Introduction to Antiviral Drugs for Influenza

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Introduction to Antiviral Drugs for Influenza

• David Shay
• Influenza Branch
• Centers for Disease Control Prevention

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Antiviral Drugs for Influenza

• Are 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

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Topics

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

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Classes of Influenza Antiviral Drugs

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

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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

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Amantadine, RimantadineMechanism 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

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Amantadine, RimantadineTreatment (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

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Amantadine, RimantadineTreatment (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

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Amantadine, RimantadineProphylaxis

• 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

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Amantadine Metabolism

• Well-absorbed, half-life 12-16 hours
• Excreted largely unchanged in the urine by
  glomerular filtration and tubular secretion
• Has the narrowest toxic to therapeutic ratio of
  available antivirals
• Dose adjustments required for relatively small
  decreases in renal function
• creatinine clearance lt50-80 ml/min
• including those typically observed with aging

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Amantadine Adverse Effects

• Commonly associated with dose-related minor CNS
  side effects
• anxiousness, difficulty concentrating, insomnia,
  lightheadedness
• Less 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

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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
• Case 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

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Rimantadine Metabolism

• gt80 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

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Rimantadine Adverse Effects

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

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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

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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

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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

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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

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Oseltamivir, Zanamivir RCTs

• In 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

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Oseltamivir, Zanamivir RCTs

• Use of oseltamivir among children aged 1-12
  years
• with fever and cough or coryza of lt48 hours
• demonstrated a reduction in the median duration
  of illness of 36 hours
• A 44 reduction in otitis media diagnoses

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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

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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

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Oseltamivir, ZanamivirTreatment 5 Days

• Treatment
• Must be administered lt 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

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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

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Oseltamivir Metabolism

• Absorption 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 lt 30 ml/min

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Oseltamivir Adverse Effects

• Mild-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

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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

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Zanamivir Metabolism

• Bioavailability 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

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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

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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

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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)

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Treatment of Influenza A and B
Oseltamivir 5 days Age 1-12 years weight ?
15 kg 30 mg twice daily weight gt 15
to 23 kg 45 mg twice daily weight gt 23 to 40
kg 60 mg twice daily weight gt 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

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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

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Prophylaxis of Influenza A B

Oseltamivir Age ? 13 years 75 mg
per day Zanamivir Not approved in the
U.S.
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Relative Costs of 5-Day Treatment Courses

• Amantadine 3.70
• Rimantadine 20.40
• Oseltamivir 63.40
• Zanamivir 51.40

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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