Regulatory Decision Summary for Rapivab

Health Canada considers that the benefit/risk profile of Rapivab is favorable when used as directed in the treatment of acute uncomplicated influenza in patients 18 years and older, who have been symptomatic for no more than 2 days.

The approval of Rapivab is based on the review of the clinical pharmacology, safety, and efficacy data submitted. The clinical benefits of Rapivab intravenous (IV) infusion regimen (600 milligram [mg] single dose) in the treatment of adult patients with acute uncomplicated influenza who have been symptomatic for no more than 2 days are adequately demonstrated by one pivotal randomized double-blind placebo-controlled Phase II study (Study 621) and one non-inferiority Phase III study (Study 631) which used oseltamivir as a comparator.

Study 621 showed a significant clinical benefit of 22 hrs sooner for the Time to Alleviation of Symptoms (TTAS) in the Rapivab groups as compared with patients receiving placebo (59.1 hrs in the 300 mg group [one-sided p=0.0046] or 59.9 hrs in the 600 mg group [one-sided p=0.003] vs. 81.8 hrs in the placebo). The 600 mg dosing group showed a significant viral titer decrease as compared to placebo (Median Tissue Culture Infective Dose was 1.5 in 600 mg group vs. 1.2 in placebo; p=0.0027). The clinical efficacy was further supported by results of Study 631 in which Rapivab was statistically non-inferior to oral oseltamivir. The primary endpoint of TTAS was comparable across treatment groups with a median of 78 hrs in the Rapivab 300 mg group, 81 hrs in the Rapivab 600 mg group vs. 81.8 hrs in the oseltamivir group. For changes in body temperature over time, it was significantly lower in the Rapivab 600 mg group at 12 hrs after dosing as compared with the oseltamivir group (p=0.0472) and both Rapivab groups showed significantly lower body temperature at 24 hrs after dosing vs. that in the oseltamivir group (p=0.016 and p=0.0064 respectively). The 600 mg dose of Rapivab achieved a better viral titer reduction at Day 2 after dosing as compared with that of the oseltamivir control (p=0.0107). Furthermore, the proportion of patients who were positive for influenza virus titer was significantly lower in the Rapivab 600 mg group than that in the oseltamivir group (p=0.0038).

Study 631 was conducted in a period of time that partially overlapped with the 2009 H1N1 pandemic influenza when the resistance-conferring H275Y mutation in the viral neuraminidase ribonucleic acid sequence was observed. A limited number of patients infected with influenza B were enrolled in the Phase II (1-2%) and the Phase III (8%) studies. Non-clinical data suggest that Rapivab has activity against influenza B comparable to that seen with the other two neuraminidase inhibitors (i.e., oseltamivir and zanamivir). Rapivab shares the same mechanism of action with oseltamivir and zanamivir which show antiviral effectiveness against influenza B strains. Therefore, it is reasonable to hypothesize that Rapivab would also be clinically effective against influenza B. The limited data from the Phase III study of Rapivab show that patients with influenza B had significantly shorter TTAS than that with oseltamivir control (p=0.0218). However, the limitation of the clinical data supporting Rapivab in the treatment of influenza B infection is presented in the Product Monograph.

The safety profile of Rapivab is consistent across clinical studies and available post-marketing reports. The drug-drug interaction potential of Rapivab is low. No Rapivab-use-associated deaths or serious adverse events were observed in the placebo controlled trials using a single dose of Rapivab in acutely infected uncomplicated adult patients. The most common treatment emergent adverse events observed in these clinical trials include diarrhea, decreased neutrophil count, and increased blood glucose, and the incident rates are similar to events observed in subjects in the control group. No dose-related safety signals have been observed. Additionally, safety signals have not been detected in special analyses evaluating "Events of Special Interest" such as neuropsychiatric events, rash, hypersensitivity, renal function, hematological abnormalities, hepatic function, and infusion site reactions. A reduced dose is recommended for patients with moderate or severe renal impairment based on human pharmacokinetic studies. Dose adjustment is also recommended for patients with chronic renal dysfunctions on hemodialysis.

Cases of anaphylactic hypersensitivity including anaphylactic shock and acute renal failure have been reported recently from post-market use in Japan, however there were no clear causal relationships with the use of Rapivab.

The uncertainties associated with the use of Rapivab include use in a variety of ages, with comorbidities, and with concomitant medications.

The overall benefits demonstrated for Rapivab are considered to outweigh the risks with a single IV dose of 600 mg in adult patients infected with acute uncomplicated influenza A or B under the conditions of use as described in the Product Monograph.

For more information on Health Canadas decision, please view the Summary Basis of Decision.