TABLE OF CONTENTS H1N1 Influenza 1-2 UIMC Executive Summary of the Management of Novel Influenza A (H1N1) Virus 3-4 Emergency Use of Peramivir Approved 5-6 P&T Committee Formulary Action 6 H1N1 Influenza The H1N1 influenza virus, also referred to as swine flu, was first detected among the human population of the United States in April 2009. Since its detection, the virus has spread rapidly from person-to-person around the globe. The World Health Organization (WHO) declared a H1N1 pandemic on June 11, 2009. The signs and symptoms of H1N1 infection are similar to traditional seasonal influenza and include fever, cough, sore throat, runny or stuffy nose, body aches, headache, chills, and fatigue. Respiratory symptoms may occur without a fever. The severity of symptoms ranges from mild to severe with the majority of infected individuals experiencing mild symptoms that do not require medical treatment. Although most individuals exposed to H1N1 have experienced mild symptoms, there have been cases of severe infection leading to hospitalization and even death. Approximately 70% of H1N1-infected hospitalized patients had 1 or more medical conditions that have been historically associated with a high risk for seasonal influenzarelated complications including pregnancy, diabetes, heart disease, asthma, and kidney disease. Of note, the H1N1 virus has been shown to produce greater disease burden in people younger than 25 years of age as compared to older (> 65 years of age) individuals. This is in contrast to traditional seasonal influenza, which disproportionately places the elderly at high risk for serious complications. Once a person has been infected with the H1N1 virus, they may spread the virus to others from 1 day prior to the onset of symptoms up to 5 to 7 days after resolution of symptoms. The duration of H1N1 transmission may be prolonged in certain patient populations such as children and people with impaired immune systems. Situation Update From August 30, 2009 through October 10, 2009, states have reported approximately 5,000 laboratory-confirmed H1N1 hospitalizations to the Centers for Disease Control and Prevention (CDC). When broken down by age, the percentage of H1N1-related hospitalizations were as follows: 19% (0 to 4 years), 25% (5 to 18 years), 9% (19 to 24 years), 24% (25 to 49 years), 15% (50 to 64 years), and 7% (65 years of age and older). With regard to deaths related to H1N1 infection, states have reported 292 laboratory-confirmed deaths to the CDC during this same time period. The majority of these deaths (65%) occurred in individuals between the ages of 25 to 64. For younger individuals, the percentages of confirmed deaths were as follows: 3% (0 to 4 years), 14% (5 to 18 years), and 7% (19 to 24 years). Twelve percent of confirmed H1N1-related deaths occurred in the elderly (> 65 years of age). In the week ending October 17, 2009, influenza activity (seasonal influenza plus H1N1) was reported to be widespread in the majority of US states with only regional activity reported in Connecticut, New Jersey, and South Carolina. Local influenza activity was reported by the District of Columbia and Hawaii. In Illinois, there have been a total of 542 confirmed H1N1 hospitalizations through October 23, 2009. In addition, 22 deaths related to H1N1 infections have been reported. The 22 deaths have occurred in 7 counties with the majority of counties reporting H1N1-related fatalities located in north-central and northeast Illinois including Cook County. A summary of the H1N1 2009 hospitalizations and deaths by age group in Illinois as of October 23, 2009 is presented in Table 1. 1
Table 1. H1N1 Hospitalizations and Deaths by Age Group in Illinois. Age range (years) Hospitalizations Deaths 0 to 4 74 1 5 to 18 163 4 19 to 24 41 2 25 to 49 117 8 50 to 64 64 4 65 + 27 3 Unknown 56 0 TOTAL 542 22 H1N1 Vaccine Information The Food and Drug Administration (FDA) has approved 4 H1N1 monovalent vaccines for prevention of infection from this novel influenza strain (see Table 2). Both live, attenuated and inactivated vaccine formulations have been approved, with each formulation being adjuvant-free and containing the strain A/California/7/2009(H1N1)pdm. These vaccines are manufactured in the same manner as the seasonal influenza vaccines; therefore, patients allergic to eggs cannot receive the H1N1 vaccination. Data from clinical trials in adults and children have shown that the most common adverse reaction is pain at the injection site. Some patients have also reported systemic