# Presentation: 487377

## Introduction to Antiviral Drugs for Influenza

**David Shay**
**Influenza Branch**
**Centers for Disease Control & Prevention**

## Antiviral Drugs for Influenza

** ****A****re effective for both early treatment and chemoprophylaxis of influenza infections**** **
** ****Likely the only virus-specific interventions available during the initial pandemic response, as a suitable vaccine is unlikely to be available for at least 6-8 months**** **
**  **

## Topics

** ****Description of the 4 currently available antivirals**
** ****Treatment and prophylaxis**
** ****Metabolism and adverse effects**
** ****Doses**
**  **

## Classes of Influenza Antiviral Drugs

**Adamantanes (M2 inhibitors)**
** ****Amantadine**
** ****Rimantadine**
**Neuraminidase inhibitors**
** ****Oseltamivir**
** ****Zanamivir**

## Amantadine, Rimantadine 

-   **Chemically related**
**  ****Orally administered (100 mg tablets and syrup for children) **
-   **Activity against**** ****influenza A viruses only, through inhibiting replication**
** ****Have comparable antiviral and clinical activities when used for prophylaxis or treatment**

## Amantadine, RimantadineMechanism of Action

-   **Interfere with the function of the transmembrane domain of the M2 protein of influenza A viruses**
** ****Interfere with virus assembly during replication of influenza A viruses**
** ****Decrease the release of influenza A viral particles into the host cell**

## Amantadine, RimantadineTreatment (3-5 days)

** ****Decreases length of illness due to influenza A by about**** ****1 day**
** ****Reduces shedding of influenza A viruses**
** ****Must be started within 2 days of illness**
** ****Placebo-controlled studies during the 1968 A(H3N2) pandemic and 1977 A(H1N1) re-appearance: both reduced fever, symptom severity, and time to resumption of normal activities**** **

## Amantadine, RimantadineTreatment (3-5 days)

** ****No placebo-controlled trials in interpandemic periods showing reductions in complications, antibiotic use, or hospitalizations**
** ****Uncontrolled studies report reduced lower respiratory complications with early treatment in nursing home patients & immunocompromised hosts**
**Pediatric studies demonstrate variable results compared with acetaminophen controls, with frequent emergence of drug-resistant variants**

## Amantadine, RimantadineProphylaxis

** ****70-90% effective in preventing illness from influenza A virus infection, although infection may still occur**
** ****Placebo-controlled studies during 1968 A(H3N2) pandemic and 1977 A(H1N1) re-appearance: effective for prophylaxis in immunologically naive adult populations**** **
** ****Does not interfere with immune response to infection or inactivated vaccine**

## Amantadine Metabolism

** ****Well-absorbed, half-life 12-16 hours**
** ****Excreted largely unchanged in the urine by glomerular filtration and tubular secretion**
** ****H****as the narrowest toxic to therapeutic**** ratio of available antivirals**
** ****D****ose adjustments required for relatively small decreases in renal function**
** ****creatinine clearance <50-80 ml/min**
** ****including those typically observed with aging**** **

## Amantadine Adverse Effects

** ****C****ommonly associated with dose-related minor CNS side effects**
** ****anxiousness, difficulty concentrating, insomnia, lightheadedness**** **
** ****Le****ss often with severe CNS toxicities**
** ****delirium, hallucinosis, acute psychosis, seizures, coma**
** ****most often in older persons and those with pre-existing renal insufficiency, seizure disorders, or psychiatric illness **

## Amantadine Adverse Effects

** ****When used for prophylaxis of pandemic influenza at doses of 200 mg daily, amantadine discontinuation rates 2-9% higher than those with placebo****  **
** ****GI**** side effects (anorexia, nausea) in 1-3%**
** ****C****ase reports of congenital anomalies in humans associated with use early in pregnancy**
** ****contraindicated in pregnancy unless the potential clinical benefit justifies the risk to the fetus**

## Rimantadine Metabolism

** ****>****80% absorption after oral administration and prolonged half-life (24-36 hours)**
** ****Undergoes extensive hepatic metabolism prior to renal excretion of the parent drug and its metabolites **
** ****Reduce dose to prevent adverse effects**
** ****Kidney or liver disease**
** ****Persons ******** 65 years**
** ****Those with any adverse effects**
** ****Avoid in persons with psychiatric disorders**

