanamivir, is approved for chemoprophylaxis
of influenza.
Side effects of the neuraminidase inhibitor drugs:
Zanamivir and oseltamivir were approved in 1999, and therefore
clinical experience to assess adverse effects is limited.
- Oseltamivir has been associated with nausea and vomiting
during controlled treatment studies compared with placebo.
- Nausea, diarrhea, dizziness, headache, and cough have
been reported during zanamivir treatment, but the frequencies
of adverse events were similar to inhaled powdered placebo
drug.
- Few serious CNS adverse effects have been reported for
the neuraminidase inhibitor drugs.
- Zanamivir generally is not recommended for use in persons
with underlying respiratory disease because of the risk
of precipitating bronchospasm. Serious adverse respiratory
events resulting from zanamivir use have been reported
in persons with chronic pulmonary disease and in healthy
adults.
- There are limited data about the use of neuraminidase
inhibitors during pregnancy.
Antiviral resistance to the neuraminidase inhibitor drugs:
Data are limited on antiviral resistance to the neuraminidase
inhibitor drugs.
- Studies have identified some evidence for the development
of neuraminidase inhibitor-resistant influenza virus strains,
but the studies have been limited by the short time that
the neuraminidase inhibitors have been available for clinical
use and by the lack of optimal methodology to detect viral
resistance to these drugs.
- One pediatric study of oseltamivir treatment reported
that 5.5% of influenza isolates had evidence of neuraminidase
resistance.
- In vitro studies have found that cross-resistance occurs
between the neuraminidase inhibitor drugs, but does not
affect susceptibility to adamantane drugs.
Adamantane Derivatives (Amantadine, Rimantadine)
The adamantane derivatives, amantadine and rimantadine,
are chemically related, orally administered drugs that are
approved for treatment and chemoprophylaxis of influenza
A. Amantadine and rimantadine specifically inhibit replication
of influenza A viruses, but not influenza B viruses.
- Amantadine is approved for the treatment of influenza
A in children aged 1 year and older and in adults.
- Rimantadine is approved for treatment of influenza A
in adults.
- Both drugs are approved for chemoprophylaxis
to prevent influenza A in people aged 1 year and older.
Antiviral activity: How do the adamantane drugs work?
Amantadine and rimantadine are thought to interfere with
influenza A virus M2 protein, a membrane ion channel protein,
and inhibit virus uncoating, which inhibits virus replication,
resulting in decreased viral shedding.
How effective are the adamantane drugs?
Treatment
When administered within 48 hours of illness onset, controlled
studies have found that both drugs decrease viral shedding
and reduce influenza A illness by approximately 1 day compared
with placebo. The usual recommended duration of treatment
is 5 days.
Chemoprophylaxis
When used for chemoprophylaxis, amantadine and rimantadine
are approximately 70% - 90% effective in preventing symptoms
of influenza A illness. The efficacy and effectiveness of
amantadine and rimantadine to prevent complications of influenza
A are unknown. Both drugs are effective when used for chemoprophylaxis
during outbreaks of influenza A in institutions, such as
nursing homes .
Side effects of the adamantane drugs:
Chemoprophylactic use of both drugs has been associated
with:
- Gastrointestinal and central nervous system (CNS) adverse
effects in healthy adults and elderly nursing home residents.
- CNS toxicity, such as lightheadedness, difficulty concentrating,
nervousness, insomnia, and seizures in patients with pre-existing
seizure disorders. Rimantadine use has been associated
with fewer CNS side effects than amantadine.
Amantadine is teratogenic and embryo toxic in animals. Rimantadine
has not been found to be mutagenic. The safety of amantadine
and rimantadine when used during pregnancy has not been established.
Antiviral resistance:
When used for treatment, amantadine and rimantadine have
been associated with the rapid development of resistant viruses.
- Drug-resistant viruses can be spread to contacts of treated
individuals, including persons receiving chemoprophylaxis.
- The mechanism of resistance is the same for both adamantane
derivatives, and influenza A viruses resistant to one drug
are also resistant to the other.
- No evidence indicates that adamantane-resistant viruses
are more transmissible or more virulent than adamantane-sensitive
viruses.
- Resistance to adamantanes does not affect susceptibility
to neuraminidase inhibitors.
- Most influenza viruses isolated from the general population
are not resistant to amantadine or rimantadine.
Adamantanes Compared with Neuraminidase Inhibitors
- No controlled studies have directly compared the adamantanes
(amantadine, rimantadine) with the neuraminidase inhibitors
(zanamivir, oseltamivir) for treatment or chemoprophylaxis
of influenza A. A meta-analysis and a systematic review
of published studies concluded that both the adamantanes
and the neuraminidase inhibitor drugs reduce the duration
of symptoms of influenza A by approximately 1 day compared
with placebo.
- Data are very limited on the efficacy or effectiveness
of any of the antiviral drugs in preventing complications
from influenza in high-risk populations.
