Recommendations of the Advisory Committee on Immunization Practices , 2007

Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices , 2007

Anthony E. Fiore

Recommendations for Using Antiviral Agents for Seasonal Influenza

Although annual vaccination is the primary strategy for preventing complications of influenza virus infections, antiviral medications with activity against influenza viruses can be effective for the chemoprophylaxis and treatment of influenza. Four licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir. Influenza A virus resistance to amantadine and rimantadine can emerge rapidly during treatment. Because antiviral testing results indicated high levels of resistance (367-370), neither amantadine nor rimantadine should be used for the treatment or chemoprophylaxis of influenza in the United States during the 2007-08 influenza season. Surveillance demonstrating that susceptibility to these antiviral medications has been reestablished among circulating influenza A viruses will be needed before amantadine or rimantadine can be used for the treatment or chemoprophylaxis of influenza A. Oseltamivir or zanamivir can be prescribed if antiviral treatment of influenza is indicated. Oseltamivir is approved for treatment of persons aged [greater than or equal to] 1 year, and zanamivir is approved for treating persons aged [greater than or equal to] 7 years. Oseltamivir and zanamivir can be used for chemoprophylaxis of influenza; oseltamivir is licensed for use as chemoprophylaxis in persons aged [greater than or equal to] 1 year, and zanamivir is licensed for use in persons aged [greater than or equal to] 5 years.

Antiviral Agents for Influenza

Zanamivir and oseltamivir are chemically related antiviral medications known as neuraminidase inhibitors that have activity against both influenza A and B viruses. The two medications differ in pharmacokinetics, adverse events, routes of administration, approved age groups, dosages, and costs. An overview of the indications, use, administration, and known primary adverse events of these medications is presented in the following sections. Package inserts should be consulted for additional information. Detailed information about amantadine and rimantadine is available in previous ACIP influenza recommendations (371).

Role of Laboratory Diagnosis

Appropriate treatment of patients with respiratory illness depends on both accurate and timely diagnosis. Influenza surveillance information and diagnostic testing can aid clinical judgment and help guide treatment decisions. For example, early diagnosis of influenza can reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because certain bacterial infections can produce symptoms similar to influenza, if bacterial infections are suspected, they should be considered and treated appropriately. In addition, secondary invasive bacterial infections can be a severe complication of influenza.

The accuracy of clinical diagnosis of influenza on the basis of symptoms alone is limited because symptoms from illness caused by other pathogens can overlap considerably with infuenza (26,39,40). Influenza surveillance by state and local health departments and CDC can provide information regarding the circulation of influenza viruses in the community. Surveillance also can identify the predominant circulating types, influenza A subtypes, and strains of influenza viruses.

Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing, reverse transcriptase-polymerase chain reaction (RT-PCR), and immunofluorescence assays (372). Sensitivity and specificity of any test for influenza can vary by the laboratory that performs the test, the type of test used, the type of specimen tested, the quality of the specimen, and the timing of specimen collection in relation to illness onset. Among respiratory specimens for viral isolation or rapid detection of influenza viruses, nasopharyngeal and nasal specimens have higher yields than throat swab specimens (373). As with any diagnostic test, results should be evaluated in the context of other clinical and epidemiologic information available to health-care providers. In addition, positive influenza tests have been reported up to 7 days after receipt of LAIV (374).

Commercial rapid diagnostic tests are available that can detect influenza viruses within 30 minutes (375,376). Certain tests are approved for use in any outpatient setting, whereas others must be used in a moderately complex clinical laboratory. These rapid tests differ in the types of influenza viruses they can detect and whether they can distinguish between influenza types. Different tests can detect 1) only influenza A viruses; 2) both influenza A and B viruses, but not distinguish between the two types; or 3) both influenza A and B and distinguish between the two. None of the rapid influenza diagnostic tests provides any information on influenza A subtypes.

The types of specimens acceptable for use (i.e., throat, nasopharyngeal, or nasal aspirates, swabs, or washes) also vary by test, but all perform best when collected as close to illness onset as possible. The specificity and, in particular, the sensitivity of rapid tests are lower than for viral culture and vary by test (372,375-372). Because of the lower sensitivity of the rapid tests, physicians should consider confirming negative tests with viral culture or other means because of the possibility of false-negative rapid test results, especially during periods of peak community influenza activity. Because the positive predictive value of rapid tests will be lower during periods of low influenza activity, when interpreting results of a rapid influenza test, physicians should consider the positive and negative predictive values of the test in the context of the level of influenza activity in their community (372). Package inserts and the laboratory performing the test should be consulted for more details regarding use of rapid diagnostic tests. Additional updated information concerning diagnostic testing is available at http://www.cdc.gov/flu/professionals/lab diagnosis.htm.

Despite the availability of rapid diagnostic tests, collecting clinical specimens for viral culture is critical for surveillance purposes and can be helpful in clinical management: Only culture isolates of influenza viruses can provide specific information regarding circulating strains and subtypes of influenza viruses and data on antiviral resistance. This information is needed to compare current circulating influenza strains with vaccine strains, to guide decisions regarding influenza treatment and chemoprophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor antiviral resistance and the emergence of novel influenza A subtypes that might pose a pandemic threat.

Antiviral Drug-Resistant Strains of Influenza

Adamantane resistance among circulating influenza A viruses has increased rapidly worldwide over the past several years. The proportion of influenza A viral isolates submitted from throughout the world to the World Health Organization Collaborating Center for Surveillance, Epidemiology, and Control of Influenza at CDC that were adamantane-resistant increased from 0.4% during 1994-1995 to 12.3% during 2003-2004 (378). During the 2005-06 influenza season, CDC determined that 193 (92%) of 209 influenza A (H3N2) viruses isolated from patients in 26 states demonstrated a change at amino acid 31 in the M2 gene that confers resistance to adamantanes (367,368). In addition, two (25%) of eight influenza A (H1N1) viruses tested were resistant (368). All 2005-06 influenza season isolates in these studies remained sensitive to neuraminidase inhibitors (367-369). Preliminary data from the 2006-07 influenza season indicates that resistance to adamantanes remains high among influenza A isolates, but resistance to neuraminidase inhibitors is extremely uncommon (<1% of isolates) (CDC, unpublished data, 2007). Amantadine or rimantidine should not be used for the treatment or prevention of influenza in the United States until evidence of susceptibility to these antiviral medications has been reestablished among circulating influenza A viruses.

