Summary Basis of Decision for Rapivab
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Rapivab is located below.
Recent Activity for Rapivab
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Rapivab
Updated:
The following table describes post-authorization activity for Rapivab, a product which contains the medicinal ingredient peramivir. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN)
- DIN 02460319 - 10 mg/mL, peramivir, solution, intravenous
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NDS # 211743 | 2017-12-08 | Issued NOC2018-01-03 | Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from Seqirus UK Limited to BioCryst Pharmaceuticals Inc. An NOC was issued. |
| SNDS # 201885 | 2017-01-12 | Issued NOC2017-06-20 | Submission filed as a Level I - Supplement to add a manufacturing and testing site for the drug product. The information was reviewed and considered acceptable. An NOC was issued. |
| NDS # 202433 | 2017-02-07 | Issued NOC2017-03-21 | Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from BioCryst Pharmaceuticals Inc. to Seqirus UK Limited. An NOC was issued. |
| NDS # 191280 | 2016-01-25 | Issued NOC2017-01-05 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Rapivab
Date SBD issued: 2017-03-07
The following information relates to the new drug submission for Rapivab.
Peramivir
10 mg/mL, solution, intravenous
Drug Identification Number (DIN):
- DIN 02460319 - 10 mg/mL, solution
BioCryst Pharmaceuticals Inc.
New Drug Submission Control Number: 191280
On January 5, 2017, Health Canada issued a Notice of Compliance to BioCryst Pharmaceuticals Inc. for the drug product Rapivab.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Rapivab is favourable for the treatment of acute uncomplicated influenza in patients 18 years and older, who have been symptomatic for no more than 2 days.
1 What was approved?
Rapivab is an antiviral drug for systemic use and acts as an inhibitor of influenza virus neuraminidase. Rapivab was authorized for the treatment of acute uncomplicated influenza in patients 18 years and older, who have been symptomatic for no more than 2 days.
Clinical trials of Rapivab did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.
Safety and efficacy of Rapivab in children less than 18 years of age have not been established.
Rapivab is contraindicated in patients with known hypersensitivity to any of the ingredients in the formulation or components of the container.
Rapivab was approved for use under the conditions stated in the Rapivab Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Rapivab (10 mg/mL peramivir) is presented as a solution, packaged in a single-use clear glass vial (200 mg/20 mL vial). Vials are supplied in cartons containing three single-use vials. In addition to the medicinal ingredient, the solution contains water for injection and sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Rapivab Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Rapivab approved?
Health Canada considers that the benefit/risk profile of Rapivab is favourable for the treatment of acute uncomplicated influenza in patients 18 years and older, who have been symptomatic for no more than 2 days.
Influenza is a respiratory infection caused by viruses that belong to the Orthomyxoviruses family of ribonucleic acid (RNA) viruses. Typical symptoms include: fever or feverishness, chills, cough, sore throat, nasal congestion, myalgia, headache, and fatigue. Although influenza can be a self-limiting disease, with resolution of symptoms within 5 to 7 days, there can also be serious complications such as bacterial pneumonia, sinusitis, and otitis media. According to the Public Health Agency of Canada, the reported number of influenza-associated adult hospitalizations over the past four influenza seasons (from the 2011/2012 season up to August 27, 2016 of the 2015/2016 season) ranged from approximately 2,000 to 8,000 per season. For the same period, the reported number of influenza-associated deaths in adults ranged from approximately 100 to 600 per season.
Two classes of influenza antiviral agents are currently approved, adamantanes and neuraminidase inhibitors.
Adamantanes (including amantadine) are not recommended for use due to the widespread resistance among influenza A virus strains. In addition, adamantanes have no activity against influenza B virus strains.
Neuraminidase inhibitors constitute a class of influenza antiviral drugs that inhibit the viral replication by selectively binding to the viral neuraminidase protein. The influenza virus neuraminidase is an enzyme responsible for the release of new viral particles from the infected cells. It may also facilitate the influenza virus spreading through the respiratory tract mucus. Two neuraminidase inhibitors (oseltamivir and zanamivir) have already been approved for treating acute uncomplicated influenza in Canada. Rapivab (peramivir) is the third drug in the neuraminidase inhibitors class and the first neuraminidase inhibitor for intravenous single-dose administration. Rapivab has demonstrated activity against influenza A and B subtypes including the 2009 novel pandemic influenza A strain (H1N1pdm09), highly pathogenic avian influenza H5N1, and the recently described novel avian influenza A (H7N9) virus.
