T A K E - H O M E

POINTS F R O M

L E C T U R E S BY

C L E V E L A N D CLINIC

A N D VIS IT ING

FACULTY

M E D I C A L G R A N D R O U N D S W I L L I A M S. W I L K E , M D , E D I T O R

Antiviral agents for treating influenza

Start antiviral agents within 48 hours of the onset of symptoms

J E N N I F E R K. L O N G , P H A R M D Department of Pharmacy, Cleveland Clinic

S H E R I F B. M O S S A D , M D * Department of Infectious Diseases, Cleveland Clinic

M O R T O N P. G O L D M A N , P H A R M D * Department of Pharmacy, Cleveland Clinic

• ABSTRACT The new neuraminidase inhibitors zanamivir and oseltamivir are important additions to the treatment of influenza, being the first class of agents active against both influenza A and influenza B. The decision to use these agents rather than amantadine or rimantadine, which are effective only against influenza A, should be based on the age of the patient, antiviral activity, side effect profile, ease of administration, drug interactions, and cost. All of these agents are effective only when started within 24 to 48 hours of onset of symptoms. To avoid inappropriate use of these agents, treatment should be continued only in patients with a confirmed diagnosis of influenza. Although effective in decreasing symptoms, none of these agents prevent pneumonia or hospitalization secondary to influenza.

ECENTLY TWO NEW DRUGS—zanamivir (Relenza) and oseltamivir (Tamiflu)—

were approved for the treatment of influenza. These drugs are the first of a new class of drugs called neuraminidase inhibitors, and unlike the two other influenza antivirals amantadine (Symmetrel) and rimantadine (Flumadine), are effective against both influenza A and B.

This article discusses the role of these agents in treating and preventing influenza.

'D i sc losu re : Dr. Mossad serves o n t h e speakers ' b u r e a u o f Roche Pharmaceut ica ls ( w h i c h makes osel tamiv i r ) ; Dr. G o l d m a n serves o n t h e speakers' bu reau o f Roche Pharmaceut ica ls a n d Glaxo W e l l c o m e Inc. ( w h i c h makes zanamiv i r ) .

Vaccination, still the first line of prevention, is also discussed.

• ANTIVIRAL AGENTS

Most treatments for influenza address only the symptoms, with antiviral agents reserved for specific situations. Patients at high risk (eg, elderly, those on dialysis, immunocompro-mised) with signs and symptoms of influenza during an epidemic in a community should be given consideration for t reatment with an antiviral agent.

Amantadine and rimantadine were the first antiviral agents approved for treating and preventing influenza. In 1999 zanamivir and oseltamivir were also approved for treating influenza. Several studies found the latter two agents effective in preventing influenza as well, but at this time only amantadine and rimantadine are FDA-approved for the pre-vention of influenza.

Mechanisms of act ion Amantadine and rimantadine block the ion channel M2, which prevents the opening and cleaving of hemagglutinin, thereby blocking the encoding of R N A and inhibiting viral replication. They are also believed to inhibit uncoating of the virus particle early in the replicative cycle.1-2

In contrast, oseltamivir and zanamivir have a different mechanism of action: they block the viral neuraminidase enzyme, which is necessary for releasing virus from infected cells. In addition, they increase formation of viral aggregates and decrease viral spread.3^

Efficacy All of the antiviral agents for influenza tend to decrease the duration of symptoms by 1 to 2 days when started within 48 hours of the onset of symptoms. Starting therapy more

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than 48 hours after symptom onset has not demonstrated clinical benefit. None of the agents decrease serious complicat ions of influenza (ie, pneumonia or hospitalization).

• DOES THE PATIENT TRULY HAVE THE FLU?

Although often confused with the common cold, influenza is a distinct syndrome, charac-terized by sudden onset, high fever, nonproduc-tive cough with chest discomfort, and constitu-tional symptoms such as headache, myalgia, and fatigue. In contrast, the common cold is slower in onset, has a greater degree of upper respiratory symptoms (runny/stuffy nose, sneez-ing), and less-intense constitutional symptoms.