Influenza A viral resistance to adamantanes can emerge rapidly during treatment because a single point mutation at amino acid positions 26, 27, 30, 31, or 34 of the M2 protein can confer cross resistance to both amantadine and rimantadine (379,380). Adamantane-resistant influenza A virus strains can emerge in approximately one third of patients when either amantadine or rimantadine is used for therapy (379,381,382). Resistant influenza A virus strains can replace susceptible strains within 2-3 days of starting amantadine or rimantadine therapy (383,384). Resistant influenza A viruses have been isolated from persons who live at home or in an institution in which other residents are taking or have recently taken amantadine or rimantadine as therapy (385,386). Persons who have influenza A virus infection and who are treated with either amantadine or rimantadine can shed susceptible viruses early in the course of treatment and later shed drug-resistant viruses, including after 5-7 days of therapy (381).

Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (387-394), but induction of resistance typically requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (395,3.96). Development of viral resistance to zanamivir or oseltamivir during treatment has been identified but does not appear to be frequent (3.97-401). One limited study reported that oseltamivir-resistant influenza A viruses were isolated from nine (18%) of 50 Japanese children during treatment with oseltamivir (402). Transmission of neuraminidase inhibitor-resistant influenza B viruses between humans is rare but has been documented (403). No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment isolates tested is limited (404,405). Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported (405).

Laboratory studies suggest that influenza viruses with oseltamivir resistance have diminished replication competence and infectivity. However, prolonged shedding of oseltamiviror zanamivir-resistant virus by severely immunocompromised patients, even after cessation ofoseltamivir treatment, has been reported (406-402). Tests that can detect clinical resistance to the neuraminidase inhibitor antiviral drugs are being developed (404,408), and postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted. Among 2,287 isolates obtained from multiple countries during 1999-2002, only eight (0.33%) had a greater-than-tenfold decrease in susceptibility to oseltamivir, and two (25%) of these eight also were resistant to zanamivir (409).

Indications for Use of Antivirals When Susceptibility Exists

Treatment

Initiation of antiviral treatment within 2 days of illness onset is recommended, although the benefit of treatment is greater as the time after illness onset is reduced. The benefit of antiviral treatment when initiated >2 days after illness onset is minimal for uncomplicated influenza. However, no data are available on the benefit for severe influenza when antiviral treatment is initiated >2 days after illness onset. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days.

Evidence for the effectiveness of these antiviral drugs is based primarily on studies of outpatients with uncomplicated influenza. Few data are available about the effectiveness of antiviral drug treatment for hospitalized patients with complications of influenza. When administered within 2 days of illness onset to otherwise healthy children or adults, zanamivir or oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day compared with placebo (133,410-425). Minimal or no benefit is reported when antiviral treatment is initiated >2 days after onset of uncomplicated influenza. Data on whether viral shedding is reduced are inconsistent. The duration of viral shedding was reduced in one study that employed experimental infection; however, other studies have not demonstrated reduction in the duration of viral shedding. A recent review that examined neuraminidase inhibitor effect on reducing ILI concluded that neuraminidase inhibitors were not effective in the control of seasonal influenza (426). However, lower or no efficacy using a nonspeciflc (compared with laboratory-confirmed influenza) clinical endpoint such as ILI would be expected (422).

More clinical data are available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A virus infection than for treatment of influenza B virus infection (414,428-438). Data from in vitro studies, treatment studies among mice and ferrets (43.9-445), and human clinical studies have indicated that zanamivir and oseltamivir have activity against influenza B viruses (397,404,414,419,446,447). However, an observational study among Japanese children with culture-confirmed influenza and treated with oseltamivir demonstrated that children with influenza A virus infection resolved fever and stopped shedding virus more quickly than children with influenza B, suggesting that oseltamivir is less effective for the treatment of influenza B (448).

Data are limited regarding the effectiveness of zanamivir and oseltamivir in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases), or for preventing influenza among persons at high risk for serious complications of influenza (411,412,414,415,419-431). In a study that combined data from 10 clinical trials, the risk for pneumonia among those participants with laboratory-confirmed influenza receiving oseltamivir was approximately 50% lower than among those persons receiving a placebo and 34% lower among patients at risk for complications (p<0.05 for both comparisons) (432). Although a similar significant reduction also was determined for hospital admissions among the overall group, the 50% reduction in hospitalizations reported in the small subset of high-risk participants was not statistically significant. One randomized controlled trial documented a decreased incidence of otitis media among children treated with oseltamivir (413). Another randomized controlled study conducted among influenza-infected children with asthma demonstrated significantly greater improvement in lung function and fewer asthma exacerbations among oseltamivir-treated children compared with those who received placebo but did not determine a difference in symptom duration (449). Inadequate data exist regarding the efficacy of any of the influenza antiviral drugs for use among children aged <1 year, and none are FDA-approved for use in this age group (371).

Chemoprophylaxis

Chemoprophylactic drugs are not a substitute for vaccination, although they are critical adjuncts in preventing and controlling influenza. In community studies of healthy adults, both oseltamivir and zanamivir had similar efficacy in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%) (414,433). Both antiviral agents also have prevented influenza illness among persons administered chemoprophylaxis after a household member had influenza diagnosed (efficacy: zanamivir, 72%-82%; oseltamivir, 68%-89%) (434,446,450,451). Experience with prophylactic use of these agents in institutional settings or among patients with chronic medical conditions is limited in comparison with the adamantanes, but the majority of published studies have demonstrated moderate to excellent efficacy (397,430,431,435-437). For example, a 6-week study of oseltamivir chemoprophylaxis among nursing home residents demonstrated a 92% reduction in influenza illness (452). The efficacy of antiviral agents in preventing influenza among severely immunocompromised persons is unknown. A small nonrandomized study conducted in a stem cell transplant unit suggested that osehamivir can prevent progression to pneumonia among influenza-infected patients (453).

When determining the timing and duration for administering influenza antiviral medications for chemoprophylaxis, factors related to cost, compliance, and potential adverse events should be considered. To be maximally effective as chemo prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. Currently, oseltamivir is the recommended antiviral drug for chemoprophylaxis of influenza.

Persons at High Risk Who Are Vaccinated After Influenza Activity Has Begun

Development of antibodies in adults after vaccination takes approximately 2 weeks (337,338). Therefore, when influenza vaccine is administered after influenza activity in a community has begun, chemoprophylaxis should be considered for persons at high risk during the time from vaccination until immunity has developed. Children aged <9 years who receive TIV for the first time might require as much as 6 weeks of chemoprophylaxis (i.e., chemoprophylaxis for 4 weeks after the first dose of TIV and an additional 2 weeks of chemoprophylaxis after the second dose). Persons at high risk for complications of influenza still can benefit from vaccination after community influenza activity has begun because influenza viruses might still be circulating at the time vaccine-induced immunity is achieved.

Persons Who Provide Care to Those at High Risk

To reduce the spread of virus to persons at high risk, chemoprophylaxis during peak influenza activity can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact might include employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by a strain of influenza that might not be covered by the vaccine, chemoprophylaxis can be considered for all such persons, regardless of their vaccination status.