symptoms such as headache, malaise, or myalgia. Children aged 6 months to 9 years should receive 2 doses of the vaccine, separated by approximately 4 weeks, and persons 10 years of age and older should receive 1 dose. If the second dose is given 21 days after the first in young children, CDC considers this dose to be valid. The live, attenuated H1N1 vaccine has the same contraindications as the live, attenuated seasonal influenza vaccine. This formulation cannot be given to children less than 2 years old, adults older than 49 years, pregnant women, persons with underlying medical conditions that confer a higher risk for influenza complications, or children < 5 years of age with one or more episodes of wheezing in the past year. Both the inactivated seasonal influenza vaccine and the inactivated H1N1 vaccine can be given simultaneous as long as different anatomic sites are used. Live, attenuated formulations of these 2 vaccines cannot be given simultaneously. Table 2. FDA Approved H1N1 Vaccines. Manufacturer Type Indication by Age CSL Limited Inactivated Persons 18 years of age and older Novartis Vaccines and Diagnostics Limited Inactivated Persons 4 years of age and older Sanofi Pasteur Inactivated Persons 6 months of age and older MedImmune Live, attenuated (nasal formulation) Persons 2 to 49 years of age The Advisory Committee on Immunization Practices (ACIP) released recommendations for use of these monovalent vaccines in late August. They identified 5 high-risk target groups that should receive the vaccination first. These 5 groups are listed in Table 3. If the supply is insufficient to meet the demand for these initial 5 high-risk groups, ACIP recommends that a subset of patients in these groups receive the vaccination first. This subset includes pregnant women, persons who live with or provide care for infants aged < 6 months, healthcare and emergency medical services personnel who have direct contact with patients or infectious material, children aged 6 months to 4 years, and children and adolescents aged 5 to 18 years who have medical conditions that put them at higher risk for influenza-like complications. Once the demand in the initial 5 target groups has been met, ACIP recommends that all persons 25 to 64 years receive the vaccination. After that, elderly patients, defined as those 65 years of age and older, should receive the vaccine. As discussed above, elderly persons are at a lower risk of complications from the H1N1 influenza. Table 3. H1N1 Vaccination Recommendations. Individuals Considered at High-risk Pregnant women Persons who live with or provide care for infants aged < 6 months Healthcare and emergency medical services personnel Children and young adults aged 6 months to 24 years Persons aged 25 to 64 years H1N1 Prevention Strategies The most important strategy to preventing H1N1 influenza is to get vaccinated. However, some patients may choose not to receive the vaccination. If this is the case, patients need to be educated on general preventative measures to help decrease the spread of the virus. The CDC has listed general measures that may help decrease the spread of H1N1 (as well as seasonal influenza). These measures include the following: Covering your nose and mouth with a tissue when you cough or sneeze. Throwing the used issue in the trash. Washing your hands often with soap and water or using an alcohol-based hand rub if soap and water are not available. Avoid touching your eyes, nose, and mouth; this will decrease the spread of germs. Staying home if you get sick. Social distancing measures, such as avoiding crowds. Following public health advice regarding school or other community closures. 2
UIMC Executive Summary of the Management of Novel Influenza A (H1N1) Virus The University of Illinois Medical Center (UIMC) has developed a policy to assist in identifying and treating individuals with H1N1 influenza and to help prevent the spread of the illness. Case Definitions Influenza-like illness (ILI): a measured temperature of 37.8 degrees Celsius (100.4 degrees Fahrenheit) and recent onset of at least 1 of the following: rhinorrhea or nasal congestion, sore throat, or cough, in the absence of a KNOWN cause other than influenza. Confirmed case H1N1 influenza: a person with an acute febrile respiratory illness with laboratory confirmed influenza A (H1N1) virus infection using real-time RT- PCR, the test currently used by UIMC. The infectious period for confirmed cases of H1N1 influenza is 1 day before symptom onset to 5-7 days after onset of illness. General Infection Control Procedures Follow droplet infection control practices when seeing patients. Wear mask, and preferably eye protection for droplet precautions. Frequent hand washing/hand hygiene with alcohol based product. Who to Test/What to Order Most patients that you see will not require influenza testing. Currently, the only patients that should be tested are those with: 1) An influenza-like illness (ILI, as defined above) and 2) Is hospitalized or recently deceased. 