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Treatment and Prevention of Influenza with Antiviral Medications - Adult/Pediatric - Inpatient

Treatment and Prevention of Influenza with Antiviral Medications - Adult/Pediatric - Inpatient - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Infection and Isolation


1
Treatment and Prevention of Influenza
with Antiviral Medications –
Adult/Pediatric – Inpatient
Clinical Practice Guideline
Note: Active Table of Contents – Click to follow link
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ...................................................................................................................................... 3
METHODOLOGY ...................................................................................................................... 3
DEFINITIONS ............................................................................................................................ 4
RECOMMENDATIONS .............................................................................................................. 5
TABLE 1. ADULT DOSING OF ENTERAL AND INHALATION ANTIVIRAL MEDICATIONS
USED TO TREAT AND PREVENT INFLUENZA ....................................................................... 8
TABLE 2. PEDIATRIC DOSING OF ENTERAL AND INHALATIONAL ANTIVIRAL
MEDICATIONS USED TO TREAT AND PREVENT INFLUENZA ............................................. 9
TABLE 3. WEIGHT-BASED OSELTAMIVIR DOSING FOR PEDIATRIC PATIENTS AGED 1
TO 12 YEARS...........................................................................................................................10
UW HEALTH IMPLEMENTATION ............................................................................................11
APPENDIX A. EVIDENCE GRADING SCHEME ......................................................................12
REFERENCES .........................................................................................................................13
Contact for Content or Changes:
Name: Philip Trapskin, PharmD, BCPS
Phone Number: 608-265-0341
Email Address: PTrapskin@uwhealth.org
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2
Guideline Authors:
Lucas Schulz, PharmD, BCPS, AQ-ID
Joshua Vanderloo, PharmD, Drug Policy Program

Coordinating Team Members: Joshua Vanderloo, PharmD, Drug Policy Program

Review Individuals/Bodies:
Barry Fox, MD, Sheryl Henderson, MD, James Conway, MD; Jeff Fish, PharmD, BCPS

Committee Approvals/Dates:
Antimicrobial Use Subcommittee September 2016
Pharmacy & Therapeutics (P&T) Committee (Last Periodic Review: September 2016)

Release Date: September 2016

Next Review Date: September 2018

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Executive Summary
Guideline Overview
This clinical practice guideline is intended to assist clinicians in the decision to treat or prevent
influenza with antiviral medications. This guideline is compiled from literature review of current
evidence and existing external clinical practice guidelines related to antiviral treatment of
influenza.

Key Practice Recommendations
1. Evaluation of influenza prophylaxis and treatment indications.
2. Dosing, duration, and potential adjustments of oseltamivir for prophylaxis and treatment.

Companion Documents
1. Influenza and Pneumococcal Vaccination ± Adult/Pediatric ± Inpatient/Ambulatory Clinical
Practice Guideline
2. Renal Function-Based Dose Adjustments ± Adult ± Inpatient Clinical Practice Guideline

Scope
Disease/Condition: Patients with suspected or diagnosed influenza

Clinical Specialty: All specialities

Intended Users: Prescribers (physicians, nurse practitioners, physician assistants) and
pharmacists

Objective(s): To provide information and guidance in the evaluation, diagnosis, and treatment
of suspected or diagnosed influenza.

Target Population: Adult and pediatric patients at risk for or diagnosed with influenza.

Major Outcomes Considered:
ξ Use of antivirals to treat confirmed influenza infections.
ξ Reduction of symptom duration with antiviral use.

Methodology
Methods Used to Collect/Select the Evidence: Electronic database searches (i.e. PUBMED)
were conducted and review members were queried to collect evidence for review; for the 2016
revision, clinical evidence dating back to July 2014 was reviewed. Additionally, hand searches
were performed within selected evidence for other relevant resources. Expert opinion, clinical
experience, and regard for patient safety/experience were also considered during discussions of
the evidence.

Methods Used to Formulate the Recommendations: All recommendations endorsed or
developed by the guideline workgroup were reviewed and approved by other stakeholders or
committees.

Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations:
Internally developed recommendations, or those adopted from external sources without an
assigned evidence grade, were evaluated by the guideline workgroup a modified Grading of
Recommendations Assessment, Development and Evaluation (GRADE) methodology.1

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Rating Scheme for the Strength of the Evidence/Strength of the Recommendations:
See Appendix A for the rating scheme used within this document.

