Influenza medical therapy

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For more information about non-human (variant) influenza viruses that may be transmitted to humans, see Zoonotic influenza

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Alejandro Lemor, M.D. [2]

## Overview

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Antiviral therapy is recommended for patients who are at higher risk of complications from the Influenza virus. Antiviral drugs diminish symptoms, shorten the time of the disease, and prevent serious complications. The two main antiviral agents used in the treatment and prevention of influenza are Oseltamivir and Zanamivir. For the majority of patients, the treatment of influenza is primarily symptomatic and includes Analgesics, Antihistamines, Decongestants and cough suppressants.

## Medical Therapy

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### Antiviral Medications

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Persons at higher risk for influenza complications recommended for antiviral treatment include:

* Children aged younger than 2 years

* Adults aged 65 years and older

* Persons with the following comorbidities:

* Chronic pulmonary (including asthma)
* Cardiovascular (except hypertension alone)
* Renal, hepatic, hematological (including sickle cell disease) or metabolic disorders (including diabetes mellitus)
* Neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy, stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury)

* Persons with immunosuppression, including that caused by medications or by HIV infection

* Women who are pregnant or postpartum (within 2 weeks after delivery)

* Persons aged younger than 19 years who are receiving long-term aspirin therapy

* American Indians/Alaska Natives

* Persons who are morbidly obese (BMI > 40)

* Residents of nursing homes and other chronic-care facilities.

* Antiviral medications with activity against influenza viruses are an important adjunct to influenza vaccine in the control of influenza.
* Influenza antiviral prescription drugs can be used to treat influenza or to prevent influenza.
* Four licensed prescription influenza antiviral agents are available in the United States.

Neuraminidase inhibitors

* Two FDA-approved influenza antiviral medications are recommended for use in the United States during the 2013-2014 influenza season:

* Oral oseltamivir (Tamiflu®)
* Inhaled zanamivir (Relenza®)

* Oseltamivir and zanamivir are chemically related antiviral medications known as neuraminidase inhibitors that have activity against both influenza A and B viruses.

Adamantanes

* Amantadine and rimantadine are antiviral drugs in a class of medications known as adamantanes.
* Adamantanes are active against influenza A viruses, but not influenza B viruses.

#### Antiviral Therapy Recommendations

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Antiviral treatment with neuraminidase inhibitors is recommended as early as possible for any patient with confirmed or suspected influenza who has any of the follwing conditions:

* Is hospitalized.
* Has severe, complicated, or progressive illness.
* Is at higher risk for influenza complications (detailed in the table on the right).

Meta-analyses of randomized controlled trials of neuraminidase inhibitors conflict with reviews by the Cochrane Collaboration[1] suggesting less benefit than reviews by industry[2]:

* "median times to alleviation were 97·5 h for oseltamivir and 122·7 h for placebo groups (difference -25·2 h, 95% CI -36·2 to -16·0)" [2]
* "a reduction in the time to first alleviation of symptoms from 7 to 6.3 days"[1]

The Cochrane assessment has evolved:

* 2000: "Eight trials with 1180 adults were included." "As a treatment, NIs shorten the duration of symptoms by one da...NIs are effective for the prevention and treatment of influenza. Overall NIs are safe..."[3]
* 2006: "We identified four prophylaxis, 13 treatment and four post-exposure prophylaxis (PEP) trials." "Because of their low effectiveness, NIs should not be used in routine seasonal influenza control"[4]
* 2012: "We included and analysed data from 25 studies (15 oseltamivir and 10 zanamivir studies). We could not use data from a further 42 studies due to insufficient information or unresolved discrepancies in their data." "We found a high risk of publication and reporting biases in the trial programme of oseltamivir."[5]
* 2014: "We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche." "Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenzasymptoms in adults, but not in asthmatic children."[1]

A subsequent, open-label trial found[6]:

* "Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone"
* "The effect does not appear to be mediated by influenza virus status, as measured using PCR analysis of swabs"

#### Drug Resistance

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* Antiviral resistance to oseltamivir and zanamivir among circulating influenza viruses is currently low, but this might change.
* Also, antiviral resistance can emerge during or after treatment in certain patients, such as immunosuppressed individuals.
* As in recent past seasons, there is a high prevalence (>99%) of influenza A(H3N2) and influenza A(H1N1) (2009 H1N1) viruses resistant to adamantanes.
* Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A viruses.

#### Antiviral Medications Recommended for Treatment and Chemoprophylaxis of Influenza

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Antiviral Agent  | Activity Against  | Use  | Recommended For  | Not Recommended for Use in  | Adverse Reactions
Oseltamivir (Tamiflu®)  | Influenza A and B  | Treatment  | Any age  | N/A  | Nausea, vomiting. Sporadic, transient neuropsychiatric events (self injury or delirium) mainly reported among Japanese adolescents and adults.
Prophylaxis  | > 3 months of age  | N/A
Zanamivir (Relenza®)  | Influenza A and B  | Treatment  | > 7 years old  | Patients with underlying respiratory disease, such as asthma or COPD  | Allergic reactions such as oropharyngeal or facial edema. Diarrhea, nausea, sinusitis, nasal signs and symptoms, bronchitis, cough, headache, dizziness, and ear, nose and throat infections.
Prophylaxis  | > 5 years old  | Patients with underlying respiratory disease, such as asthma or COPD
Table adapted from CDC [7]

#### Recommended Dosage and Duration of Influenza Antiviral Medications for Treatment or Chemoprophylaxis

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Antiviral Agent  | Patient  | Treatment (5 days)  | Prophylaxis (7 days)
Oseltamivir
(Tamiflu®)  | Children  |

* < 1 yr: 3 mg/kg/dose twice daily
* > 1 yr: dose depends on weight.