Persons Who Have Immune Deficiencies

Chemoprophylaxis can be considered for persons at high risk who are more likely to have an inadequate antibody response to influenza vaccine. This category includes persons infected with HIV, chiefly those with advanced HIV disease. No published data are available concerning possible efficacy of chemoprophylaxis among persons with HIV infection or interactions with other drugs used to manage HIV infection. Such patients should be monitored closely if chemoprophylaxis is administered.

Other Persons

Chemoprophylaxis throughout the influenza season or during increases in influenza activity within the community might be appropriate for persons at high risk for whom vaccination is contraindicated. Chemoprophylaxis also can be offered to persons who wish to avoid influenza illness. Health-care providers and patients should make decisions regarding whether to begin chemoprophylaxis and how long to continue it on an individual basis.

Control of Influenza Outbreaks in Institutions

Use of antiviral drugs for treatment and chemoprophylaxis of influenza is a key component of influenza outbreak control in institutions. In addition to antiviral medications, other outbreak-control measures include instituting droplet precautions and establishing cohorts of patients with confirmed or suspected influenza, re-offering influenza vaccinations to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients (454-156).

The majority of published reports concerning use of antiviral agents to control influenza outbreaks in institutions are based on studies of influenza A outbreaks among persons in nursing homes who received amantadine or rimantadine (457-461). Less information is available concerning use of neuraminidase inhibitors in influenza A or B institutional outbreaks (430,431,436,452,462). When confirmed or suspected outbreaks of influenza occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. In these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice can substantially expedite administration of antiviral medications.

When outbreaks occur in institutions, chemoprophylaxis should be administered to all eligible residents, regardless of whether they received influenza vaccinations during the previous fall, and should continue for a minimum of 2 weeks. If surveillance indicates that new cases continue to occur, chemoprophylaxis should be continued until approximately 1 week after the end of the outbreak. Chemoprophylaxis also can be offered to unvaccinated staff members who provide care to persons at high risk. Chemoprophylaxis should be considered for all employees, regardless of their vaccination status, if indications exist that the outbreak is caused by a strain of influenza virus that is not well-matched by the vaccine. Such indications might include multiple documented breakthrough influenza-virus infections among vaccinated persons or circulation in the surrounding community of suspected index case(s) of strains not contained in the vaccine.

In addition to use in nursing homes, chemoprophylaxis also can be considered for controlling influenza outbreaks in other closed or semiclosed settings (e.g., dormitories, correctional facilities, or other settings in which persons live in close proximity). To limit the potential transmission of drug-resistant virus during outbreaks in institutions, whether in chronic or acute-care settings or other closed settings, measures should be taken to reduce contact between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis.

Dosage

Dosage recommendations vary by age group and medical conditions (Table 6).

Adults

Zanamivir. Zanamivir is approved for treatment of adults with uncomplicated acute illness caused by influenza A or B virus, and for chemoprophylaxis of influenza among adults. Zanamivir is not recommended for persons with underlying airways disease (e.g., asthma or chronic obstructive pulmonary diseases).

Oseltamivir. Oseltamivir is approved for treatment of adults with uncomplicated acute illness caused by influenza A or B virus and for chemoprophylaxis of influenza among adults. Dosages and schedules for adults are listed (Table 6).

Children

Zanamivir. Zanamivir is approved for treatment of influenza among children aged [greater than or equal to] 7 years. The recommended dosage of zanamivir for treatment of influenza is 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 rag) twice daily (approximately 12 hours apart). Zanamivir is approved for chemoprophylaxis of influenza among children aged [greater than or equal to] 5 years; the chemoprophylaxis dosage of zanamivir for children aged [greater than or equal to] 5 years is 10 mg (2 inhalations) once a day (405,463).

Oseltamlvir. Oseltamivir is approved for treatment and chemoprophylaxis among children aged [greater than or equal to] 1 year. Recommended treatment dosages vary by the weight of the child: 30 mg twice a day for children who weigh [less than or equal to] 15 kg, 45 mg twice a day for children who weigh > 15-23 kg, 60 mg twice a day for those who weigh >23-40 kg, and 75 mg twice a day for those who weigh >40 kg (397,463). Dosages for chemoprophylaxis are the same for each weight group, but doses are administered only once per day rather than twice.

Persons Aged [greater than or equal to] 65 Years

Zanamivir and Oseltamivir. No reduction in dosage is recommended on the basis of age alone.

Persons with Impaired Renal Function

Zanamivir. Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir, decreases in renal clearance, increases in half-life, and increased systemic exposure to zanamivir were reported (405). However, a limited number of healthy volunteers who were administered high doses of intravenous zanamivir tolerated systemic levels of zanamivir that were substantially higher than those resulting from administration of zanamivir by oral inhalation at the recommended dose (464,465). On the basis of these considerations, the manufacturer recommends no dose adjustment for inhaled zanamivir for a 5-day course of treatment for patients with either mild-to-moderate or severe impairment in renal function (405).

Oseltamivir. Serum concentrations of oseltamivir carboxylate, the active metabolite of oseltamivir, increase with declining renal function (397,466). For patients with creatinine clearance of 10-30 mL per minute (397), a reduction of the treatment dosage of oseltamivir to 75 mg once daily and in the chemoprophylaxis dosage to 75 mg every other day is recommended. No treatment or chemoprophylaxis dosing recommendations are available for patients undergoing routine renal dialysis treatment.

Persons with Liver Disease

Use of zanamivir or oseltamivir has not been studied among persons with hepatic dysfunction.

Persons with Seizure Disorders

Seizure events have been reported during postmarketing use of zanamivir and oseltamivir, although no epidemiologic studies have reported any increased risk for seizures with either zanamivir or oseltamivir use.

Route

Oseltamivir is administered orally in capsule or oral suspension form. Zanamivir is available as a dry powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Patients should be instructed about the correct use of this device.

Pharmacokinetics

Zanamivir

In studies of healthy volunteers, approximately 7%-21% of the orally inhaled zanamivir dose reached the lungs, and 70%-87% was deposited in the oropharynx (405,467). Approximately 4%-17% of the total amount of orally inhaled zanamivir is absorbed systemically. Systemically absorbed zanamivir has a half-life of 2.5-5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (405,465).

Oseltamivir

Approximately 80% of orally administered oseltamivir is absorbed systemically (466). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxylate has a half-life of 6-10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (397,468). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (468).

Adverse Events

When considering use of influenza antiviral medications (i.e., choice of antiviral drug, dosage, and duration of therapy), clinicians must consider the patient’s age, weight, and renal function (Table 6); presence of other medical conditions; indications for use (i.e., chemoprophylaxis or therapy); and the potential for interaction with other medications.