Recognition of Potential Health Care Disparities: No potential disparities identified.

Definitions
Risk factors for complications from influenza:2-4
ξ Children < 2 years of age
ξ $GXOWV�•����\HDUV�RI�DJH
ξ Patients with chronic pulmonary conditions (including COPD and asthma)
ξ Cardiovascular disease (excluding hypertension alone)
ξ Renal or hepatic disease
ξ Hematological disease (including sickle cell disease)
ξ Metabolic disorders (including diabetes mellitus)
ξ Neurologic or neurodevelopmental conditions (including cerebral palsy, epilepsy, stroke,
developmental delay, muscular dystrophy etc.)
ξ Patients with immunosuppression (including HIV infection, immunosuppression caused
by medications)
ξ Women who are pregnant, or within 2 weeks postpartum
ξ Patients < 19 years of age receiving chronic aspirin therapy
ξ American Indians/Alaskan Natives
ξ 0RUELGO\�REHVH�SDWLHQWV�ZLWK�D�%0,�•���
ξ Residents of nursing homes and other chronic-care facilities

Introduction
Influenza is an infectious virus causing illness characterized by fever, malaise, headache,
nonproductive cough, sore throat and rhinitis.5 Uncomplicated illness usually resolves in three to
seven days, however, complications from influenza, can be severe and may require
hospitalization. Complications from influenza include pneumonia, secondary bacterial co-
infection, respiratory failure, shock, and death.2,5 Globally, influenza results in 250,000 to
500,000 deaths each year.6 Influenza is spread from person to person through respiratory
droplet transmission.7 Large-particle respiratory droplets typically do not travel more than six
feet through air, therefore transmission requires close contact.7 Contaminated surfaces may
also serve as a vehicle for transmission, although this is less common.7 Influenza virus has an
incubation period of one to four days and can be shed from one day prior to symptom onset
through five to ten days after symptom onset.8-10

Vaccination against influenza is the best method for prevention and is recommended annually
for all individuals six months of age and older.2

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Recommendations

Post-exposure Prevention (See Tables 1, 2, and 3)
1. The neuraminidase inhibitors, oseltamivir (Tamiflu®) and zanamivir (Relenza®), may be
used for preventing influenza in patients with suspected exposure to the influenza virus and
are the preferred agents for chemoprophylaxis.2,3,11 (UW Health Weak/Conditional
Recommendation, Moderate Quality of Evidence)
1.1. These antiviral medications are approximately 70% to 90% effective in preventing
influenza.4,12
1.2. Ideally, post-exposure prophylaxis should be started within 48 hours of influenza
exposure.2-4 (UW Health Weak/Conditional Recommendation, Very Low Quality of
Evidence)
1.3. Prophylaxis with oseltamivir is dosed 75 mg PO once daily for 10 days for household
contacts.13 For non-household contacts, the duration is 7 days. (UW Health Strong
Recommendation, Moderate Quality of Evidence)
1.3.1. Dosage adjustments are required for patients with CrCL below 30 mL/min and
patients receiving hemodialysis, CAPD, or CRRT (Tables 1 and 2).13-16 (UW
Health Strong Recommendation, Moderate Quality of Evidence)
1.4. Prophylaxis with zanamivir is dosed 10 mg inhaled once daily for 10 days.17
1.5. Peramivir (Rapivab®) should not be used be used for influenza prophylaxis. (UW
Health Weak/Conditional Recommendation, Very Low Quality of Evidence)
2. The decision to administer antiviral medication for prophylaxis of influenza should be
weighed against WKH�SDWLHQW¶V�ULVN�IRU�influenza complications (see Definitions), the extent of
possible viral contact, the time since symptom onset, and clinical judgment.2,3 (UW Health
Weak/Conditional Recommendation, Very Low Quality of Evidence)
2.1. Judicious use of antiviral medications for chemoprophylaxis is recommended to prevent
antiviral resistance.2-4 (UW Health Weak/Conditional Recommendation, Very Low
Quality of Evidence)
2.2. Situations where chemoprophylaxis may be warranted include: (UW Health
Weak/Conditional Recommendation, Very Low Quality of Evidence) 2,4
2.2.1. Patients with high risk for influenza complications exposed to potential infection
during the two weeks following influenza vaccination;
2.2.2. Patients with severe immune deficiency exposed to potential infection;
2.2.3. Patients with high risk for influenza complications exposed to potential infection
and who cannot receive influenza vaccine due to contraindications;
2.2.4. Residents of institutions (long-term care facilities or jails) during an influenza
outbreak at the institution.
3. Adamantanes, amantadine and rimantadine, have limited use in preventing influenza due to
widespread resistance to influenza A virus strains and lack of efficacy against influenza B
virus strains. They generally should not be used for chemoprophylaxis. 2,3,18 (UW Health
Weak/Conditional Recommendation, Moderate Quality of Evidence)
4. Influenza prophylaxis does not eliminate the risk for influenza and is not a substitute for
influenza vaccination.2,3 (UW Health Strong Recommendation, Very Low Quality of
Evidence)