Rapivab has been shown to be efficacious in the treatment of acute uncomplicated influenza in adult patients who have been symptomatic for no longer than 2 days. The market authorization was primarily based on 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.
The pivotal Study 621 demonstrated that a single intravenous dose of Rapivab 600 mg in patients with influenza virus infection resulted in a 22-hour reduction in median time to resolution of influenza symptoms as compared to placebo. Additional clinical evidence to support the clinical efficacy of Rapivab was derived from Study 631 in which Rapivab was shown to be statistically non-inferior to oral oseltamivir.
The efficacy and safety of Rapivab were also evaluated in several other Phase II and III studies conducted in hospitalized patients (Study 301 and 303), at-risk patients (Study 632), and studies conducted with an intramuscular formulation of Rapivab (Study 211, 212, and 311). However, due to differences in trial design, patient population, primary and secondary endpoints as well as clinical effectiveness, only tolerability and safety data from these studies were considered in the Health Canada review.
The safety profile of Rapivab was consistent across clinical studies and available post-marketing reports. The drug-drug interaction potential of Rapivab is low. No deaths or serious adverse events associated with Rapivab were observed in the placebo-controlled studies using a single dose of Rapivab in adult patients with acute uncomplicated influenza. The most common treatment-emergent adverse events observed in these clinical studies included diarrhea, decreased neutrophil count, and increased blood glucose, and their incident rates were similar to those observed in the control groups. No dose-related safety signals have been observed. Additionally, safety signals have not been detected in evaluating events of special interest such as neuropsychiatric events, rash, hypersensitivity, renal function, hematological abnormalities, hepatic function, and infusion site reactions. However, 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 impairment who are maintained on hemodialysis. These issues have been specifically addressed through appropriate labelling in the Rapivab Product Monograph.
Cases of anaphylactic hypersensitivity including anaphylactic shock, and cases of acute renal failure have been reported from post-marketing use of Rapivab in Japan. However, there have been no clear causal relationships with Rapivab use. In addition, rare cases of serious skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with Rapivab in clinical studies or in post-marketing experience. Therefore, the Warnings and Precautions section of the Rapivab Product Monograph includes description of serious skin/hypersensitivity reactions and requires appropriate monitoring if a serious skin reaction or anaphylaxis occurs or is suspected.
There have also been post-marketing reports from Japan of delirium and abnormal behavior leading to injury in patients with influenza (primarily in children or the elderly) who were receiving neuraminidase inhibitors, including Rapivab. A definitive relationship has not been confirmed between the use of neuraminidase inhibitors and reported neuropsychiatric events. Influenza itself can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These neuropsychiatric events and the need for monitoring patients for signs of abnormal behaviour are highlighted in the Warnings and Precautions section of the Rapivab Product Monograph.
Hepatic events reported in the post-marketing data (mainly from Japan) have no clear causal relationship with Rapivab use, however, the role of Rapivab in hepatic abnormalities could not be ruled out. Therefore, the post-marketing adverse drug reactions in the Rapivab Product Monograph list hepatic dysfunction and jaundice.
A Risk Management Plan (RMP) for Rapivab was submitted by BioCryst Pharmaceuticals Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
A Look-alike Sound-alike assessment was performed and the proposed name Rapivab was accepted.
Overall, the therapeutic benefits of Rapivab are considered to outweigh the potential risks. Rapivab has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and appropriate monitoring. Appropriate warnings and precautions are in place in the Rapivab Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Rapivab?
Submission Milestones: Rapivab
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2015-09-16 |
| Submission filed: | 2016-01-25 |
| Screening | |
| Screening Acceptance Letter issued: | 2016-03-11 |
| Review | |
| Quality Evaluation complete: | 2016-12-29 |
| Clinical Evaluation complete: | 2016-12-15 |
| Labelling Review complete: | 2017-01-03 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2017-01-05 |
In accordance with the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the Canadian regulatory decision was based on a critical assessment of the non-clinical, clinical pharmacology, and Phase I clinical studies reviews completed by the United States Food and Drug Administration (FDA). The clinical review conducted by Health Canada focused on Phase II and Phase III efficacy and safety studies.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Peramivir, the medicinal ingredient of Rapivab, is an inhibitor of influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells.