Zanamivir

Limited data are available regarding the safety or efficacy of zanamivir for persons with underlying respiratory disease or for persons with complications of acute influenza, and zanamivir is approved only for use in persons without underlying respiratory or cardiac disease (469). In a study of zanamivir treatment of ILI among persons with asthma or chronic obstructive pulmonary disease in which study medication was administered after use of a B2-agonist, 13% of patients receiving zanamivir and 14% of patients who received placebo (inhaled powdered lactose vehicle) experienced a >20% decline in forced expiratory volume in 1 second (FEV1) after treatment (405,430). However, in a phase-I study of persons with mild or moderate asthma who did not have ILI, one of 13 patients experienced bronchospasm after administration of zanamivir (405). In addition, during postmarketing surveillance, cases of respiratory function deterioration after inhalation of zanamivir have been reported. Because of the risk for serious adverse events and because the efficacy has not been demonstrated among this population, zanamivir is not recommended for treatment for patients with underlying airway disease (405). Allergic reactions, including oropharyngeal or facial edema, also have been reported during postmarketing surveillance (405,430).

In clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and for those receiving placebo (i.e., inhaled lactose vehicle alone) (410-415,430). The most common adverse events reported by both groups were diarrhea, nausea, sinusitis, nasal signs and symptoms, bronchitis, cough, headache, dizziness, and ear, nose, and throat infections. Each of these symptoms was reported by <5% of persons in the clinical treatment studies combined (405). Zanamivir does not impair the immunologic response to TIV (470).

Oseltamivir

Nausea and vomiting were reported more frequently among adults receiving oseltamivir for treatment (nausea without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without vomiting, approximately 6%; vomiting, approximately 3%) (397, 416, 417, 471). Among children treated with oseltamivir, 14% had vomiting, compared with 8.5% of placebo recipients. Overall, 1% discontinued the drug secondary to this side effect (419), whereas a limited number of adults who were enrolled in clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (397). Similar types and rates of adverse events were reported in studies of oseltamivir chemoprophylaxis (397). Nausea and vomiting might be less severe if oseltamivir is taken with food (397). No published studies have assessed whether oseltamivir impairs the immunologic response to TIV.

Transient neuropsychiatric events (self-injury or delirium) have been reported postmarketing among persons taking oseltamivir; the majority of reports were among adolescents and adults living in Japan (472). FDA advises that persons receiving oseltamivir be monitored closely for abnormal behavior (397).

Use During Pregnancy

Oseltamivir and zanamivir are both “Pregnancy Category C” medications, indicating that no clinical studies have been conducted to assess the safety of these medications for pregnant women. Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these two drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus; the manufacturers’ package inserts should be consulted (397,405). However, no adverse effects have been reported among women who received oseltamivir or zanamivir during pregnancy or among infants born to such women.

Drug Interactions

Clinical data are limited regarding drug interactions with zanamivir. However, no known drug interactions have been reported, and no clinically critical drug interactions have been predicted on the basis of in vitro and animal study data (397,405,473).

Limited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and oseltamivir carboxylate are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and probenecid resulted in reduced clearance of oseltamivir carboxylate by approximately 50% and a corresponding approximate twofold increase in the plasma levels of oseltamivir carboxylate (468).

No published data are available concerning the safety or efficacy of using combinations of any of these influenza antiviral drugs. Package inserts should be consulted for more detailed information about potential drug interactions.

Sources of Information Regarding Influenza and Its Surveillance

Information regarding influenza surveillance, prevention, detection, and control is available at http://www.cdc.gov/ flu. During October-May, surveillance information is updated weekly. In addition, periodic updates regarding influenza are published in the MMWR Weekly Report (http://www.cdc.gov/mmwr). Additional information regarding influenza vaccine can be obtained by calling 1-800-CDCINFO (1-800-232-4636). State and local health departments should be consulted concerning availability of influenza vaccine, access to vaccination programs, information related to state or local influenza activity, reporting of influenza outbreaks and influenza-related pediatric deaths, and advice concerning outbreak control.

Responding to Adverse Events After Vaccination

Health-care professionals should report all clinically significant adverse events after influenza vaccination promptly to VAERS, even if the health-care professional is not certain that the vaccine caused the event. Clinically significant adverse events that follow vaccination should be reported at http:/! www.vaers.hhs.gov. Reports may be filed securely online or by telephone at 1-800-822-7967 to request reporting forms or other assistance.

The National Vaccine Injury Compensation Program (VICP), established by the National Childhood Vaccine Injury Act of 1986, as amended, provides a mechanism through which compensation can be paid on behalf of a person determined to have been injured or to have died as a result of receiving a vaccine covered by VICP. The Vaccine Injury Table lists the vaccines covered by VICP and the injuries and conditions (including death) for which compensation might be paid. If the injury or condition is not on the Table, or does not occur within the specified time period on the Table, persons must prove that the vaccine caused the injury or condition.

For a person to be eligible for compensation, the general filing deadlines for injuries require claims to be filed within 3 years after the first symptom of the vaccine injury; for a death, claims must be filed within 2 years of the vaccine-related death and not more than 4 years after the start of the first symptom of the vaccine-related injury from which the death occurred. When a new vaccine is covered by VICP or when a new injury/condition is added to the Table, claims that do not meet the general filing deadlines must be filed within 2 years from the date the vaccine or injury/condition is added to the Table for injuries or deaths that occurred up to 8 years before the Table change. Persons of all ages who receive a VICP-covered vaccine might be eligible to file a claim. Both the intranasal (LMV) and injectable (TIV) trivalent influenza vaccines are covered under VICE Additional information about VICP is available at http//www.hrsa.gov/vaccinecompensation or by calling 1-800-338-2382.

Reporting of Serious Adverse Events After Antiviral Medications

Severe adverse events associated with the administration of antiviral medications used to prevent or treat influenza (e.g., those resulting in hospitalization or death) should be reported to MedWatch, FDA’s Safety Information and Adverse Event Reporting Program, at telephone 1-800-FDA-1088, by facsimile at 1-800-FDA-O178, or via the Internet by sending Report Form 3500 (available at http://www.fda.gov/med watch/safety/3500.pdf). Instructions regarding the types of adverse events that should be reported are included on MedWatch report forms.

Additional Information Regarding Influenza Virus Infection Control Among Specific Populations

Each year, ACIP provides general, annually updated information regarding control and prevention of influenza. Other reports related to controlling and preventing influenza among specific populations (e.g., immunocompromised persons, HCP, hospital patients, pregnant women, children, and travelers) also are available in the following publications:

* CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR 2006;55(No. RR-15).

* CDC. Influenza vaccination of health-care personnel: recommendations of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(No. RR-2).

