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Efficacy and Safety of Peramivir

By Amesh A. Adalja, MD*, November 19, 2010

At the start of the 2009 H1N1 pandemic, only 2 antivirals were available for use—oseltamivir and zanamivir—as the virus was fully resistant to the adamantane class of (oral) antivirals. Neither of these drugs is administered parenterally. Because a parenteral antiviral was needed for critically ill patients for whom oral bioavailabilty may be erratic, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for peramivir, a parenteral neuraminidase inhibitor. Since the pandemic has abated, the EUA is no longer in effect. However, peramivir has been fully approved for use in Japan, and results of a trial evaluating the efficacy and safety of intravenous peramivir have just been published in the November 2010 issue of the journal Antimicrobial Agents and Chemotherapy.1

Trial Participants Were Seasonal Influenza Patients

The 300 person double-blind placebo-controlled trial was performed in Japan during the 2007-08 flu season. Inclusion criteria included the following:

  • Age between 20 and 64 years
  • Influenza like symptoms within 48 hours
  • Diagnosis of influenza by rapid antigen test, fever and clinical criteria (2 of 7 symptoms required: headache, myalgias/arthralgias, fatigue, cough, sore throat, or nasal congestion)

Patients were excluded if they were immunocompromised, pregnant, or allergic to anti-influenza drugs; also excluded were those who had respiratory disease requiring treatment, had a suspected bacterial infection, or had used anti-influenza drugs within the previous 7 days.1

Subjects were randomized to receive either a 300 mg or a 600 mg dose of intravenous peramivir or placebo, and they kept logs of their symptoms and adverse effects. Nasal swabs to assess for the presence of influenza were collected at 4 points throughout the trial. The primary endpoint was the time to alleviation of symptoms; secondary endpoints included changes in symptom severity scores at 24 hours, presence of fever, changes in influenza titers, and incidence of complications.1

No serious adverse events occurred during the trial, and the rates of all adverse events were similar in both the placebo and treatment groups.1

Seasonal H1N1 Was the Predominant Isolate

Approximately 70% to 75% of subjects’ influenza isolates were of the H1N1 subtype; approximately 25% were H3N2; the rest were type B. Most of the isolates were sensitive to peramivir, with median half maximal inhibitory concentrations (IC50) for the viruses ranging from 1.11 to 2.81 nmol/liter. There were 3 viral isolates for which the IC50 exceeded 3 standard deviations from the mean. These viruses were sequenced, and 1 was found to harbor the H275Y mutation that confers resistance to oseltamivir and peramivir.1

Duration of Symptoms Significantly Reduced

Compared with placebo, both the 300 mg and 600 mg doses of peramivir reduced symptom duration significantly, from approximately 82 hours to approximately 60 hours. A significant increase in the percentage of subjects with defervescence by 24 hours was seen with peramivir as compared with placebo. Additionally, those receiving peramivir returned to their normal activities on average 40 hours earlier than those receiving placebo. Viral presence was also significantly decreased at day 3 in the peramivir treated subjects.1

Severely Ill Not Included in Trial

As the authors note, the trial’s generalizability is limited for several reasons. The chief limitation is the exclusion of severely ill patients and the immunocompromised—2 groups that may benefit the most from pharmacologic intervention. Additionally, the trial utilized a single dose of peramivir and not the EUA proscribed dosage of 600 mg daily for 5–10 days. Extended dosing may have an impact on the prevalence of adverse events.1

Other Antiviral Options for Influenza

Currently there are 4 drugs from 2 classes approved by the FDA for the treatment of influenza:

  • Adamantanes: Amantadine and Rimantidine
  • Neuraminidase Inhibitors: Oseltamivir and Zanamivir (inhaled)

In Japan, in addition to peramivir, the newly approved neuraminidase inhibitor laninamivir is also available. Laninamivir is an inhaled compound administered in a single dose. Like zanamivir, but not peramivir, it has activity against oseltamivir-resistant viruses.2

Parenteral formulations of zanamivir, which are not licensed in the U.S. but which were utilized via an investigational new drug (IND) application during the 2009 H1N1 pandemic, are available on a compassionate use basis from the drug’s manufacturer GSK. Ribavirin, an antiviral utilized in the treatment of hepatitis C and RSV, also is known to have activity against influenza and has been utilized off-label in the treatment of some critically ill influenza patients.

References

  1. Kono S, Kida H, Mizuguchi M, et al. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza infection. Antimicrob Agents Chemother 2010;54:4568-4574.
  2. Watanabe A, Chang S, Kim MJ, et al. Long‐acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: a double‐blind, randomized, noninferiority clinical trial. Clin Infec Dis 2010;51:1167-75.

* The author is a shareholder of BioCryst Pharmaceuticals, the manufacturer of peramivir.