Rapivab (Page 5 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies by intravenous injection of peramivir were not performed. However, in an oral carcinogenicity study in Sprague-Dawley rats no drug-related neoplasms were observed at drug exposures 0.2- to 0.5-fold that of humans at the clinically recommended dose of 600 mg/day.

Mutagenesis

Peramivir was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay, the Chinese hamster ovary chromosomal aberration test, and the in vivo mouse micronucleus test with intravenous administration.

Impairment of Fertility

Peramivir had no effects on mating or fertility in rats up to 600 mg/kg/day, at which exposures were approximately 8-fold of those in humans at the clinically recommended dose.

13.2 Animal Toxicology and/or Pharmacology

Peramivir caused renal tubular necrosis and abnormal renal function in rabbits. Toxicities included tubular dilatation and necrosis with protein casts in cortical areas, dilated tubules with mineralization in corticomedullary junction areas, and multifocal tubular regeneration. The rabbit appeared to be the sensitive species for peramivir renal toxicity, which was noted at exposures approximately 2- to 4-fold those in humans at the clinically recommended dose.

14 CLINICAL STUDIES

14.1 Acute Uncomplicated Influenza in Adults

Study 621 was a randomized, multicenter, blinded study conducted in Japan that evaluated a single intravenous administration of RAPIVAB 300 mg, RAPIVAB 600 mg, or placebo administered over 30 minutes in subjects 20 to 65 years of age with acute uncomplicated influenza. Subjects were eligible if they had fever ≥38°C (axillary) and a positive rapid antigen test for influenza virus, accompanied by at least 2 symptoms (cough, nasal symptoms, sore throat, myalgia, chills/sweats, malaise, fatigue, or headache). In addition, all subjects enrolled were allowed to take fever-reducing medications.

Study treatment was started within 48 hours of onset of symptoms. Subjects participating in the study were required to self-assess their influenza symptoms as “none”, “mild”, “moderate”, or “severe” twice daily. The primary endpoint, time to alleviation of symptoms, was defined as the number of hours from initiation of study drug until the start of the 24-hour period in which all 7 symptoms of influenza (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) were either absent or present at a level no greater than mild for at least 21.5 hours.

The overall efficacy population, consisting of subjects with confirmed influenza and administered study drug, totaled 297 subjects. Among the 98 subjects enrolled in the RAPIVAB 600 mg dose group, the mean age was 34 years; 55% were male; 34% were smokers; 99% were infected with influenza A virus and 1% were infected with influenza B virus. The majority of subjects (53%) had influenza illness lasting <24 hours at the time of presentation.

Overall, subjects receiving RAPIVAB 600 mg experienced alleviation of their combined influenza symptoms a median of 21 hours sooner than those receiving placebo. The median time to recovery to normal temperature (<37°C) in the 600 mg group was approximately 12 hours sooner compared to placebo.

Insufficient numbers of subjects infected with influenza B virus were enrolled to determine efficacy of RAPIVAB in this influenza type.

14.2 Acute Uncomplicated Influenza in Pediatric Subjects

Study 305 was a randomized, multicenter, open-label, active-controlled trial to evaluate the safety, pharmacokinetics, and efficacy of a single intravenous dose of RAPIVAB administered for a minimum of 15 minutes in subjects 6 months to 17 years of age with acute uncomplicated influenza who had fever ≥37.8°C (oral) with at least one respiratory symptom (cough or rhinitis) or a positive influenza rapid antigen test. Study treatment was started within 48 hours of onset of symptoms. Subjects were randomized to receive RAPIVAB 600 mg (13 to 17 years of age), RAPIVAB 12 mg/kg up to a maximum dose of 600 mg (6 months to 12 years of age), or oral oseltamivir taken twice daily for 5 days. In addition, all enrolled subjects were allowed to take fever-reducing medications.

The overall efficacy population, consisting of subjects with confirmed influenza who were administered study drug, totaled 97 subjects. Among the 81 subjects treated with RAPIVAB, the median age was 7.5 years; 52% were male; 60% were infected with influenza A virus, 33% were infected with influenza B virus, and 6% were co-infected with influenza A and B viruses.

The primary endpoint was the safety of peramivir compared to oseltamivir as measured by adverse events, laboratory analysis, vital signs, and physical exams. Secondary endpoints included efficacy outcomes such as time to resolution of influenza symptoms and time to resolution of fever; however, the study was not powered to detect statistically significant differences in these secondary endpoints. Subjects receiving RAPIVAB experienced a median time to alleviation of their combined influenza symptoms of 79 hours (interquartile range: 31 to 126 hours) compared to 100 hours (interquartile range: 57 to 145 hours) in subjects receiving oseltamivir. The median time to recovery to normal temperature (<37°C) was 40 hours (interquartile range: 21 to 68 hours) and 35 hours (interquartile range: 16 to 42 hours) in subjects receiving RAPIVAB and oseltamivir, respectively [see Use in Specific Populations (8.4)].