It is important to differentiate these dis-eases, as the antiviral drugs available for influenza are not effective against the common cold. Yet antiviral agents must be started soon after the onset of symptoms to be effective.

Our approach is to have the pat ient come in the same day he or she calls, obtain a nasopharyngeal swab for a direct fluores-cent antigen test for the influenza virus, and in those high risk patients we believe truly have influenza, s tart an ant ivira l agent immediately. Depending on the result of the test, the agent can be stopped, cont inued, or changed (F I G U R E 1 ) .

• WHAT AGENT TO USE FOR TREATMENT?

The neuraminidase inhibitors may have some small advantages over the older agents, but no head-to-head comparisons of these agents have been conducted and there is no evidence that any agent is superior to another. Therefore, the choice of agent should be individualized. T h e following factors may affect the choice.5-11

Age of the patient. A m a n t a d i n e is approved for use in children and adults, but rimantadine, zanamivir, and oseltamivir are approved for use in adults only.

Antiviral activity. Aman tad ine and rimantadine are active only against influenza A, but zanamivir and oseltamivir are active against both influenza A and influenza B. Whi le most pandemics have been due to influenza A , in the 1998-1999 influenza sea-son more than 20% of cases were due to influenza B.12

Using antiviral agents to treat influenza Typical symptoms of influenza in a high-risk patient, during an epidemic period within 48 hours of onset

I Check nasopharyngeal direct fluorescent antigen (NP DFA) for influenza +

Start an antiviral agent

NP DFA negative

Stop antiviral treatment

NP DFA positive

Influenza A

I Continue any of the antiviral agents

Influenza B

I Change to or continue a neuraminidase inhibitor for 5 days

FIGURE 1. A p p r o a c h t o t r e a t i n g i n f l u e n z a w i t h a n t i v i r a l agen ts .

Side effect profile. T h e newer agents have fewer side effects than the older agents, especially amantadine. In particular, amanta-dine can cause central nervous system side effects including confus ion and seizures ( T A B L E 1 ) . These occur more frequently in the elderly and in patients with renal insufficien-cy. Rimantadine has side effects similar to amantadine's but to a much lesser extent.

Zanamivir is available as an inhaled pow-der, which can cause throat discomfort and can exacerbate bronchospasm in patients with asthma. Patients with asthma or chronic obstructive pulmonary disease are advised to have a fast-acting bronchodilator available while using zanamivir. Patients should contact their physicians if they develop difficulty with breathing.11

Osel tamivir has relatively few side effects. Clinical trials did demonstrate an increased rate of nausea compared with placebo.

Ease of administration. Because zanamivir is an inhaled powder, it may be difficult for patients who have problems with dexterity to use this product. Oseltamivir is available as a capsule. Rimantadine and amantadine are available as tablets and in liquid dosage forms,

We obtain a DFA when we start an antiviral agent

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M E D I C A L G R A N D R O U N D S

T A B L E 1

A n t i v i r a l a g e n t s a p p r o v e d f o r t r e a t i n g i n f l u e n z a I O N C H A N N E L M 2 BLOCKERS A m a n t a d i n e ( S y m m e t r e l )

Indications Prophylaxis and treatment of influenza A in adults

and children Dosage

Prophylaxis, adults: 200 mg daily or 100 mg twice a day* Prophylaxis, children (1 to 9 years): 5 mg/kg daily in

1 to 2 divided doses (maximum 150 mg) Treatment, adults: 200 mg daily or 100 mg twice a day*

for 24 to 48 hours after symptoms disappear Treatment, children (1 to 9 years): 5 mg/kg daily in 1 to 2

divided doses (maximum 150 mg) for 24 to 48 hours after symptoms disapppear

Adverse effects CNS: Dizziness, insomnia, anxiety, impaired

concentration, seizures (occur more frequently and severely in geriatric patients)