The clinical pharmacological data support the use of Rapivab for the specified indication.
In accordance with the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, and Method 1 for the use of foreign reviews, the Canadian regulatory decision-making process included a critical assessment of the clinical pharmacology review conducted by the United States Food and Drug Administration (FDA).
The pharmacokinetics of Rapivab was evaluated in Phase I trials in adults. The pharmacokinetic parameters following intravenous administration of Rapivab showed a linear relationship between dose and exposure parameters.
In a renal impairment study, when compared to a concurrent cohort with normal renal function, no change in mean maximum serum concentration (Cmax) was observed (6 subjects per cohort). However, mean area under the concentration-time curve from time zero to infinity (AUC0-∞) after a single 2 mg/kg intravenous dose was increased by 28%, by 302%, and by 412% in subjects with creatinine clearances of 50-79 mL/min, 30-49 mL/min, and 10-29 mL/min, respectively. Therefore, a reduced dose of Rapivab is recommended for patients with a creatinine clearance below 50 mL/min. Further, hemodialysis was effective in reducing systemic exposure of peramivir by 73% to 81%. Hence, in patients with chronic renal impairment maintained on hemodialysis, Rapivab should be administered after dialysis at a dose adjusted according to the renal function.
For further details, refer to the Rapivab Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Rapivab has been demonstrated in one pivotal placebo-controlled Phase II study (Study 621) and supported mainly by data derived from a non-inferiority Phase III study (Study 631) which used oral oseltamivir as a comparator.
Study 621 was a Phase II double-blind, parallel group, comparative dose-finding single-dose study conducted in Japan. A total of 300 adult patients with confirmed influenza infection (mostly infected with influenza A virus strains) were enrolled into this study. Randomized and treated patients (the intention-to-treat infected cohort) included 296 patients who received a single dose of either Rapivab 300 mg (number of patients, n = 99), Rapivab 600 mg (n = 97), or placebo (n = 100), administered by intravenous infusion over 30 minutes.
The study met its primary efficacy endpoint of time to alleviation of symptoms. The time to alleviation of symptoms (time to disappearance of influenza symptoms/duration of influenza) was defined as the time from the start of Rapivab dosing to the time point at which all of the seven influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, aches or pains of the muscle or joints, and fatigue), showed a score of "0: none" or "1: mild," as recorded by the patients, and when this condition persisted for at least 21.5 hours (24 hours-10%). Patients in both Rapivab treatment groups experienced a significantly shorter median time to alleviation of symptoms in comparison to the placebo group. The median duration of influenza was 59.1 hours in the Rapivab 300 mg group (one-sided p = 0.0046), 59.9 hours in the Rapivab 600 mg group (one-sided p = 0.003), and 81.8 hours in the placebo group.
Secondary efficacy endpoints included time to resolution of fever, change in virus titer and time to resumption of usual activities.
The median time to resolution of fever was 29.3 hours in the Rapivab 300 mg group, 30.2 hours in the Rapivab 600 mg group, and 42.4 hours in the placebo group. In comparison to the placebo group, both the Rapivab 300 mg group and Rapivab 600 mg group showed a significant reduction in the median time to resolution of fever (p = 0.0010 and 0.0005, respectively).
The change in virus titer (50% tissue culture infective dose [TCID50]/mL) from the time of screening to Day 3 (48 hours after dosing) was significantly larger in the Rapivab 600 mg group (p = 0.0027) but not in the Rapivab 300 mg group (p = 0.0968), as compared to the placebo group. The proportion of virus titer-positive patients at Day 3 was significantly lower in both Rapivab groups than in the placebo group. Few patients in any treatment group had detectable virus on Day 9.
The median time to resumption of usual activities was also significantly shorter (p<0.05) in both Rapivab groups in comparison to the placebo group.