* CDC. Recommended immunization schedules for persons aged 0-18 years–United States, 2007. MMWR 2007;55:Q1-4.

* CDC. Recommended adult immunization schedule-United States, October 2006-September 2007. MMWR 2006;55:Q1-4.

* CDC. Guidelines for preventing health-care-associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR 2003;53(No. RR-3).

* CDC. Respiratory hygiene/cough etiquette in health-care settings. Atlanta, GA: US Department of Health and Human Services, CDC; 2003. Available at http://www.cdc. govlflulprofessionalslinfectioncontrollresphygiene.htm.

* CDC. Prevention and control of vaccine-preventable diseases in long-term care facilities. Atlanta, GA: US Department of Health and Human Services, CDC; 2006. Available at http://www.cdc.gov/flu/professionals/infection control/longtermcare.htm.

* Sneller V-P, Izurieta H, Bridges C, et al. Prevention and control of vaccine-preventable diseases in long-term care facilities. Journal of the American Medical Directors Association 2000; 1 (Suppl):S2-37.

* American College of Obstetricians and Gynecologists. Influenza vaccination and treatment during pregnancy. ACOG committee opinion no. 305. Obstet Gynecol 2004; 104:1125-6.

* American Academy of Pediatrics. 2006 red book: report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

* Bodnar UR, Maloney SA, Fielding KL, et al. Preliminary guidelines for the prevention and control of influenzalike illness among passengers and crew members on cruise ships. Atlanta, GA: US Department of Health and Human Services, CDC; 1999. Available at http://www. cdc.gov/travel/CDCguideflufnl.PDE

* CDC. General recommendations for preventing influenza A infection among travelers. Atlanta, GA: US Department of Health and Human Services, CDC; 2003. Available at http://www2.ncid.cdc.gov/travel/yb/utilsl ybGet.asp?section=dis&obj=influenza.htm.

* US Public Health Service and the Infectious Diseases Society of America. Guidelines for the prevention of opportunistic infections among HIV-infected persons-2002: recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Washington, DC: US Department of Health and Human Services; 2002. Available at http://aidsinfo.nih. gov/contentfiles/OIpreventionGL.pdf.

* CDC. Infection control guidance for the prevention and control of influenza in acute-care facilities. Atlanta, GA: US Department of Health and Human Services, CDC; 2007. Available at http://www.cdc.gov/flu/professionals/ infectioncontrol/health-carefacilities.htm.

* Food and Drug Administration. FDA Pandemic influenza preparedness strategic plan. Washington, DC: Food and Drug Administration; 2007. Available at http://www. fda.gov/oc/op/pandemic/strategicplan03_07.html.

* World Health Organization. Recommendations for influenza vaccines. Geneva, Switzerland: World Health Organization; 2007. Available at http:llwww.who.intlcsrldiseaselinfluenza/ vaccinerecommendationslenlindex.html.

The material in this report originated in the National Center for Immunization and Respiratory Diseases, Anne Schuchat, MD, Director; the Influenza Division, Nancy Cox, PhD, Director; and the Immunization Services Division, Lance Rodewald, MD, Director. Corresponding preparer. Anthony Fiore, MD, Influenza Division, National Center for Immunization and Respiratory Diseases, CDC, 1600 Clifton Road, NE, MS A-20, Atlanta, GA 30333. Telephone: 404-639-2552; Fax: 404-639-2334; E-mail: afiore@cdc.gov.

Acknowledgments

Assistance in the preparation of this report was provided by Carolyn Bridges, MD, Lenee Blanton, MPH, Scott Epperson, MPH, Larisa Gubareva, MD, PhD, Influenza Division; Jeanne Santoli, MD, Gary L. Euler, DrPH, Peng-jun Lu, PhD, Abigail Shefer, Immunization Services Division; Beth Bell, MD, Office of the Director, National Center for Immunization and Respiratory Diseases, CDC.

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(464.) Calfee DP, Peng AW, Cass LM, et al. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimicrob Agents Chemother 1999;43:1616-20.

(465.) Cass LM, Efthymiopoulos C, Bye A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet 1999;36(Suppl 1):1-11.

(466.) Bardsley-Elliot A, Noble S. Oseltamivir. Drugs 1999;58:851-62.

(467.) Cass LM, Brown J, Pickford M, et al. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clin Pharmacokinet 1999;36(Suppl 1):21-31.

(468.) He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 1999;37:471-84.

(469.) Food and Drug Administration. Subject: safe and appropriate use of influenza drugs [Public Health Advisory]. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration; 2000.

(470.) Webster A, Boyce M, Edmundson S, et al. 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):51-8.

(471.) 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. JAMA 1999;282:1240-6.

(472.) New concerns about oseltamivir [Editorial]. Lancet 2007;369:1056.

(473.) Daniel MJ, Barnett JM, Pearson BA. The low potential for drug interactions with zanamivir. Clin Pharmacokinet 1999;36(Suppl 1):41-50.

* A list of members appears on the inside back cover of this report.

Prepared by

Anthony E. Fiore, MD (1)

David K. Shay, MD (1)

Penina Haber, MPH (3)

John K. Iskander, MD (3)

Timothy M. Uyeki, MD (1)

Gina Mootrey, DO (2)

Joseph S. Bresee, MD (1)

Nancy J. Cox, PhD (1)

(1)Influenza Division, National Center for Immunization and Respiratory Diseases

(2)Immunization Services Division, National Center for Immunization and Respiratory Diseases

(3) Immunization Safety Office, Office of the Director

TABLE 1. Month of peak influenza activity * during

31 influenza seasons–United States, 1976-2006

Month

Nov Dec Jan Feb

No. (%) of years 1 (3) 4 (13) 6 (19) 14 (45)

with peak

influenza

activity

Month

Mar Apr May

No. (%) of years 4 (13) 1 (3) 1 (3)

with peak

influenza

activity

* The peak month of activity was defined as the month with the

greatest percentage of respiratory specimens testing positive

for influenza virus. Laboratory data were provided by the U.S.

World Health Organization Collaborating Laboratory (CDC,

National Center for Immunization and Respiratory Diseases,

unpublished data, 1976-2006).