3) Any patient who is admitted and whose diagnosis may be related to influenza and/ or whose clinical condition deteriorates. *Certain patient populations that are not hospitalized may be tested to protect populations at higher risk for complications from influenza. Examples of such situations at this time (but are subject to change) are CLUSTERS of ILI in: 1) Healthcare workers or 2) Children attending a daycare or daycare workers or 3) Students living in a dormitory setting. To order the correct test, refer to Clinical care guideline for Influenza H1N1. Treatment and Chemoprophylaxis Treatment At this time antiviral treatment with oseltamivir or zanamavir is recommended for the following: 1. All hospitalized patients with suspected, probably or confirmed H1N1 influenza, even if symptom onset > 48 hours. 2. All hospitalized patients with severe febrile, unexplained respiratory illness (including ARDS, pneumonia or respiratory distress) pending testing for influenza. 3. Patients with mild influenza-like illness AND underlying conditions that increase the risk for more severe illness or complications due to influenza (e.g., chronic pulmonary, cardiovascular, renal, hepatic, hematological or metabolic disorders, immunosuppression, compromised respiratory function, including conditions which increase the risk for aspiration, long-term aspirin therapy, pregnancy, age > 65 years, and age < 5 years). 4. Treatment for any patient with mild influenza-like illness (ILI) should only be started if within 48 hours of symptom onset. 5. Treatment should not wait for laboratory confirmation of influenza because laboratory testing can delay treatment and because a negative rapid test for influenza does not rule out influenza. The sensitivity of rapid tests can range from 10 to 70%. At this time, antiviral treatment with oseltamivir or zanamivir can be considered, but is NOT strongly recommended for the following: 1. Patients with mild illness who do not have underlying conditions. For these individuals, antiviral treatment can be offered at the discretion of their provider. However, as above, treatment should only be started if within 48 hours of symptom onset. See Tables 4 and 5 for Dosing Recommendations Chemoprophylaxis Antiviral chemoprophylaxis (pre-exposure or post-exposure) with either oseltamivir or zanamivir is only recommended for the following individuals: 1. Household close contacts of a confirmed case who are at high-risk for complications of influenza (e.g., persons with certain chronic medical conditions, persons 65 or older, children younger than 5 years old, and pregnant women). 2. School children who are at high-risk for complications of influenza (children with certain chronic medical conditions) who have had close contact (face-to-face) with a confirmed case. 3. Caregivers of persons who are at high-risk for complications of influenza and who have had contact with confirmed case. 3
4. Health care workers or public health workers who are high-risk for complications of influenza during close contact (3 feet and prolonged face-toface) with an ill, confirmed case of H1N1 influenza infection during the infectious period. Antiviral prophylaxis is generally NOT recommended in the following settings: 1. Healthy children or adults based on potential exposures in the community, school, camp or other settings. 2. If more than 48 hours have elapsed since the last contact with an infectious person. 3. If close contact with ill person occurred before or after, but not during, the ill person s infectious period (definite as one day before, until 24 hours after, fever ends). Unique Populations Pregnant Women Treatment and prophylaxis with oseltamivir or zanamivir is recommended for pregnant women with suspected or confirmed influenza and can be taken during any trimester of pregnancy. Oseltamivir and zanamivir are Pregnancy Category C medications. However, pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. H1N1 Influenza Reporting/Surveillance The Chicago Department of Public Health (CDPH) requests reporting of the following cases/conditions: 1. Patient has died AND patient tests positive for influenza (including rapid test, RT-PCR, DFA, IFA, or culture). 