Healio
Healio
Issue: January 2016
ByLeah Molloy, PharmD
January 19, 2016
5 min read
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Rapivab: An IV neuraminidase inhibitor

Issue: January 2016
ByLeah Molloy, PharmD
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The 2014-2015 influenza season was notable for a higher-than-average rate of hospitalizations. A poor match between vaccine and circulating virus, owing to an antigenic drift of the H3N2 virus, led to reduced vaccine effectiveness. Another significant development last season was the December 2014 approval of Rapivab, an IV neuraminidase inhibitor.

Neuraminidase inhibitors (NIs) are the only antiviral drugs recommended for the treatment of influenza A and B infections. NIs function by preventing the enzyme neuraminidase from releasing viral particles from host cells after replication, which prevents further spread of infection. Currently available NIs include oral Tamiflu (oseltamivir, Genentech), inhaled Relenza (zanamivir, GlaxoSmithKline), and now IV Rapivab (peramivir, BioCryst Pharmaceuticals). Before this approval the only longstanding NI option for patients unable to receive enteral or inhalation therapy was the acquisition of an IV preparation of zanamivir through a clinical trial or submission of an emergency investigational new drug request. This remains an option for the 2015-2016 influenza season. Peramivir briefly became available for use during the 2009 H1N1 influenza pandemic through an FDA-granted Emergency Use Authorization (EUA). At that time, peramivir use was authorized for hospitalized adults and children either unresponsive to or intolerant of oral or inhaled therapy.

Peramivir is indicated for the treatment of adults with uncomplicated influenza, to be administered as a single IV dose within 2 days of symptom onset. This approval is based on findings from a randomized controlled trial that assigned previously healthy adult patients with uncomplicated influenza to receive either peramivir 300 mg (n = 99), peramivir 600 mg (n = 97), or placebo (n = 100). Patients receiving peramivir had significantly shorter median time to alleviation of symptoms (59.1 hours vs. 59.9 hours vs. 81.8 hours).

Leah Molloy

Currently available NIs are approved only for the treatment of acute, uncomplicated influenza infection, but potential utility in severe illness requiring hospitalization is acknowledged by the CDC in its recommendations for the 2015-2016 influenza season. While the CDC concludes that data are insufficient regarding peramivir in this setting, oseltamivir is recommended for hospitalized patients and consideration of IV peramivir or IV zanamivir is suggested for those patients unable to absorb or tolerate oral oseltamivir.

A randomized controlled trial investigating peramivir for hospitalized patients found no benefit over placebo. In that study, patients received either peramivir or placebo in addition to institutional standard of care. Of the 338 patients in the intention-to-treat infected population, 217 received a concomitant NI. Among the remaining 121 patients who did not receive a concomitant NI, median time to clinical resolution was 42.5 hours in the peramivir group and 49.5 hours in the placebo arm. (P = .97) A larger though still not statistically significant effect was observed among patients with symptom onset of 48 hours or less at time of randomization (42.9 hours vs. 58.2 hours) and those requiring admission to an ICU (31.5 hours vs. 50.2 hours). The study was ultimately halted for futility, concluding that peramivir did not offer a significant clinical benefit over placebo for patients already receiving standard of care. However, as other studies have identified a benefit of using oseltamivir in hospitalized patients, a potential role for peramivir as a substitute may be considered for critically ill patients unable to absorb or tolerate enterally administered oseltamivir.

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Peramivir is approved only as a single 600-mg dose for adult patients with acute, uncomplicated influenza infection. Peramivir is supplied as 200 mg in a 20-mL single-use vial, requiring three vials per dose for the single 600-mg dose recommended for adults with uncomplicated infection. When given as a single dose per package insert, dose adjustment is needed for patients with renal impairment yielding a creatinine clearance (CrCl) below 50 mL/min. For the labeled single-dose administration, dose reduction to 200 mg is recommended for CrCl 30-49 mL/min, and a 100-mg dose should be given to patients with CrCl 10-29 mL/min. As described above, peramivir has also been studied and was briefly authorized under the 2009 H1N1 EUA for treatment of hospitalized patients with severe and complicated infection. In these settings, doses of 600 mg daily for 5 to 10 days, to allow for the anticipated prolonged duration of viral shedding in critically ill patients, were used. While also outside of its approved indication, peramivir has been used in the treatment of children hospitalized for severe illness. The studied dose recommended for children aged 6 years and older during the 2009 H1N1 EUA was 10 mg/kg daily, up to a maximum dose of 600 mg, for the same 5- to 10-day duration used for adult patients. Renal dose adjustments recommended for treatment were 150 mg daily for adult patients with CrCl 31-49 mL/min, and 100 mg daily for patients with CrCl 10-30 mL/min or after hemodialysis. Peramivir may be diluted per manufacturer directions in saline, dextrose or Lactated Ringer’s solutions for IV over 15 to 30 minutes.

NIs are generally well-tolerated, and adverse reactions related to peramivir are consistent with class effects. Like oseltamivir and zanamivir, the peramivir package insert carries warnings for neuropsychiatric events and hypersensitivity reactions including Stevens-Johnson syndrome. No clinically significant drug-drug interactions have been described for this class of drug; however, administration of live-attenuated influenza vaccine within 2 weeks before or 48 hours after peramivir should be avoided because the two products may interfere with each other. In contrast, no such precautions are needed when administering inactivated influenza vaccine to patients who have recently received or will receive peramivir. While uncommon in the United States, NI resistance has been described, and in those cases peramivir is not expected to offer any susceptibility advantage over other NIs. In contrast, H1N1 viruses resistant to oseltamivir and peramivir may remain susceptible to zanamivir.

Peramivir is significantly more expensive than oseltamivir. A single 600-mg dose for treatment of acute, uncomplicated influenza costs $950 compared with $124 for a comparable 5-day course of oseltamivir for the same indication. As such, for the 2015–2016 influenza season, peramivir may be prioritized for off-label treatment of severe infection among critically ill patients requiring an IV route of administration.

  • For more information:
  • Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at lmolloy@dmc.org.

Disclosure: Molloy reports no relevant financial disclosures.

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