TABLE 2. Estimated rates of influenza-associated

hospitalization, by age group and risk group for

selected studies–United States

Study years Population Age group

1973-1993 * Tennessee 0-11 mos

([dagger]) Medicaid 1-2 yrs

3-4 yrs

5-14 yrs

1992-1997 Two health 0-23 mos

([section]) maintenance 2-4 yrs

([paragraph]) organizations 5-17 yrs

1968-1969 Health 15-44 yrs

maintenance

organizations

1970-1971 45-64 yrs

1972-1973 ** [greater than

([dagger][dagger]) or equal to]

65 yrs

1969-1995 Discharge <65 yrs

([dagger][dagger]) Data

([section][section])

1969-1995 [greater than

([dagger][dagger]) or equal to]

([section][section]) 65 yrs

1979-2001 National All ages

([dagger][dagger] Hospital

[dagger]) Discharge

Data

1996-2000 Three health 18-49 yrs

([paragraph][paragraph] maintenance 50-64 yrs

[paragraph]) organizations [greater than

or equal to]

65 yrs

2000-2001 **** Two counties <1 yr

([dagger][dagger] 1 yr

[dagger][dagger]) 2-<5 yrs

2001-2004 ([dagger] Large [less than

[dagger][dagger] children’s or equal to] [dagger]) ([section] hospital 6 mos

[section][section] 6-11 mos

[section]) ([paragraph] 1-<2 yrs

[paragraph][paragraph] 2-<3 yrs

[paragraph][paragraph])

2000-2004 ([dagger] Three [less than

[dagger][dagger] counties or equal to] [dagger]) ([paragraph] 6 mos

[paragraph][paragraph] 6-23 mos

[paragraph][paragraph]) 24-59 mos

2003-2004 ([dagger] 9 states [less than

[dagger][dagger] or equal to] [dagger]) ***** 6 mos

1994-2000 ([dagger] Health 6-23 mos

[dagger][dagger] maintenance 2-4 yrs

[dagger][dagger]) organization

2000-2004 ([dagger] Large 0-23 mos

[dagger][dagger] children’s 2-4 yrs

[dagger]) ([section] hospital 5-11 yrs

[section][section] 12-17 yrs

[section][section])

Hospitalizations/ Hospitalizations/

100,000 persons 100,000 persons

with high-risk without high-risk

Study years conditions conditions

1973-1993 * 1,900 496-1,038

([dagger]) 800 186

320 86

92 41

1992-1997 144-187

([section]) 0-25

([paragraph]) 5-12

1968-1969 56-110 23-25

1970-1971 392-635 13-23

1972-1973 ** 399-518 —

([dagger][dagger])

1969-1995 — 20-42 ([paragraph]

([dagger][dagger]) [paragraph]) ***

([section][section])

1969-1995 — 125-228 ***

([dagger][dagger])

([section][section])

1979-2001 — 88 ([section]

([dagger][dagger] [section] [dagger]) [section])

1996-2000 40 5

([paragraph][paragraph] 123 18

[paragraph]) 556 187

2000-2001 **** — 170

([dagger][dagger] 50

[dagger][dagger]) 20

2001-2004 ([dagger] 253

[dagger][dagger] 113

[dagger]) ([section] 96

[section][section] 36

[section]) ([paragraph] [paragraph][paragraph] [paragraph][paragraph])

2000-2004 ([dagger] 240

[dagger][dagger] 60

[dagger]) ([paragraph] 20

[paragraph][paragraph] [paragraph][paragraph])

2003-2004 ([dagger] 311 118

[dagger][dagger] [dagger]) *****

1994-2000 ([dagger] 213 51

[dagger][dagger] 142 32

[dagger][dagger])

2000-2004 ([dagger] 416

[dagger][dagger] 70

[dagger]) ([section] 19

[section][section] 18

[section][section])

* Sources: Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR.

Effect of influenza on hospitalizations, outpatient visits, and courses

of antibiotics in children. N Engl J Med 2000;342:225-31. Neuzil KM,

Wright PF, Mitchel EF Jr, Griffin MR. Burden of influenza illness in

children with asthma and other chronic medical conditions. J Pediatr

2000;137:856-64.

([dagger]) Outcomes were for acute cardiac or pulmonary conditions.

The low estimate is for infants aged 6-11 months, and the high estimate

is for infants aged 0-5 months.

([section]) Source: Izurieta HA, Thompson WW, Kramarz P, Mitchel EF Jr,

Griffin MR. Influenza and the rates of hospitalization for respiratory

disease among infants and young children. N Engl J Med 2000;342:232-9.

([paragraph]) Outcomes were for acute pulmonary conditions.

Influenza-attributable hospitalization rates for children at high risk

were not included in this study.

** Source: Barker WH, Mullooly JP. Impact of epidemic type A influenza

in a defined adult population. Am J Epidemiol 1980;112:798-811.

([dagger][dagger]) Outcomes were limited to hospitalizations in

which either pneumonia or influenza was listed as the first condition

on discharge records or included anywhere in the list of discharge

diagnoses.

([section][section]) Source: Simonsen L, Fukuda K, Schonberger LB,

Cox NJ. Impact of influenza epidemics on hospitalizations. J Infect

Dis 2000;181:831-7.

([paragraph][paragraph]) Persons at high risk and not at high risk

for influenza-related complications are combined.

*** The low estimate is the average during influenza A (H1 N1) or

influenza B-predominate seasons, and the high estimate is the average

during influenza A (H3N2)-predominate seasons.

([dagger][dagger][dagger]) Source: Thompson WW, Shay DK, Weintraub

E, et al. Influenza-associated hospitalizations in the United States.

JAMA 2004;292:1333-40.

([section][section][section]) Outcomes were for rate of primary

respiratory and circulatory hospitalizations. Rate for all ages of

persons, both with and without high-risk conditions.

([paragraph][paragraph][paragraph]) Source: Mullooly JP, Bridges

CB, Thompson WW, et al. Influenza- and RSV-associated hospitalizations

among adults. Vaccine 2006;25:846-55.

**** Source: Iwane MK, Edwards KM, Szilagyi PG, et al.

Population-based surveillance for hospitalizations associated with

respiratory syncytial viirus, influenza virus, and parainfluenza

viruses among young children. Pediatrics 2006;113:1758-64.

([dagger][dagger][dagger][dagger]) Laboratory-confirmed

influenza virus infection.

([section][section][section][section]) Source: Ampofo K,

Gesteland PH, Bender J, et al. Epidemiology, complications, and cost

of hospitalization in children with laboratory-confirmed influenza

infection. Pediatrics 2006;118:2409-17.

([paragraph][paragraph][paragraph][paragraph]) Source: Poehling

KA, Edwards KM, Weinberg GA, et al. The underrecognized burden of

influenza in young children. N Engl J Med 2006;355:31-40.

***** Source: Schrag SJ, Shay DK, Gershman K, et al. Multistate

surveillance for laboratory-confirmed, influenza-associated

hospitalizations in children, 2003-2004. Pediatr Infect Dis J

2006;25:395-400.

([dagger][dagger][dagger][dagger][dagger]) Source: O’Brien MA,

Uyeki TM, Shay DK, et al. Incidence of outpatient visits and

hospitalizations related to influenza in infants and young children.

