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ADVISORIES FOR PRESCRIBING NEW INFLUENZA DRUGS
ATLANTA--
A new class of antiviral
drugs has been added to the armamentarium of agents used for the treatment
of influenza. The two neuraminidase inhibitors--inhaled zanamivir and
oral oseltamivir--were approved in 1999 by the US Food and Drug Administration
(FDA), and appear to be effective against influenza A and B.[1] However,
a new report from the Centers for Disease Control and Prevention (CDC)
and a public health advisory from the FDA highlight important limitations
on the use of these drugs.
INDICATIONS AND USAGE
Zanamivir and oseltamivir are approved for treatment of uncomplicated acute influenza but not for prophylaxis. In contrast, the older influenza medications amantadine and rimantadine are effective only against influenza A. Amantadine and rimantadine are also approved for prophylaxis of influenza A. Zanamivir is approved for use in patients age 12 years or older, whereas oseltamivir is approved only for adults age 18 years or older (Table 1).
Table
1
ANTIVIRAL AGENTS FOR INFLUENZA
|
| |
Amantadine |
Rimantadine |
Zanamivir |
Oseltamivir |
| Influenza
virus inhibited |
Influenza
A |
Influenza
A |
Influenza
A/B |
Influenza
A/B |
| Administration
Route |
Oral
(tablet, capsule, syrip) |
Oral (tablet,
capsule) |
Oral (inhalation*) |
Oral (capsule) |
| Approved
ages |
at
least 1 yr |
at least 14
yr |
at least 12
yr |
at least 18
yr |
| Approved
for prophylaxis? |
Yes
(for patients at least 1 yr old) |
Yes (for patients
at least 1 yr old) |
No |
No |
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* Zanamivir is administered
using a specially designed device that is included with the medication.
Adapted from Winquist
AG, et all 1999. [1]
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"[Neuraminidase inhibitors] have to be used within the first 48 hours of symptom onset to be effective," stressed Andrea G. Winquist, MD, lead author of the CDC report, in an interview with Respiratory Reviews. When given within this time frame, zanamivir and oseltamivir can reduce the duration of moderate or severe influenza symptoms by about a day.[2]
However, neither drug has been shown to prevent serious influenza-related complications, such as bacterial or viral pneumonia, cautioned Dr. Winquist, a medical epidemiologist in the CDC's Division of Viral and Rickettsial Diseases. Furthermore, it is unknown whether these agents are effective against influenza in patients at high risk for serious complications, or whether they are safe or effective in pregnant women.
Limited information is available regarding the safety and efficacy of zanamivir in patients with mild to moderate or severe renal impairment. Nonetheless, the manufacturer does not recommend a dosage reduction in these patients because, even in the presence of decreased renal clearance, the systemic levels of zanamivir resulting from oral inhalation at the recommended dose could not be expected to exceed levels that have been well tolerated.
A dosage reduction is, however, recommended for patients with impaired renal function who are taking oseltamivir. Those patients with a creatinine clearance below 30 mL/min should receive 75 mg once daily. The safety and efficacy of oseltamivir in patients with a creatinine clearance below 10 mL/min is unknown.
The recommended regimen for zanamivir is two 5-mg inhalations (10 mg/d) twice daily; for oseltamivir, it is 75 mg twice daily. Either drug should be taken for five days.
Systemically absorbed zanamivir (about 4% to 17% of the amount inhaled) is excreted in the urine; the unabsorbed drug is excreted in the feces. Approximately 80% of orally administered oseltamivir is absorbed systemically and eventually excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway.
SIDE EFFECTS AND RESISTANCE
Adverse events were uncommon in clinical studies of zanamivir. Both the treatment and placebo groups had less than a 5% rate of diarrhea, nausea, sinusitis, nasal symptoms, bronchitis, and other problems. However, caution is advised if zanamivir is used in patients with chronic obstructive pulmonary disease or asthma (see box below).
| FDA
Issues Warning on
Flu Drug Safety
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Several
reports have linked zanamivir with acute deterioration of respiratory
function in patients with chronic obstructive pulmonary disease
or asthma, according to an FDA public health advisory.[1] These
reports, however, do not establish a cause-and-effect relationship;
they only raise the possibility of a potentially fatal adverse effect
of zanamivir in a selected patient group. (The zanamivir package
insert warns specifically of the risk of bronchospasm.)
Physicians should therefore weigh the risks and benefits when giving
zanamivir to patients with underlying airway disease, the advisory
said. These patients require close monitoring and appropriate supportive
care, particularly easy access to short-acting bronchodilators.
The advisory also included two other important reminders:
- Vaccination
remains the primary method of preventing and controlling influenza.
- Always
consider the possibility of primary or concomitant bacterial
infection when making treatment decisions for patients with
suspected influenza. The FDA has received several reports of
patients with serious bacterial infections and influenza-like
symptoms whose bacterial infections progressed during antiviral
treatment.
Reference
1. Lumpkin
MM. Food and Drug Administration Public Health Advisory. Safe and
appropriate use of influenza drugs. Available at http://www.fda.gov/cder/drug/advisory/influenza.htm
January 12, 1999.
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Nausea and vomiting are more common with oseltamivir than placebo (about 10% vs about 6% for nausea, and 9% vs 3% for vomiting). In clinical trials, few subjects stopped treatment because of these side effects, which may be less severe when the drug is taken with food.
Clinical data on drug interactions with zanamivir and oseltamivir are limited. Zanamivir has no known drug interactions and, based on in vitro and rat studies, researchers do not anticipate any. Furthermore, zanamivir does not appear to impair the immunologic response to influenza vaccination.[2]
With oseltamivir, on the other hand, a potential exists for interaction with other agents excreted in the urine by glomerular filtration and tubular secretion. For example, combining the drug with probenecid causes about a 50% reduction in clearance of GS4071, the product of oseltamivir metabolism. The result is a doubling of plasma GS4071.
Better diagnostic tests are necessary to accurately determine the frequency of influenza resistance to neuraminidase inhibitors. Researchers, Dr. Winquist noted, have been able to induce influenza viral resistance to both medications in vitro. And resistance to both drugs has been detected in patients.
OLD VERSUS NEW
No studies have directly compared the neuraminidase inhibitors with older influenza medications. "But based on the available evidence, it looks like they're comparable in their ability to reduce the duration of uncomplicated illness due to influenza A," Dr. Winquist reported.
The old and new influenza medications differ in side effects and cost. Central nervous system side effects, such as nervousness, anxiety, and difficulty concentrating, are concerns with amantadine and, to a lesser extent, with rimantadine but have been infrequently reported with the neuraminidase inhibitors. Amantadine may also increase the incidence of seizures in patients with a history of seizure disorders.
"The neuraminidase inhibitors are more expensive than the older drugs," said Dr. Winquist. And rimantadine, she noted, is more expensive than amantadine.
--Timothy Begany
References
1. Winquist AG, Fukuda K, Bridges CB, Cox NJ. Neuraminidase inhibitors
for treatment of influenza A and B infections. MMWR Morb Mortal Wkly
Rep. 1999;48(RR-14):1-9.
2. Webster A, Boyce M, Edmundson S, Miller I. Coadministration of orally
inhaled zanamivir with inactivated trivalent influenza vaccine does not
adversely affect the production of antihaemagglutinin antibodies in the
serum of healthy volunteers. Clin Pharmacokinet. 1999;36(suppl
1):51-58.
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