14.3 Serious Influenza Requiring Hospitalization

The efficacy of RAPIVAB could not be established in patients with serious influenza requiring hospitalization [see Indications and Usage (1)].

A randomized, double-blind, multicenter, placebo-controlled trial (Study 301) was conducted in 398 subjects with serious influenza requiring hospitalization. Subjects were randomized to receive RAPIVAB 600 mg daily for 5 days plus standard of care versus standard of care plus placebo within 72 hours of start of symptoms. The primary endpoint was time to clinical resolution defined as the time in hours from initiation of study treatment until resolution of at least 4 of 5 signs (temperature, oxygen saturation, respiration rate, heart rate, or systolic blood pressure), maintained for at least 24 hours. RAPIVAB plus standard of care did not improve median time to clinical resolution compared with standard of care alone.

16 HOW SUPPLIED/STORAGE AND HANDLING

RAPIVAB injection is a clear, colorless sterile, isotonic solution. Each single-use vial contains 200 mg per 20 mL (10 mg/mL) of peramivir in a clear glass vial (NDC # 72769-181-01). RAPIVAB injection is supplied in cartons containing 3 single-use vials (NDC # 72769-181-03).

Store vials of RAPIVAB injection in original cartons at 20°C to 25°C (68°F to 77°F). Excursions are permitted to 15°C to 30°C (59°F to 86°F).

Do not use if seal over bottle opening is broken or missing.

17 PATIENT COUNSELING INFORMATION

Advise patients of the following:

• There is a risk of severe allergic reactions (including anaphylaxis) or serious skin reactions with RAPIVAB use. Advise patients to seek immediate medical attention if an allergic-like reaction occurs or is suspected [see Warnings and Precautions (5.1)].
• There is a risk of neuropsychiatric events in patients with influenza. Patients should contact their physician if they experience signs of abnormal behavior after receiving RAPIVAB [see Warnings and Precautions (5.2)].

RAPIVAB is a registered trademark of BioCryst Pharmaceuticals, Inc.

Manufactured for and distributed by:
BioCryst Pharmaceuticals, Inc.
Durham, NC 27703

RAP:8PI

PRINCIPAL DISPLAY PANEL — 200 mg/20 mL Vial Carton

Rx Only

NDC 72769-181-03

Rapivab^®
peramivir injection

200 mg/20 mL per vial
(10 mg/mL)

For Intravenous
Infusion Only
Dilute Before Use

Carton contains 3 vials

RAPIVAB peramivir solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72769-181 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength peramivir (peramivir anhydrous) peramivir anhydrous 600 mg in 60 mL

Inactive Ingredients Ingredient Name Strength Sodium Chloride Hydrochloric Acid Sodium Hydroxide Water

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:72769-181-03 3 VIAL, GLASS in 1 CARTON contains a VIAL, GLASS (72769-181-01) 1 NDC:72769-181-01 20 mL in 1 VIAL, GLASS This package is contained within the CARTON (72769-181-03)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA206426 12/20/2014

Labeler — BioCryst Pharmaceuticals, Inc. (618194609)

Establishment
Name	Address	ID/FEI	Operations
Alcami Carolinas Corporation		117877975	ANALYSIS (72769-181)

Establishment
Name	Address	ID/FEI	Operations
Cilag Ag		483237103	API MANUFACTURE (72769-181), ANALYSIS (72769-181)

Establishment
Name	Address	ID/FEI	Operations
Eurofins Lancaster Laboratories Inc.		069777290	ANALYSIS (72769-181)

Establishment
Name	Address	ID/FEI	Operations
Galbraith Laboratories Inc.		042456145	ANALYSIS (72769-181)

Establishment
Name	Address	ID/FEI	Operations
Jubilant HollisterStier LLC		069263643	MANUFACTURE (72769-181), PACK (72769-181), LABEL (72769-181), ANALYSIS (72769-181)

Establishment
Name	Address	ID/FEI	Operations
Patheon Manufacturing Services LLC		079415560	MANUFACTURE (72769-181), PACK (72769-181), LABEL (72769-181), ANALYSIS (72769-181)

Establishment
Name	Address	ID/FEI	Operations
Siegfried USA, LLC		001213784	API MANUFACTURE (72769-181), ANALYSIS (72769-181)

Revised: 11/2022 BioCryst Pharmaceuticals, Inc.