- The costs, routes of administration, adverse effects,
contraindications, and potential for antiviral resistance
differ among the four drugs.
- There are insufficient data on the use of any of the
four antiviral agents during pregnancy.
- In general, clinical studies have reported that the neuraminidase
inhibitors have resulted in fewer serious side effects
compared to placebo than have been reported for amantadine
and rimantadine. However, the relative frequency or severity
of adverse effects of the adamantanes compared with the
neuraminidase inhibitors has not been directly compared
in controlled trials when used for treatment or chemoprophylaxis.
Table 1: Recommended Daily Dosage
of Influenza Antiviral Medications for Treatment and Prophylaxis
| Antiviral Agent |
Age Groups (yrs) |
| 1-6 |
7-9 |
10-12 |
13-64 |
> 65 |
| Amantadine* |
Treatment,
influenza A |
5mg/kg/day up to 150 mg in 2 divided doses † |
5mg/kg/day up to 150 mg in 2 divided doses † |
100mg twice daily § |
100mg twice daily § |
< 100 mg/day |
Prophylaxis,
influenza A |
5mg/kg/day up to 150 mg in two divided
doses † |
5mg/kg/day up to 150 mg in two divided
doses † |
100mg twice daily § |
100mg twice daily § |
< 100 mg/day |
| Rimantadine¶ |
| Treatment, ** influenza A |
NA †† |
NA |
NA |
100mg twice daily § §§ |
100 mg/day |
Prophylaxis,
influenza A |
5mg/kg/day up to 150 mg in two divided
doses † |
5mg/kg/day up to 150 mg in two divided
doses † |
100mg twice daily § |
100mg twice daily § |
100 mg/day ¶¶ |
| Zanamivir***††† |
| Treatment, influenza A and B |
NA |
10mg twice daily |
10mg twice daily |
10mg twice daily |
10mg twice daily |
| Oseltamivir |
| Treatment, §§§ influenza
A and B |
Dose varies by child's weight ¶¶¶ |
Dose varies by child's weight ¶¶¶ |
Dose varies by child's weight ¶¶¶ |
75mg twice daily |
75mg twice daily |
| Prophylaxis, influenza A and B |
NA |
NA |
NA |
75mg/day |
75mg/day |
NOTE: Amantadine manufacturers
include Endo Pharmaceuticals (Symmetrel ®–tablet and
syrup) and Geneva Pharms Tech (Amantadine HCL–capsule);
USL Pharma (Amantadine HCL – capsule and tablet); and Alpharma,
Carolina Medical, Copley Pharmaceutical, HiTech Pharma, Mikart,
Morton Grove, and Pharmaceutical Associates (Amantadine HCL–syrup).
Rimantadine is manufactured by Forest Laboratories (Flumadine
(R)–tablet and syrup); Corepharma , Impax Labs (Rimantadine
HCL – tablet), and Amide Pharmaceuticals (Rimantadine HCL – tablet).
Zanamivir is manufactured by Glaxo Smithkline (Relenza (R)
– inhaled powder). Oseltamivir is manufactured by Hoffman-LaRoche,
Inc. (Tamiflu (R) — tablet). Information based on data published
by the US Food and Drug Administration at www.fda.gov.
* The drug package insert should be consulted for dosage
recommendations for administering amantadine to persons with
creatinine clearance < 50 ml/min/1.73m 2.
† 5 mg/kg of amantadine or rimantadine syrup = 1 tsp/22
lbs.
§ Children > 10 years who weigh <40 kg
should be administered amantadine or rimantadine at a dosage
of 5 mg/kg/day.
¶ A reduction in dosage to 100 mg/day of rimantadine
is recommended for persons who have severe hepatic dysfunction
or those with creatinine clearance < 10 mL/min.
Other persons with less severe hepatic or renal dysfunction
taking 100 mg/day of rimantadine should be observed closely,
and the dosage should be reduced or the drug discontinued,
if necessary.
** Only approved by FDA for treatment among adults.
†† Not applicable.
§§ Rimantadine is approved by FDA for treatment
among adults. However, certain experts in the management
of influenza consider it appropriate also for treatment among
children. (See American Academy of Pediatrics, 2000 Red Book.)
¶ ¶ Older nursing-home residents should be administered
only 100 mg/day of rimantadine. A reduction in dosage to
100 mg/day should be considered for all persons aged > 65
years if they experience possible side effects when taking
200 mg/day.
*** Zanamivir administered via inhalation using a plastic
device included in the medication package. Patients will
benefit from instruction and demonstration of the correct
use of the device.
††† Zanamivir is not approved for prophylaxis.
§§§ A reduction in the dose of oseltamivir
is recommended for persons with creatinine clearance <30
ml/min.
¶¶¶ The dose recommendation for children
who weigh < 15 kg is 30 mg twice a day, for >15
to 23 kg children the dose is 45 mg twice a day, for >23
to 40 kg children the dose is 60 mg twice a day, and for
children >40 kg, the dose is 75 mg twice a day.
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