Diagnosis
5. Diagnosis of influenza should be made through clinical assessment and diagnostic tests
including viral PCR and rapid diagnostic antigen testing.2,3 (UW Health Weak/Conditional
Recommendation, Moderate Quality of Evidence)
5.1. The viral PCR is the most accurate and sensitive test for detecting influenza viruses.2,3
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5.2. Rapid diagnostic tests have lower sensitivities (40% to 70%) than viral PCR resulting in
a high rate of false negative results.2-4
6. In patients with a high clinical suspicion for influenza, treatment with antiviral agents should
not be withheld while viral PCR results are pending.2-4,19 (UW Health Strong
Recommendation, High Quality of Evidence)

Treatment (See Tables 1, 2, and 3)
7. Treatment with antiviral agents is recommended as soon as possible for patients requiring
hospitalization even if the time from exposure is greater than 48 hours.2,3,19-22 (UW Health
Weak/Conditional Recommendation, Moderate Quality of Evidence)
7.1. Oseltamivir use is associated with a reduction in influenza-related complications and
pneumonia, faster alleviation of influenza symptoms, and reduced antibiotic use.23-26
7.2. Earlier antiviral treatment within 48 hours of illness onset is associated with less severe
disease progression and may lead to reduced complications due to influenza and
reduced length of hospital stay.19,27 However, for hospitalized patients, or those with
severe complicated illness, antiviral treatment administered greater than 48 hours from
illness onset may reduce morbidity and mortality.19,20,28,29
7.3. Several studies have demonstrated improved survival in critically ill patients treated with
antiviral agents within 5 days of symptoms compared to those receiving no
treatment.19,20,28,29
8. Begin treatment with oseltamivir 75mg twice daily for the critically ill and non-critically ill
patient. Treatment duration should last for five days.2,3,13 (UW Health Strong
Recommendation, Moderate Quality of Evidence)
8.1. Dosage adjustments are required for patients with CrCL below 30 mL/min and patients
receiving hemodialysis, CAPD, or CRRT (Tables 1 and 2).13-16 (UW Health Strong
Recommendation, Moderate Quality of Evidence)
8.1.1. In patients receiving CRRT, doses of 150 mg twice daily resulted in
supratherapeutic oseltamivir carboxylate concentrations when effluent rates of
3300 ±919 mL/hour. A dose of 75 mg once daily is recommended, however, a
higher dose may be needed when using higher effluent rates.14
8.2. The duration of treatment may be extended to longer than five days in patients with
severe protracted illness or those with immunosuppression.2-4 (UW Health
Weak/Conditional Recommendation, Very Low Quality of Evidence)
8.3. Some evidence suggests doses of 150 mg twice daily may be beneficial in the
treatment of influenza B but not influenza A.30 There is some evidence that suggests
this practice is not beneficial.31 If patients are not improving and have documented
influenza B, 150 mg twice daily may be appropriate.3,30 Oseltamivir is well tolerated in
severely ill patients with influenza.32,33 (UW Health Weak/Conditional Recommendation,
High Quality of Evidence)
8.4. In patients unable to take oral medications, oseltamivir may be administered via
nasogastric or nasojejunal tube. Capsules should be opened and dissolved in 10 mL to
30 mL of water. After administration, the tube should be flushed with water.14,15,34 (UW
Health Strong Recommendation, Moderate Quality of Evidence)
9. Oseltamivir doses probably do not need to be adjusted for obesity as pharmacokinetic
disposition of oseltamivir is similar between obese and non-obese patients.35 (UW Health
Weak/Conditional Recommendation, Low Quality of Evidence)
10. Oseltamivir is probably safe to use in pregnancy.36 (UW Health Weak/Conditional
Recommendation, Moderate Quality of Evidence)
11. Oseltamivir is associated with nausea/vomiting and potentially psychiatric events. 24,26
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12. Injectable peramivir is reasonable for influenza treatment in patients who are unable to take
oral or other enteral oseltamivir (e.g. strict NPO, unable to reliably take enteral medications)
(UW Health Strong Recommendation, Moderate Quality of Evidence)
12.1. UWHC peramivir use is restricted to Infectious Disease approval AND unable to take
oral oseltamivir (e.g. strict NPO, unable to reliably take enteral medications) AND
patient presents with influenza symptoms with 48 hours of onset AND the suspected
phenotype is peramivir susceptible. Peramivir restriction may be found at the
Lexicomp peramivir monograph.
12.2. Peramivir should not be used for influenza prophylaxis.
13. Antiviral treatment in patients with confirmed or suspected influenza who are at high risk for
complications (see Definitions) is recommended as soon as possible post-exposure.2,3,11
(UW Health Strong Recommendation, Moderate Quality of Evidence)
14. Treatment of influenza with adamantanes (amantadine and rimantadine) is not
recommended due to high rates of resistance against influenza A viruses and lack of activity
against influenza B viruses.2,3,18 (UW Health Strong Recommendation, Moderate Quality of
Evidence)