## Rimantadine Adverse Effects

** ****Gastrointestinal: nausea, vomiting**
** ****Central nervous system**
** ****similar to, but less common than amantadine**
** ****in part related to lower plasma drug concentrations**
** ****C****omparative study of long-term prophylaxis in younger adults**
** ****CNS side effects in 13% of amantadine**
** ****6% of rimantadine**
** ****and 4.5% of placebo recipients**

## Rimantadine Adverse Effects

** ****Cross-over study in an elderly nursing home population compared prolonged amantadine and rimantadine prophylaxis**
** ****doses of 100 mg/day, adjusted for renal function**
** ****10-fold higher frequencies of  severe CNS adverse events during amantadine use**
** ****All antivirals are category C agents, have not been adequately studied in pregnant women, cross the placenta and are excreted in breast milk  **

## Amantadine, Rimantadine Resistance

**Rapid development of resistance to amantadine and rimantadine in 30% of treated patients (can develop in 2-5 days)**
**Cross-resistance: viruses resistant to amantadine are also resistant to rimantadine**

## Neuraminidase Inhibitors  Oseltamivir, Zanamivir

**	**

-  **Newer medications: became available in 1999**
** ****Have activity against both influenza A and influenza B viruses**
** ****Chemically related, but have different routes of administration**

## Oseltamivir, Zanamivir Mechanism of Action 

**	**

-   **Block the active site of neuraminidase, present in all influenza A and B viruses**
** ****Reduce the number of viral particles released from infected cells**

## Oseltamivir, Zanamivir RCTs

**	**

-  **I****n adults, treatment with oseltamivir or zanamivir**
** ****reduces the duration of influenza illnesses by about 1 day**
** ****reduces MD-diagnosed LRT complications leading to antibiotic use by 40-50%**
** ****when febrile influenza patients treated within 36-48 hours of symptom onset**
** ****Published data from treatment of elderly and other persons at high-risk for influenza complications are limited **** **

## Oseltamivir, Zanamivir RCTs

**	**

** ****Use of oseltamivir among children aged 1-12 years**
** ****with fever and cough or coryza of <48 hours**
** ****demonstrated a reduction in the median duration of illness of 36 hours**
** ****A 44% reduction in otitis media diagnoses **** **
** **

## Oseltamivir

**	**

** ****Orally administered: 75 mg tablets and syrup for children**
** ****Approved for treatment and prophylaxis of influenza A and B**
** ****Treatment ******** 1 year**
**  ****Chemoprophylaxis ******** 13 years**

## Zanamivir

**	**

** ****Inhalational delivery of dry powered drug (5 mg per package) in a lactose carrier**
** ****A proprietary device is used to deliver drug (Diskhaler)**
** ****Approved for treatment**** ****of **
**influenza A & B**
** ****Among those aged ******** 7 years**

## Oseltamivir, ZanamivirTreatment: 5 Days

**	**

**Treatment**
** ****Must be administered < 48 hours after onset of illness**
** ****Reduce symptoms and decrease length of illness due to influenza A & B virus infections by approximately 1 day**
** ****Decrease viral shedding**

## Oseltamivir, Zanamivir

**	**

**Prophylaxis**
** ****Oseltamivir and zanamivir are both approximately 80% effective in preventing illness**
** ****Can prevent influenza in family members after one family member in the home has influenza**
** ****Uncontrolled studies of both oseltamivir and zanamivir report termination of nursing home outbreaks that continued despite the use of amantadine**** **

## Oseltamivir Metabolism

** ****A****bsorption of pro-drug oseltamivir is high**
** ****Following de-esterification in the gut, liver, and blood, the bioavailability of the active carboxylate form is ~80%**
** ****Active drug has a serum half-life of 8-10 hours, and is excreted unchanged by the kidney**
** ****Frequency of oseltamivir dosing be reduced when creatinine clearance < 30 ml/min**