Pediatrics 2004;113:585-93.

([section][section][section][section][section]) Source: Coffin

SE, Zaoutis TE, Rosenquist AB, et al. Incidence, complications, and

risk factors for prolonged stay in children hospitalized with

community-acquired influenza. Pediatrics 2007;119:740-8.

TABLE 3. Live, attenuated influenza vaccine (LAIV) compared with

inactivated influenza vaccine (TIV)

Factor LAIV TIV

Route of Intranasal spray Intramuscular

administration injection

Type of vaccine Live virus Killed virus

No. of included 3 (2 influenza A, 3 (2 influenza A,

virus strains 1 influenza B) 1 influenza B)

Vaccine virus Annually Annually

strains updated

Frequency of Annually * Annually *

administration

Approved age and Healthy persons Persons aged

risk groups aged 5-49 yrs [greater than

([section]) or equal to]-6 mos

Interval between 2 6-10 weeks 4 weeks

doses recommended

for children aged

[greater than or

equal to]-6 mos-8

years who are

receiving influenza

vaccine for the

first time

Can be administered to Yes Yes

family members or close

contacts of

immunosuppressed

persons not requiring

a protected environment

Can be administered to No Yes

family members or close

contacts of

immunosuppressed persons

requiring a protected

environment (e.g.,

hematopoietic stem cell

transplant recipient)

Can be administered to Yes Yes

family members or close

contacts of persons at

high risk but not

severely

immunosuppressed

Can be simultaneously Yes ([paragraph]) Yes **

administered with

other vaccines

If not simultaneously Prudent to space Yes

administered, can be 4 weeks apart

administered within

4 wks of another

live vaccine

If not simultaneously Yes Yes

administered, can be

administered within

4 wks of an

inactivated vaccine

* Children aged [greater than or equal to] 6 months who have never

received influenza vaccine before should receive 2 doses. Those who

received only 1 dose in their first year of vaccination should receive

2 doses in the following year.

([dagger]) LAIV is currently licensed to be administered only to

persons aged ([greater than or equal to]) 5 years.

([section]) Annual vaccination against influenza is recommended for 1)

all persons, including school-aged children, who want to reduce the

risk of becoming ill with influenza or of transmitting influenza to

others; 2) all children aged 6-59 months (i.e., 6 months-4 years); all

persons aged [greater than or equal to] 50 years; 3) children and

adolescents (aged 6 months-18 years) receiving long-term aspirin

therapy who therefore might be at risk for experiencing Reye syndrome

after influenza virus infection; 4) women who will be pregnant during

the influenza season; 5) adults and children who have chronic pulmonary

(including asthma), cardiovascular (except hypertension), renal,

hepatic, hematologic or metabolic disorders (including diabetes

mellitus); 6) adults and children who have immunosuppression

(including immunosuppression caused by medications or by human

immunodeficiency virus ); 7) adults and children who have any

condition (e.g., cognitive dysfunction, spinal cord injuries, seizure

disorders, or other neuromuscular disorders) that can compromise

respiratory function or the handling of respiratory secretions or that

can increase the risk for aspiration; 8) residents of nursing homes

and other chronic-care facilities; 9) health-care workers; 10) healthy

household contacts (including children) and caregivers of children

aged 50 years, with particular focus on

vaccinating contacts of children aged <6 months; and 11) healthy

household contacts (including children) and caregivers of persons with

medical conditions that put them at higher risk for severe

complications from influenza. However, no vaccine is approved for

children aged <6 months.

([paragraph]) No data are available regarding effect on safety or

efficacy.

** Inactivated influenza vaccine coadministration has been evaluated

systematically only among adults with pneumococcal polysaccharide

vaccine.

TABLE 4. Approved influenza vaccines for different

age groups–United States, 2007-08 season

Trade

Vaccine name Manufacturer

TIV * Fluzone[R] Sanofi Pasteur

TIV * Fluvirin [TM] Novartis Vaccine

TIV * Fluarix [TM] GlaxoSmithKline

TIV * FIuLuval [TM] GlaxoSmithKline

LAIV FluMist [TM] ** Medlmmune

([paragraph])

Thimerosal

mercury

content

(mcg Hg/

Vaccine Presentation 0.5 mL dose)

TIV * 0.25-mL prefilled syringe 0

0.5-mL prefilled syringe 0

0.5 mL vial 0

5.0-mL multidose vial 25

TIV * 5.0-mL multidose vial 24.5

TIV * 0.5-mL prefilled syringe <1.0

TIV * 5.0-mL multidose vial 25

LAIV 0.2-mL sprayer 0

([paragraph])

Vaccine Age group No. of doses

TIV * 6-35 mos 1 or 2 ([dagger])

[greater than or 1 or 2 ([dagger])

equal to] 36 mos

[greater than or 1 or 2 ([dagger])

equal to] 36 mos

[greater than or 1 or 2 ([dagger])

equal to] 6 mos

TIV * [greater than or 1 or 2 ([dagger])

equal to] 4 yrs

TIV * [greater than or 1

equal to] 18 yrs

TIV * [greater than or 1

equal to] 18 yrs

LAIV 5-49 yrs 1 or 2 ([double

([paragraph]) dagger])

Vaccine Route

TIV * Intramuscular ([section])

Intramuscular ([section])

Intramuscular ([section])

Intramuscular ([section])

TIV * Intramuscular ([section])

TIV * Intramuscular ([section])

TIV * Intramuscular ([section])

LAIV Intranasal

([paragraph])

* Trivalent inactivated vaccine (TIV). A 0.5-mL dose contains 15 mcg

each of A/Solomon Islands/3/2006 (H1 N1)-like, A/Wisconsin/67/2005

(H3N2)-like, and B/Malaysia/2506/2004-like antigens.

([dagger]) Two doses administered at least 1 month apart are

recommended for children aged 6 months-8 years who are receiving TIV

for the first time and those who only received 1 dose in their first

year of vaccination should receive 2 doses in the following year.

([section]) For adults and older children, the recommended site of

vaccination is the deltoid muscle. The preferred site for infants and

young children is the anterolateral aspect of the thigh.

([paragraph]) Live attenuated influenza vaccine (LAIV).

** FluMist dosage and storage requirements have changed for the 2007-08

influenza season. FIuMist is now shipped to end users at

35[degrees]F-46[degrees]F (2[degrees]C-8[degrees]C). LAIV should be

stored at 35[degrees]F-46[degrees]F (2[degrees]C-8[degrees]C) upon

receipt and should remain at that temperature until the expiration date

is reached. The dose is 0.2 mL, divided equally between each nostril.

([double dagger]) Two doses administered at least 6 weeks apart are

recommended for children aged 5-8 years who are receiving LAIV for

the first time, and those who received only 1 dose in their first year

of vaccination should receive 2 doses in the following year.