Gl: Nausea, vomiting Drug interactions

Anticholinergic agents, CNS stimulants, and antihistamines may worsen CNS side effects of amantadine; hydrochlorothiazide, quinidine, and quinine may decrease the renal clearance of amantadine

Cost (5-day course) $3.50§

N E U R A M I N I D A S E INHIBITORS Z a n a m i v i r ( R e l e n z a )

Indications Treatment of influenza A and B in adults and children

>12 years Dosage

10 mg twice a day for 5 days (two inhalations twice a day with the Diskhaler inhalation device)

Adverse effects Nasal and throat discomfort, cough, headache Bronchospasm has occurred in patients with asthma

Drug interactions No drug interactions have been observed

Cost (5-day course) $44.00

R i m a n t a d i n e ( F l u m a d i n e ) Indications

Prophylaxis of influenza A in adults and children Treatment of influenza A in adults

Dosage Prophylaxis, adults: 100 mg twice a day* Prophylaxis, children (< 10 years): 5 mg/kg daily Treatment: 100 mg twice a day+ for 5 to 7 days

Adverse effects Similar to amantadine but with less frequency and severity

Drug interactions Acetaminophen and aspirin reduce the peak levels and

area under the curve of rimantadine Cimetidine increases the renal clearance of rimantadine

Cost (5-day course) $8.75§

O s e l t a m i v i r ( T a m i f l u ) Indications

Treatment of influenza A and B in adults Dosage

75 mg twice a day for 5 days' Adverse effects

Nausea, vomiting, headache Drug interactions

No drug interactions have been observed Cost (5-day course)

$53.00

'Preferred dosing regimen for elderly patients; patients wi th renal dysfunction may require 100 mg once daily + Elderly patients and those with severe renal dysfunction should receive 100 mg once daily * Patients wi th a creatinine clearance less than 30 mL/minute should receive 75 mg once daily §Cost based on actual wholesale price as listed in Drug Topics Red Book, Montvale, NJ: Medical Economics, 1999.

TAB_E A D A P T E D F R O M REFERENCES 1 1 , 2 0 - 2 5

94

which is easier for children and adults who cant drug interactions. T h e interactions of have trouble swallowing pills. rimantadine and amantadine are listed in TABLE 1.

Drug interactions. T h e neuraminidase Cost. The new agents are as much as 15 inhibitors have not been shown to have signifi- times as expensive as amantadine.

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• VACCINATION STILL THE BEST STRATEGY

Each year, influenza kills from 20,000 to 40,000 people in the United States,13 and necessitates more than 100,000 hospitaliza-tions, mostly in people older than 65 years.

Our best option in preventing influenza epidemics is to improve the vaccination rate. Vaccination rates have doubled from 33% to 66% in the last 10 years in persons 65 years of age and older. However, persons younger than 65 who have medical conditions that place them at high risk should also be vaccinated, and in this group the rate is still 30% or less. O t h e r groups that should be vaccinated, according to the Advisory Commit tee on Immunizat ion Practices, are heal th care providers, all close contacts of patients at high risk for influenza complications, and any per-son who wishes to reduce the chances of con-tracting influenza.

Multiple studies have confirmed the effica-cy and cost-effectiveness of the inactivated

influenza vaccine in various risk groups. M, 15 Fortunately, this protection does not decrease with annually repeated influenza vaccination.16

Suggested measures to improve vaccina-tion rates include:

• Automat ic reminders to patients and health care providers that vaccinations are due.

• Educational programs for the public and patients that emphasize that the vaccine cannot cause influenza since it does not con-tain live virus, and that minor illnesses do not contraindicate the use of the vaccine.

• Easier access to vaccination in medical or public health settings.17 Reducing out-of-pocket costs is also an incent ive—when Medicare started reimbursing for vaccination in 1993, the vaccination rate increased in people 65 and older.

A live-attenuated, cold-adapted, triva-lent, intranasal influenza vaccine has also shown promise1 8 '1 9 and will probably be approved for the 2000-2001 flu season. £3

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None of the antiviral agents is proven superior to the others

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