## Oseltamivir Adverse Effects

** ****M****ild-to-moderate nausea/vomiting in 10-15% of adults; symptoms are not usually dose-limiting**
** ****Fewer GI symptoms if given with food**
** ****Only 1-2% stop because of adverse events**
** ****Headache reported in older adults**
** ****Cases of hypersensitivity reactions, rash, hepatotoxicity, and thrombocytopenia reported rarely**** **

## Oseltamivir Resistance

**	**

**  ****Less common **
** ****5.5% of influenza isolates were resistant in a pediatric treatment study**
** ****Higher rates in recent Japanese study**
** ****Assays to assess resistance are not widely available**
** ****Surveillance is needed: Global Neuraminidase Inhibitor Susceptibility Network**

## Zanamivir Metabolism

**	**

** ****B****ioavailability of zanamivir delivered by inhalation is ~10 to 20%**
** ****Serum half-life is 2.5 to 5 hours**
** ****Zanamivir is excreted unchanged by the kidney**
** ****But dose adjustments are not necessary in renal insufficiency****  **

## Zanamivir Adverse Effects

**	**

** ****Gastrointestinal (nausea, diarrhea)**
** ****Headache**
** ****Cough**
** ****Use**** in influenza-infected persons with pre-existing lower airway tract disease associated infrequently with bronchospasm**
** ****Rarely with a severe or fatal outcome**
** ****Influenza can cause acute bronchospasm**
** ****Not recommended in those with obstructive lung disease **

## Zanamivir Resistance 

**	**

** ****Appears to be uncommon**
** ****Not much data on use**
** ****Assays to assess resistance are not widely available**
** ****Surveillance is needed: Global Neuraminidase Inhibitor Susceptibility Network**

## Treatment of Influenza A

**	**

**Amantadine:****  ****3-5 days**
**Ages 1-9 years:    5 mg/kg/day divided twice daily**
**	****	****         ****(not to exceed 150 mg per day) **
**Ages 10-64 years:  100 mg twice daily **
**Ages ******** 65 years:    ******** 100 mg per day**
**Rimantadine: 3-5 days**
**Adults:  ****	****	****100 mg twice daily **
**Ages ******** 65 years:    100 mg per day**
**(Physicians often use the amantadine dosing for children ******** 1 year)**

## Treatment of Influenza A and B

**	**

**Oseltamivir: 5 days**
**Age 1-12 years:****  **
**	****weight ******** 15 kg:           30 mg twice daily**
**	****weight > 15 to 23 kg:  45 mg twice daily**
**	****weight > 23 to 40 kg:  60 mg twice daily**
**	****weight > 40 kg:           75 mg twice daily**
**Age ******** 13 years:****              ****	****    ****75 mg twice daily**
**Zanamivir: 5 days**
**Age ******** 7 years:****	****2 inhalations (5 mg each) ****	****	****	****twice daily**

## Prophylaxis of Influenza A

**	**

**Amantadine:****  **
**Ages 1-9 years:    5 mg/kg/day divided twice daily**
**	****	****         ****(not to exceed 150 mg per day) **
**Ages 10-64 years:  100 mg twice daily **
**Ages ******** 65 years:    ******** 100 mg per day**
**Rimantadine: **
**Ages 1-9 years:    5 mg/kg/day divided twice daily**
**	****	****         ****(not to exceed 150 mg**
**Ages 10-64 years: ****	****100 mg twice daily **
**Ages ******** 65 years:    100 mg per day**

## Prophylaxis of Influenza A & B

**	**

**Oseltamivir:**
**Age ******** 13 years:              75 mg per day **
**Zanamivir:  Not approved in the U.S.**

## Relative Costs of 5-Day Treatment Courses

-  **Amantadine:    $3.70**
**Rimantadine: $20.40 **
**	**
**Oseltamivir:   $63.40**
**Zanamivir:      $51.40**

## Summary

**All antivirals can reduce symptoms and duration of illness due to influenza by about one day**
**All antivirals are effective in preventing influenza, but not all are approved**
**Antivirals differ by route of administration, approved ages, adverse effects, emergence of antiviral resistance, costs **
**Not all antivirals are available worldwide**