TABLE 5. Influenza vaccination * coverage levels among population

groups–National Health Interview Survey (NHIS) and National

Immunization Survey (NIS), United States, 2005

Crude Influenza

sample vaccination level

size

Population group ([dagger]) % (95% CI ([section]))

Persons with an

age indication

Aged 6-23 mos

(NIS ([parallel])) 12,056 33.4 (32.0-34.8)

Aged 50-64 yrs 7,241 22.9 (21.9-24.0)

Aged >65 yrs 5,944 59.6 (58.0-61.0)

Persons with high-risk

conditions **

Aged 2-17 yrs 985 28.4 (25.3-31.8)

Aged 18-49 yrs 2,576 18.0 (16.3-19.7)

Aged 50-64 yrs 2,350 34.2 (32.0-36.4)

Aged 18-64 yrs 4,926 25.3 (24.0-26.7)

Persons without high-risk

conditions ([paragraph])

Aged 2-17 yrs 8,631 12.6 (11.7-13.6)

Aged 18-49 yrs 14,970 9.5 (8.9-10.0)

Aged 50-64 yrs 4,880 17.8 (16.6-19.1)

Pregnant women

([dagger][dagger]) 304 15.6 (11.2-21.2)

Health-care personnel

(HCP)

([section][section]) 2,135 33.5 (31.5-35.7)

Household contacts

of persons at high

risk, including

children aged

< 2 years

([paragraph][paragraph])

Aged 2-17 yrs 2,150 16.6 (14.7-18.7)

Aged 18-49 yrs 2,331 8.9 (7.7-10.3)

* Answered yes to this question, “During the past 12 months, have

you had a flu shot (flu spray),” during a face-to-face interview

conducted any day during 2005.

([dagger]) Population sizes by subgroups are listed at

http://www.cdc.gov/flu/professionals/vaccination/pdf

/targetpopchart.pdf.

([section]) Confidence interval.

([paragraph]) NIS uses provider-verified vaccination status to

improve the accuracy of the estimate.

** Adults categorized as being at high risk for

influenza-related complications self-reported one or more of the

following: 1) ever being told by a physician they had diabetes,

emphysema, coronary heart disease, angina, heart attack, or other

heart condition; 2) having a diagnosis of cancer during the

previous 12 months (excluding nonmelanoma skin cancer) or ever

being told by a physician they have lymphoma, leukemia, or blood

cancer during the previous 12 months; 3) being told by a physician

they have chronic bronchitis or weak or failing kidneys; or

4) reporting an asthma episode or attack during the preceding

12 months. For children aged <18 years, high-risk conditions

included ever having been told by a physician of having diabetes,

cystic fibrosis, sickle cell anemia, congenital heart disease,

other heart disease, or neuromuscular conditions (seizures,

cerebral palsy, and muscular dystrophy), or having an asthma

episode or attack during the preceding 12 months.

([dagger][dagger]) Aged 18-44 years, pregnant at the time of

the survey, and without high-risk conditions.

([section][section]) Adults were classified as HCP if they

were currently employed in a health-care occupation or in a

health-care-industry setting, on the basis of recoded broad

groups of standard occupation and industry categories.

([paragraph][paragraph]) Interviewed adult or sample child in

each household containing at least one of the following: a child

aged 65 years, or any person aged 5-17

years at high risk (see previous ** footnote). To obtain information

on household composition and high-risk status of household members,

the sampled adult, child, and person files from NHIS were merged.

Interviewed adults who were HCP or who had high-risk conditions

and sample children with high-risk conditions were excluded.

Information could not be assessed regarding high-risk status of

other adults aged 18-64 years or children aged 2-17 years in

the household; thus, certain persons aged 2-64 years who lived

with a person aged 2-64 years at high risk were not included

in the analysis.

TABLE 6. Recommended daily dosage of influenza antiviral medications

for treatment and chemoprophylaxis–United States Age group (yrs)

Age group (yrs)

Antiviral agent 1-6 7-9 10-12

Zanamivir *

Treatment, NA 10 mg 10 mg

influenza ([dagger]) (2 (2

A and B inhalations) inhalations)

twice daily twice daily

1-4 5-9

Chemoprophylaxis, NA 10 mg 10 mg

influenza (2 (2

A and B inhalations) inhalations)

once daily once daily

Oseltamivir

Treatment, Dose varies by Dose varies by Dose varies

([section]) child’s weight child’s weight by child’s

influenza ([paragraph]) ([paragraph]) weight

A and B ([paragraph])

Chemoprophylaxis, Dose varies by Dose varies by Dose varies

influenza child’s child’s by child’s

A and B weight ** weight ** weight **

Age group (yrs)

([greater

than or

equal to]

Antiviral agent 13-64 65

Zanamivir *

Treatment, 10 mg 10 mg

influenza (2 (2

A and B inhalations) inhalations)

twice daily twice daily

Chemoprophylaxis, 10 mg 10 mg

influenza (2 (2

A and B inhalations) inhalations)

once daily once daily

Oseltamivir

Treatment, 75 mg 75 mg

([section]) twice daily twice daily

influenza

A and B

Chemoprophylaxis, 75 mg/day 75 mg/day

influenza

A and B

NOTE: Zanamivir is manufactured by GlaxoSmithKline

(Relenza[R]–inhaled powder). Zanamivir is approved

for treatment of persons aged [greater than or equal

to] 7 years and approved for chemoprophylaxis of persons

aged [greater than or equal to] 5 years. Oseltamivir is

manufactured by Roche Pharmaceuticals (Tamiflu[R]-tablet).

Oseltamivir is approved for treatment or chemoprophylaxis

of persons aged >1 year. No antiviral medications are

approved for treatment or chemoprophylaxis of influenza

among children aged <1 year. This information is based

on data published by the Food and Drug Administration

(available at http://www.fda.gov).

* Zanamivir is administered through oral inhalation by

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

recommended for those persons with underlying airway disease.

([dagger]) Not applicable.

([section]) A reduction in the dose of oseltamivir

is recommended for persons with creatinine clearance

<30 mL/min.

([paragraph]) The treatment dosing recommendation for

children weighing <15 kg is 30 mg twice a day; for children

weighing >15-23 kg, the dose is 45 mg twice a day; for

children weighing >23-40 kg, the dose is 60 mg twice a day;

and for children weighing >40 kg, the dose is 75 mg twice

a day.

** The chemoprophylaxis dosing recommendation for children

weighing <15 kg is 30 mg once a day; for children weighing

>15-23 kg, the dose is 45 mg once a day; for children

weighing >23-40 kg, the dose is 60 mg once a day; and for

children weighing >40 kg, the dose is 75 mg once a day.

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