2. Patient is hospitalized ( 24 hours) AND patient tests positive for influenza (including rapid test, RT- PCR, DFA, IFA, or culture). 3. Cluster of 3 or more cases of influenza of ILI associated with a hospital, long-term care facility, homeless shelter, jail, or other congregate living facility. Templates For Cerner/Powernote/Powerchart => Encounter Pathway: type influenza => Note type is: Influenza like illness For Clinical Notes: (F3 and autotext capability) 1. Search: Influenza-like Illness template under your clinic note type. 2. Under Note type : select Flu Clinic note. Influenza-like illness template is available. Discharge Forms A common discharge information sheet is to be provided to the patient. Where to Send Patients When the influx of patients exceeds capacity of clinics, there will be designated clinic areas for patients who do not have existing clinic appointments and present to be evaluated for mild influenza-like illness. Table 4. H1N1 Influenza Antiviral Medication Dosing Recommendations.* Agent, group Treatment Chemoprophylaxis Oseltamivir (TAMIFLU) Adults 75 mg capsule BID x 5 days 75 mg capsule once a day Children (age, 12 months), weight: 15 kg 30 mg BID x 5 days 30 mg once a day 15 to 23 kg 45 mg BID x 5 days 30 mg once a day 24 to 40 kg 60 mg BID x 5 days 60 mg once a day > 40 kg 75 mg BID x 5 days 75 mg once a day Zanamivir (RELENZA) Adults Two 5 mg inhalations (10 mg total) BID x 5 days Two 5 mg inhalations (10 mg total) once a day Children Two 5 mg inhalations (10 mg total) BID x 5 days (age, 7 years or older) Two 5 mg inhalations (10 mg total) once a day (age, 5 years or older) *Table extracted from IDSA guidelines for seasonal influenza. Table 5. Dosing Recommendations for Antiviral Medications for Children Younger Than 1 year. Age Treatment Chemoprophylaxis Oseltamivir (TAMIFLU) ONLY, Zanamivir (RELENZA) is not approved for use in children < 5 years of age. < 3 months 12 mg BID x 5 days Not recommended unless situation critical, due to limited data on use in this age group 3 to 5 months 20 mg BID x 5 days 20 mg once a day x 10 days 6 to 11 months 25 mg BID x 5 days 25 mg once a day x 10 days 4
Emergency Use of Peramivir Approved On October 23, the FDA issued an emergency use authorization for intravenous (IV) peramivir, a neuraminidase inhibitor, for the treatment of specific adult and pediatric patients with suspected or laboratory confirmed H1N1 infection. Peramivir is only indicated for patients who are admitted to a hospital and under the care or consultation of a licensed clinician and meet 1 or more of the following criteria: Patient is not responding to either oral or inhaled antiviral therapy (adult and pediatric criteria), Drug delivery by a route other than IV is not expected to be dependable or is not feasible (adult and pediatric criteria), and/or The clinician deems that IV therapy is appropriate because of other circumstances (adult criteria only). Peramivir can only be obtained from the CDC via the Strategic National Stockpile. Clinicians who wish to use the drug must read and understand the content of the FDA issued Emergency Use Authorization of Peramivir IV: Fact Sheet for Health Care Providers prior to initiating a request to the CDC. In addition, clinicians must acknowledge and agree to all the terms associated with use of this agent. Some of the terms include giving the patient/caregiver the fact sheet, mandatory FDA MedWatch reporting of all medication errors and adverse events within 7 days from the onset of the event, and acknowledgment that peramivir has minimal safety and efficacy data. A request for peramivir can be submitted at http://emergency.cdc.gov/ h1n1antivirals/3.asp. Dosage and Administration Patients with known or suspected renal function impairment must have their renal function assessed prior to initiating peramivir. The recommend dose for adults with normal renal function is 600 mg, given IV over 30 minutes, once daily for 5 to 10 days. Infusion rates cannot exceed 40 mg per minute. Dosage adjustments for adult patients with impaired renal function are summarized in Table 6. The recommended dose for pediatric patients is based on age, weight, and renal function (estimated using the Schwartz formula). Pediatric dosing recommendations are printed in the Emergency Use Authorization of Peramivir IV: Fact Sheet for Health Care Providers document. On