* ≤ 15 kg: 30 mg twice a day
* > 15 to 23 kg: 45 mg twice a day
* > 23 to 40 kg: 60 mg twice a day
* > 40 kg: 75 mg twice a day

* Not recommended for children < 3 months old.
* 3 months to 1 yr: 3 mg/kg/dose once daily
* > 1 yr: dose depends on weight.

* ≤ 15 kg: 30 mg once a day
* > 15 to 23 kg: 45 mg once a day
* > 23 to 40 kg: 60 mg once a day
* > 40 kg: 75 mg once a day

Adults  |

* 75 mg twice a day

* 75 mg once a day

Zanamivir
(Relenza®)  | Children  | For children > 7 yrs old.

* 10 mg (two 5-mg inhalations) twice daily

| For children > 7 yrs old.

* 10 mg (two 5-mg inhalations) once daily

Adults  |

* 10 mg (two 5-mg inhalations) twice daily

* 10 mg (two 5-mg inhalations) once daily

Peramivir (Rapivab®)  | Children  | N/A  | N/A
Adults  | 600 mg IV for 15-30 minutes (single dose)  | N/A
Table adapted from CDC (as of 2015) [7]

#### Recommended Oseltamivir and Peramivir Dose Adjustments for Treatment or Chemoprophylaxis of Influenza in Adult Patients with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

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Antiviral Agent  | Creatinine Clearance  | Recommended Treatment Regimen  | Recommended Chemoprophylaxis Regimen
Oral Oseltamivir  | Creatinine clearance 61 to 90 mL/min  | 75 mg twice a day  | 75 mg once daily
Creatinine clearance 31 to 60 mL/min  | 30 mg twice a day  | 30 mg once daily
Creatinine clearance 10 to 30 mL/min  | 30 mg once daily  | 30 mg every other day
ESRD Patients on Hemodialysis (Creatinine clearance ≤10 mL/min)  | 30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days  | 30 mg after alternate hemodialysis cycles
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis (Creatinine clearance ≤10 mL/min)  | A single 30 mg dose administered immediately after a dialysis exchange  | 30 mg once weekly immediately after dialysis exchange
Intravenous Peramivir (single dose)  | Creatinine clearance > 50 mL/min  | 600 mg  | N/A
Creatinine clearance 30-49 mL/min  | 200 mg  | N/A
Creatinine clearance 10-29 mL/min  | 100 mg  | N/A
ESRD Patients on Hemodialysis  | Dose administered after dialysis at a dose adjusted based on creatinine clearance  |

### Symptomatic Therapy

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Over the counter (OTC) medicines may be taken to relieve influenza symptoms, but they do not affect the virus. [8]

Symptom(s)  | OTC Medicine

|

Fever, Aches, Pains, Sinus pressure, Sore throat | Analgesics
Nasal congestion, Sinus pressure  | Decongestants
Sinus pressure, Runny nose, Watery eyes, Cough | Antihistamines
Cough | Cough suppressant
Sore throat | Local anesthetics

* Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin as taking aspirin in the presence of influenza infection (especially Influenzavirus B) can lead to Reye's syndrome, a rare but potentially fatal disease of the liver.[9]

## References

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1. ↑ 1.0 1.1 1.2 T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ; et al. (2014). "inhibitors for preventing and treating influenza in healthy adults and children". Cochrane Database Syst Rev (4): CD008965. doi:10.1002/14651858.CD008965.pub4. PMID 24718923.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)  Review in: Evid Based Med. 2014 Dec;19(6):211 Review in: Ann Intern Med. 2014 Oct 21;161(8):JC2
2. ↑ 2.0 2.1 Dobson J, Whitley RJ, Pocock S, Monto AS (2015). "Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials". Lancet. 385 (9979): 1729–37. doi:10.1016/S0140-6736(14)62449-1. PMID 25640810.CS1 maint: Multiple names: authors list (link)
3. ↑ T, Demicheli V, Deeks J, Rivetti D (2000). "inhibitors for preventing and treating influenza in healthy adults". Cochrane Database Syst Rev (2): CD001265. doi:10.1002/14651858.CD001265. PMID 10796625.CS1 maint: Multiple names: authors list (link)
4. ↑ TO, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D (2006). "inhibitors for preventing and treating influenza in healthy adults". Cochrane Database Syst Rev (3): CD001265. doi:10.1002/14651858.CD001265.pub2. PMID 16855962.CS1 maint: Multiple names: authors list (link)
5. ↑ T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R; et al. (2012). "inhibitors for preventing and treating influenza in healthy adults and children". Cochrane Database Syst Rev. 1: CD008965. doi:10.1002/14651858.CD008965.pub3. PMID 22258996.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)  Review in: Ann Intern Med. 2012 Sep 18;157(6):JC3-5
6. ↑ Butler CC, van der Velden AW, Bongard E, Saville BR, Holmes J, Coenen S; et al. (2020). "Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial". Lancet. 395 (10217): 42–52. doi:10.1016/S0140-6736(19)32982-4. PMID 31839279.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
7. ↑ 7.0 7.1 "CDC Influenza Antiviral Medications: Summary for Clinicians".
8. ↑ "Cold and Flu Guidelines: Influenza". American Lung Association. Retrieved 2007-09-16.
9. ↑ Molotsky, Irvin (1986-02-15). "Consumer Saturday - Warning on Flu and Aspirin". New York Times. Retrieved 2007-05-25.

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