RAPIVAB Solution for injection Ref.[10158] Active ingredients: Peramivir

Peramivir is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].

The pharmacokinetics of RAPIVAB was evaluated in Phase 1 trials in adults. The pharmacokinetic parameters following intravenous administration of RAPIVAB (0.17 to 2 times the recommended dose) showed a linear relationship between dose and exposure parameters (C_max and AUC).

Following intravenous administration of a single dose of RAPIVAB 600 mg over 30 minutes, a maximum serum concentration (C_max) of 46,800 ng/mL (46.8 μg/mL) was reached at the end of infusion. AUC_0-∞ values were 102,700 ng•hr/mL.

Distribution

In vitro binding of peramivir to human plasma proteins is less than 30%.

Based on a population pharmacokinetic analysis, the central volume of distribution was 12.56 L.

Metabolism and Elimination

Peramivir is not a substrate for CYP enzymes, does not affect glucuronidation, and is not a substrate or inhibitor of P-glycoprotein mediated transport.

Peramivir is not significantly metabolized in humans.

The elimination half-life of RAPIVAB following IV administration to healthy subjects of 600 mg as a single dose is approximately 20 hours. The major route of elimination of RAPIVAB is via the kidney. Renal clearance of unchanged peramivir accounts for approximately 90% of total clearance. Negligible accumulation was observed following multiple doses, either once or twice daily, for up to 10 days.

Specific Populations

Race

Pharmacokinetics of peramivir was evaluated primarily in Caucasians and Asians. Based on a population pharmacokinetic analysis including race as a covariate, volume of distribution was dependent on weight and Asian race. No dose adjustment is required based on weight or Asian race.

Gender

Peramivir pharmacokinetics was similar in male and female subjects.

Pediatric Patients

The pharmacokinetics of peramivir has been evaluated in a study in pediatric subjects 2 to 17 years of age with acute uncomplicated influenza. Pharmacokinetic sampling in this study was limited to approximately 3 hours after administration of peramivir. Pharmacokinetics of peramivir in subjects 13 to 17 years of age was similar to those in adult subjects, with a C_max of 54,300 ng/mL and AUC_0-last of 72,400 ng•h/mL after administration of a single 600 mg dose. Pharmacokinetics of peramivir in subjects 2 to 12 years of age (C_max of 61,300 ng/mL and AUC_0-last of 81,700 ng•h/mL) administered a single 12 mg/kg dose was also similar to that in adult subjects administered a single 600 mg dose.

Geriatric Patients

Peramivir pharmacokinetics in elderly subjects was similar to non-elderly subjects. Peak concentrations of peramivir after a single 4 mg/kg IV dose were approximately 10% higher in elderly subjects when compared to young adults (22,647 vs 20,490 ng/mL, respectively). Exposure (AUC_0-12) to peramivir at steady state was roughly 34% higher in elderly subjects compared to young adults (61,572 vs 46,000 ng•hr/mL, respectively). Dose adjustment is not required for elderly patients.

Patients with Impaired Renal Function

A trial was conducted in adult subjects with various degrees of renal impairment. When compared to a concurrent cohort with normal renal function, no change in mean C_max was observed (6 subjects per cohort). However, mean AUC_0-∞ after a single 2 mg/kg IV dose was increased by 28%, by 302%, and by 412% in subjects with creatinine clearance 50-79, 30-49, and 10-29 mL/min, respectively.

Hemodialysis was effective in reducing systemic exposure of peramivir by 73% to 81%.

A reduced dose of RAPIVAB is recommended for patients with creatinine clearance below 50 mL/min [see Dosage and Administration (2.2)].

The pharmacokinetics of peramivir has not been studied in pediatric subjects with renal impairment. Given that the pharmacokinetics in pediatric subjects is comparable to that observed in adults, the same proportional dose reduction in pediatric patients is recommended [see Dosage and Administration (2.2)].

Patients with Hepatic Impairment

The pharmacokinetics of peramivir in subjects with hepatic impairment has not been studied. No clinically relevant alterations to peramivir pharmacokinetics are expected in patients with hepatic impairment based on the route of peramivir elimination.

Assessment of Drug Interactions

The potential for CYP mediated interactions involving RAPIVAB with other drugs is low, based on the known elimination pathway of RAPIVAB, and data from in vitro studies indicating RAPIVAB does not induce or inhibit cytochrome P450.

There was no evidence of drug-drug interactions when RAPIVAB was administered with oral rimantadine, oseltamivir, or oral contraceptives containing ethinyl estradiol and levonorgestrel; or when peramivir IM was administered with oral probenecid.

RAPIVAB is primarily cleared in the urine by glomerular filtration.