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8
Table 1. ADULT dosing of enteral and inhalation antiviral medications used to treat and prevent influenza
Oseltamivir (Tamiflu®) Zanamivir (Relenza®)
Treatment Prophylaxis Treatment Prophylaxis
CrCL > 30 mL/minA
Adult General Care: 75 mg PO
twice daily x 5 daysB,13
Adult Critical Care:
75mg PO twice daily x 5-10
daysB
(150mg PO twice daily if not
improving with influenza B)
75 mg PO once daily x 10
days13
2 inhalations twice daily x 5
days17
(each inhalation delivers 5 mg,
total dose of 10 mg)
2 inhalations once daily x 10
days17
(each inhalation delivers 5 mg,
total dose of 10 mg)
CrCL ≤ 30 mL/minA 75 mg PO once daily x 5
days13
75 mg PO every other day x 10
days13
OR
30 mg once daily x 10 days13
Hemodialysis 75 mg PO after each HD session x 5 days7
Adults: 75 mg PO after every
other HD session x 5 days16
CAPD 30 mg PO once weekly after a
dialysate exchange16
30 mg PO once weekly after a
dialysate exchange16
CRRT 75 mg PO once daily14 30 mg PO once
daily
Obesity (BMI > 40)
No adjustment needed:
75 mg PO twice daily x 5
days13,15,37
No adjustment needed:
75 mg PO once daily x 10
days13,15,37
Liver dysfunction
Respiratory disease Not
recommended17
Not
recommended17
A
Dosing recommendation deviates from package insert. Oseltamavir therapeutic window is wide and availability of 30 mg capsule
product may be limited in the ambulatory pharmacy setting.
B
Consider switching therapy to 150mg PO BID if critically ill and influenza B positive.
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Table 2. PEDIATRIC dosing of enteral and inhalational antiviral medications used to treat and prevent influenza
Oseltamivir (Tamiflu®) Zanamivir (Relenza®)
Treatment Prophylaxis Treatment Prophylaxis
CrCL > 30 mL/min
ξ •���\HDUV���)ROORZ�DGXOW�
dosing

ξ 1-12 years: Weight-based,
follow Table 3

ξ 2 weeks to <1 year:3
mg/kg** PO twice daily4
ξ •���\HDUV���)ROORZ�DGXOW�
dosing

ξ 1-12 years: Weight-based,
follow Table 3

ξ 2 weeks to <1 year: Not
approved4
Indicated for 7 years or older at
the adult dosing:
2 inhalations twice daily x 5
days17