November 19, 2009, the FDA updated the Peramivir IV Fact Sheet for Health Care Providers with revised dosing recommendations for end-stage renal disease (ESRD) patients. Table 6 includes the the latest updated peramivir dosing recommendation for patients with ESRD on intermittent hemodialysis (HD) and patients with creatnine clearance(crcl) less than 10 ml/min who are not on HD or continuous renal replacement therapy(crrt). For renally impaired patients on CRRT, select the dose from Table 6 using the CRRT clearance instead of the CrCl. The healthcare provider managing the CRRT should be consulted for most accurate estimate of CRRT clearance. Table 6. Dosage Recommendations for Peramivir for Adult Patients with Impaired Renal Function. Renal Impairment Mild renal impairment, CrCl 50 to 80 ml/min Moderate renal impairment, CrCl 31 to 49 ml/min Severe renal impairment, CrCl 10 to 30 ml/min ESRD, CrCl < 10 ml/min NOT on HD or CRRT ESRD on Intermittent Hemodialysis (HD) CrCl=creatinine clearance Daily Dose (IV) 600 mg 150 mg 100 mg 100mg on Day 1, followed by 15mg Daily 100mg on Day 1, then 100mg given 2hrs after each HD session on dialysis days only Efficacy and Safety Data Peramivir is an unapproved investigational product with limited efficacy and safety data. Only 4 IV trials have been completed thus far, which includes 3 trials in acute uncomplicated influenza and 1 trial in hospitalized patients with acute influenza. None of these trials have been conducted in patients with the H1N1 virus and no pediatric patients have been enrolled in any of these trials. In a Phase 2 trial conducted in Japan, patients with confirmed influenza were randomized to a single IV dose of peramivir 300 mg (n=99), peramivir 600 mg (n=97), or placebo (n=100). Patients were required to enroll within 2 days of symptom onset. Both doses of peramivir resulted in an approximately 1 day treatment benefit for alleviation of symptoms compared to placebo. In a Phase 3 trial conducted in Japan, Korea, and Taiwan, patients were randomized to a single IV dose of peramivir 300 mg (n=364) or peramivir 600 mg (n=362), or oseltamivir 75 mg twice daily for 5 days (n=365). All 3 treatments resulted in a similar time to alleviation of symptoms (median range 78.0 to 81.8 hours). Another trial in 42 patients with poorly controlled diabetes, chronic respiratory conditions, or on immunosuppressive therapy (n=37 patients included in the efficacy analysis) randomized patients to peramivir 300 mg once daily (n=18) or peramivir 600 mg once daily (n=19) for 1 to 5 days. Of the 18 patients given 300 mg, 7 received 1 dose, 9 received 2 doses, 1 received 3 doses, and 1 received 4 doses. Of the 19 patients given 600 mg, 3 received 1 dose, 14 received 2 doses, and 1 patient each received 3 and 4 doses, respectively. Preliminary results showed that time to alleviation of symptoms was shorter for the 600 mg IV group compared to the 300 mg IV group and shorter in patients given multiple doses of peramivir compared to a single dose. The trial in hospitalized patients compared peramivir 200 mg once daily (n=41), peramivir 400 mg once daily (n=40), and oseltamivir 75 mg twice daily, each given for 5 days. 5
No difference was noted between the 3 treatment groups for the primary endpoint of time to clinical stability or for various secondary endpoints such as time to resumption of usual activities or time to hospital discharge. Two intramuscular, single dose trials have also been completed in patients with acute uncomplicated influenza. No significant difference with respect to time to alleviation of symptoms was noted between peramivir 150 mg and 300 mg and placebo in the first trial or between peramivir 600 mg and placebo in the second trial. A total of 1891 adult patients have been exposed to peramivir during the clinical trials. The most common adverse events were diarrhea, nausea, vomiting, and a reduction in neutrophil count. Peramivir is contraindicated in patients with a history of serious allergic reaction to any of the other neuraminidase inhibitors or an ingredient of the IV peramivir formulation. In addition, serious allergiclike reactions and psychiatric adverse events have been reported with use of peramivir. P&T Committee Formulary Action Additions - Budesonide/Formoterol for inhalation Line extensions - Ofloxacin 0.3%, 0.25mL otic solution Deletions - Ketorolac 0.5% 0.4mL ophthalmic solution - Diltiazem SR Authors: Mike Gabay, PharmD, JD, BCPS; Maria Tanzi, PharmD; Jamie Paek, PharmD Editor: Maria Tanzi, PharmD 6