The clinical efficacy of Rapivab in patients with influenza virus infection was further supported by data derived from Study 631, a non-inferiority Phase III, double-blind, parallel group, comparative study of single-dose intravenous Rapivab with oral oseltamivir phosphate. A total of 1,099 adult patients were enrolled in this study, within 48 hours of symptoms onset. The intention-to-treat infected cohort (n = 1,091) included randomized patients with positive rapid antigen test, who received a single intravenous dose of Rapivab 300 mg (n = 364) or 600 mg (n = 362), or oral oseltamivir phosphate 75 mg twice daily for 5 days (n = 365).
This study met its primary efficacy endpoint, the time to alleviation of symptoms (as defined in Study 621). The median time to alleviation of symptoms was comparable among the treatment groups: 78 hours in the Rapivab 300 mg group, 81 hours in the Rapivab 600 mg group, and 81.8 hours in the oseltamivir group. In both Rapivab groups, the upper limits of the 97.5% confidence interval (CI) for the hazard ratio to the oseltamivir group were below the predefined non-inferiority margin of 1.17, which demonstrated non-inferiority.
Similarly, most secondary efficacy endpoints of Study 631 (time to alleviation of individual symptoms, time to resolution of fever, time to resumption of normal activities) showed comparable results among the three treatment groups. However, the proportions of patients reporting normal temperature 24 hours after dosing were significantly higher in the Rapivab 300 mg and 600 mg groups than in the oseltamivir group. In addition, the virus titer measured at Visit 2 (Day 2 of treatment) in the Rapivab 600 mg group was significantly lower compared with the oseltamivir group. There were no significant viral titer changes from Day 3 onward, which was consistent with the results of the pivotal Study 621.
Notably, Study 631 was conducted in a period of time that partially overlapped with the 2009 influenza A/H1N1 pandemic when the resistance-conferring H275Y mutation in the viral neuraminidase ribonucleic acid sequence was observed. This may have affected the efficacy data for Rapivab (as well as for oseltamivir) when compared to the Rapivab efficacy data derived from the placebo-controlled Study 621.
A limited number of patients infected with influenza B virus strains were enrolled in the Phase II (1%-2%) and the Phase III (8%) studies of Rapivab. Non-clinical data suggest that Rapivab demonstrates activity against influenza B virus strains comparable to that of the other two neuraminidase inhibitors (oseltamivir and zanamivir). In addition, Rapivab shares the same mechanism of action with oseltamivir and zanamivir, both of which show effectiveness against influenza B virus strains. Therefore, it may be reasonable to hypothesize that Rapivab would also be clinically effective against influenza B virus strains. The limited data from the Phase III study of Rapivab show that patients with influenza B had significantly shorter time to alleviation of symptoms than those treated with oseltamivir (p = 0.0218). The limitation of clinical data regarding Rapivab efficacy in influenza B patients has been highlighted in the Warnings and Precautions section of the Rapivab Product Monograph.
For more information, refer to the Rapivab Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety evaluation of Rapivab was primarily based on data derived from the Study 621 and Study 631 (described in the Clinical Efficacy section). Safety data from three studies conducted with an intramuscular formulation of Rapivab (Study 211, Study 212 and Study 311) were also evaluated, as Phase I studies had demonstrated bioequivalence with the intravenous formulation. In addition, the safety review included post-marketing data and data derived from emergency use of Rapivab.
In the pivotal Study 621, the most common adverse drug reactions included nausea, vomiting, and abnormal changes in laboratory findings such as decreased white blood cell counts, increased lymphocyte and eosinophil fractions, and increased aspartate aminotransferase levels. No significant difference was observed in the incidence of adverse drug reactions between the Rapivab 300 mg group, the Rapivab 600 mg group, and the placebo group. No deaths or serious adverse events were reported. The adverse drug reactions mostly occurred within three days after dosing and most of them were mild to moderate in severity, followed by prompt recovery or improvement.
In Study 631, significant adverse drug reactions with an incidence of five events or more in at least one of the treatment groups were diarrhea, nausea, and decreased neutrophil count. Among them, diarrhea occurred more frequently in the Rapivab 600 mg group as compared to the oseltamivir group.