Mechanism of Action

Peramivir is an inhibitor of influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells. The median neuraminidase inhibitory activities (IC₅₀ values) of peramivir in biochemical assays against influenza A/H1N1 virus, influenza A/H3N2 virus, and influenza B virus clinical isolates were 0.16 nM (n=44; range 0.01-1.77 nM), 0.13 nM (n=32; range 0.05-11 nM), and 0.99 nM (n=39; range 0.04-54.2 nM), respectively, in a neuraminidase assay with a fluorescently labeled MUNANA substrate.

Antiviral Activity

The antiviral activity of peramivir against laboratory strains and clinical isolates of influenza virus was determined in cell culture. The concentrations of peramivir required for inhibition of influenza virus in cell culture varied depending on the assay method used and the virus tested. The median 50% effective concentrations (EC₅₀ values) of peramivir in cell culture assays were 2.6 nM (n=13; range 0.09-21 nM), 0.08 nM (n=17; range 0.01-1.9 nM) and 4.8 nM (n=11; range 0.06-120 nM) for influenza A/H1N1 virus, A/H3N2 virus, and B virus strains, respectively.

The relationship between the antiviral activity in cell culture, inhibitory activity in the neuraminidase assay, and the inhibition of influenza virus replication in humans has not been established.

Resistance

Cell culture

Influenza A and B virus isolates with reduced susceptibility to peramivir were recovered by serial passage of virus in cell culture in the presence of increasing concentrations of peramivir. Reduced susceptibility of influenza virus to inhibition by peramivir may be conferred by amino acid substitutions in the viral neuraminidase or hemagglutinin proteins (Table 4).

Table 4. Amino Acid Substitutions Selected by Peramivir in Cell Culture Studies:

^* Numbering based on A/California/04/2009
^† Numbering based on A/Texas/50/2012
^‡ Numbering based on B/Massachusetts/02/2012
^§ Numbering begins after the predicted signal peptide.

In vivo

Influenza A and B virus isolates with amino acid substitutions associated with reduced susceptibility to peramivir were observed in clinical isolates collected during clinical trials with peramivir (Table 5). Amino acid substitutions have also been observed in viral isolates sampled during community surveillance studies which may be associated with reduced susceptibility to peramivir (Table 5). The clinical impact of this reduced susceptibility is unknown and may be strain-dependent.

Table 5. Neuraminidase Amino Acid Substitutions Associated with Reduced Susceptibility to Peramivir in Clinical Virus Isolates:

^* Numbering based on A/California/04/2009
^† Numbering based on A/Texas/50/2012
^‡ Numbering based on B/Massachusetts/02/2012

Circulating seasonal influenza strains expressing neuraminidase resistance-associated substitutions have been observed in individuals who have not received RAPIVAB. Prescribers should consider available information from the CDC on influenza virus drug susceptibility patterns and treatment effects when deciding whether to use RAPIVAB.

Cross Resistance

Cross-resistance between peramivir, oseltamivir and zanamivir was observed in neuraminidase biochemical assays and cell culture assays. The amino acid substitutions that resulted in reduced susceptibility to peramivir and either oseltamivir or zanamivir are summarized in Table 6. The clinical impact of this reduced susceptibility is unknown and may be strain-dependent.

Table 6. Summary of Amino Acid Substitutions with Cross-Resistance between Peramivir and Oseltamivir or Zanamivir in Susceptibility Assays:

^* Numbering based on A/California/04/2009
^† Numbering based on A/Texas/50/2012
^‡ Numbering based on B/Massachusetts/02/2012
^§ Numbering begins after the predicted signal peptide.

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). However, a virus may carry a neuraminidase inhibitor resistance-associated substitution in neuraminidase and an M2 ion channel inhibitor resistance-associated substitution in M2 and may therefore be resistant to both classes of inhibitors. The clinical relevance of phenotypic cross-resistance evaluations has not been established and may be strain-dependent.

Immune Response

No influenza vaccine/peramivir interaction study has been conducted.

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.

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.

14.1 Acute Uncomplicated Influenza in Adults

Study 621 was a randomized, multicenter, blinded trial 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 greater than or equal to 38°C (axillary) and a positive rapid antigen test for influenza virus, accompanied by at least two 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 trial 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 seven 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 less than 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 (less than 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 2 to 17 years of age with acute uncomplicated influenza who had fever greater than or equal to 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 (2 to 12 years of age), or oral oseltamivir BID 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 84 subjects. Among the 69 subjects treated with RAPIVAB, the median age was 7.9 years; 55% were male; 58% were infected with influenza A virus, 36% 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 trial 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: 34-122 hours) compared to 107 hours (interquartile range: 57-145 hours) in subjects receiving oseltamivir. The median time to recovery to normal temperature (less than 37°C) was 40 hours (interquartile range: 19-68 hours) and 28 hours (interquartile range: 15-41 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.