(each inhalation delivers 5 mg,
total dose of 10 mg)
Indicated for 7 years or older at
the adult dosing:
2 inhalations once daily x 10
days17

(each inhalation delivers 5 mg,
total dose of 10 mg)
CrCL ≤ 30 mL/min
ξ •���\HDUV���)ROORZ�DGXOW�
dosing

ξ 1-12 years: Weight-based,
follow Table 3

ξ 2 weeks to <1 year: 3
mg/kg** PO once daily
ξ •���\HDUV���)ROORZ�DGXOW�
dosing

ξ 1-12 years: Weight-based,
follow Table 3

ξ 2 weeks to <1 year: Not
approved
Hemodialysis Not available Not available
CAPD Not available Not available
CRRT Not available Not available
Obesity (BMI > 40)
No adjustment needed No adjustment needed Liver dysfunction
Respiratory disease Not
recommended17
Not
recommended17
** There is no data in pediatric patients for doses greater than 75mg.


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10
Table 3. Weight-based oseltamivir dosing for pediatric patients aged 1 to 12 years
Weight Treatment Prophylaxis
C
rC
L
>
30

m
L/
mi
n ”���NJ 30 mg PO twice daily x 5 days 30 mg PO once daily x 10 days
15 to 23 kg 45 mg PO twice daily x 5 days 45 mg PO once daily x 10 days
23 to 40 kg 60 mg PO twice daily x 5 days 60 mg PO once daily x 10 days
•���NJ 75 mg PO twice daily x 5 days 75 mg PO once daily x 10 days


Cr
CL
<
30

mL
/
mi
n ”���NJ 30 mg PO once daily x 5 days 30 mg PO every other day x 10 days
15 to 23 kg 45 mg PO once daily x 5 days 45 mg PO every other day x 10 days
23 to 40 kg 60 mg PO once daily x 5 days 60 mg PO every other day x 10 days
•���NJ 75 mg PO once daily x 5 days 75 mg PO every other day x 10 days


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11
UW Health Implementation
Potential Benefits and Harms:
The benefit of this guideline is management of patients with known or suspected influenza and
successful treatment or prophylaxis of these patients. The risk of implementing this guideline
and administering anti-influenza medications is exposure and potential side effects of these
medications

Pertinent UW Health Policies & Procedures
None

Patient Resources
1. Lexicomp Patient Education - Oseltamivir

Guideline Metrics
1. Oseltamavir and peramivir use per influenza season
2. Morbidity and mortality rate with influenza infection

Implementation Plan/Clinical Tools
1. Guideline will be posted on uConnect in a dedicated location for Clinical Practice Guidelines.
1. Release of the guideline will be advertised in the Physician/APP Briefing newsletter.
Pharmacists will be educated about Guideline in team meetings.
2. Guideline will be linked to electronic medication records for oseltamivir and zanamivir.
3. Content and hyperlinks within clinical tools, documents, or Health Link related to the
guideline recommendations will be reviewed for consistency and modified as appropriate.

Delegation Protocol
IP ± Renal Function-Based Dose Adjustment - Adult ± Inpatient/Ambulatory [8]

Disclaimer
Clinical practice guidelines assist clinicians by providing a framework for the evaluation and
treatment of patients. This guideline outlines the preferred approach for most patients. It is not
LQWHQGHG�WR�UHSODFH�D�FOLQLFLDQ¶V�MXGJPHQW�RU�WR�HVWDEOLVK�D�SURWRFRO�IRU�DOO�SDWLHQWV��,W�LV�
understood that some patients will not fit the clinical condition contemplated by a guideline and
that a guideline will rarely establish the only appropriate approach to a problem.
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Appendix A. Evidence Grading Scheme

Figure 1. GRADE Methodology adapted by UW Health1



GRADE Ranking of Evidence
High We are confident that the effect in the study reflects the actual effect.
Moderate We are quite confident that the effect in the study is close to the true effect, but it is also
possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.

GRADE Ratings for Recommendations For or Against Practice
Strong The net benefit of the treatment is clear, patient values and circumstances are
unlikely to affect the decision.
Weak/conditional Recommendation may be conditional upon patient values and preferences, the
resources available, or the setting in which the intervention will be implemented.

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13
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