In the five randomized, double-blind, controlled studies (Study 621, Study 631, Study 211, Study 212, and Study 311), a total of 1,399 patients with acute uncomplicated influenza received a single dose of Rapivab, administered intravenously or intramuscularly, at doses up to 600 mg. Among the 664 patients with acute uncomplicated influenza who received (intravenously or intramuscularly) Rapivab 600 mg, the most common adverse reaction was diarrhea occurring in 8% of Rapivab-treated patients and 7% of placebo-treated patients. None of the patients who received Rapivab 600 mg experienced a serious adverse event and less than 1% discontinued study because of an adverse reaction. Clinically significant laboratory abnormalities (increases in alanine aminotransferase, serum glucose, and creatine phosphokinase; and decreases in the neutrophil count) occurred more frequently in patients treated with Rapivab 600 mg (administered intravenously or intramuscularly) than placebo.
In the post-marketing setting, there have been three reports of serious skin reactions, including one of Stevens-Johnson syndrome, and two of exfoliative dermatitis. Cases of anaphylactic hypersensitivity including anaphylactic shock, and cases of acute renal failure have also been reported from the post-marketing use of Rapivab in Japan. There have also been post-marketing reports (from Japan) of delirium and abnormal behavior leading to injury in patients with influenza (primarily in children or the elderly) who were receiving neuraminidase inhibitors, including Rapivab.
Overall, Rapivab has demonstrated a consistent safety profile across clinical studies and in post-marketing experience and is considered safe and well-tolerated. The most common treatment-emergent adverse events observed in the clinical studies included diarrhea, decreased neutrophil count, and increased blood glucose. These were similar to events observed in patients administered oseltamivir or placebo and were generally consistent with the acute illness and underlying concomitant medical conditions of the study subjects.
Appropriate warnings and precautions are in place in the approved Rapivab Product Monograph to address the identified safety concerns.
For more information, refer to the Rapivab Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical pharmacology and toxicology studies support the use of peramivir, the medicinal ingredient of Rapivab, for the specified indication.
In accordance with the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, and Method 1 for the use of foreign reviews, the Canadian regulatory decision making process included a critical assessment of the pre-clinical review conducted by the United States Food and Drug Administration (US FDA).
Single-dose toxicity studies conducted in rats, mice, and dogs revealed that intravenous and intramuscular routes of administration caused local irritation. A single-dose oral study conducted in rabbits elicited renal toxicity including discolored foci in the kidneys, without microscopic changes, at 2,400 mg/kg, whereas a single intravenous dose at 200 mg/kg or 300 mg/kg produced renal tubular necrosis accompanied by an increased blood urea nitrogen (BUN), creatinine, urine volume, and altered sodium and chloride excretions. Multiple-dose studies also elicited renal toxicity. The nephrotoxicity studies were consistent in the identification of a no-observed-adverse-effect-level (NOAEL) of 100 mg/kg/day in the rabbit with respect to acute tubular necrosis. The rabbit appeared to be the sensitive species for the nephrotoxic effects of peramivir, which occurred at exposures approximately 2- to 4-fold higher than those of humans at the clinically recommended dose. Renal toxicity did occur at high drug exposures in monkeys or with longer treatment duration in rats. Abnormal liver function was observed concurrently with nephrotoxicity in rabbits at high intravenous doses (≥200 mg/kg). Significant liver toxicity was not reported in other animal species.
Reduced susceptibility of influenza virus to inhibition by peramivir may be conferred by amino acid substitutions in the viral neuraminidase or hemagglutinin proteins. The amino acid substitutions associated with reduced susceptibility to peramivir were observed in influenza A and B virus isolates collected during clinical trials with peramivir and in community surveillance studies.
Cross-resistance between peramivir, oseltamivir and zanamivir was observed in neuraminidase biochemical assays and cell culture assays. No single amino acid substitution has been identified that could confer cross-resistance between the neuraminidase inhibitor class (peramivir, oseltamivir, zanamivir) and the m2 ion channel inhibitor class (amantadine, rimantadine).
The results of the non-clinical studies as well as the potential risks to humans have been included in the Rapivab Product Monograph. In view of the intended use of Rapivab, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Rapivab Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Rapivab has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 60 months is acceptable when the drug product is stored between 15ºC and 30ºC.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| RAPIVAB | 02460319 | BIOCRYST PHARMACEUTICALS INC | PERAMIVIR 10 MG / ML |