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Peramivir Fact Sheet for Health Care Providers (cont.)

OVERDOSAGE

There is no human experience of acute overdosage with Peramivir. Treatment of overdose with Peramivir IV should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with Peramivir IV.

Peramivir IV is cleared by hemodialysis.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of Peramivir IV have been evaluated in adults in several phase 1 trials. The pharmacokinetic parameters following IV administration of Peramivir (dose range 0.5 mg/kg up to 8 mg/kg) showed a linear relationship between dose and the exposure parameters (Cmax and AUC). The half-life of Peramivir IV following administration of 0.5 mg/kg to 8 mg/kg as a single dose or 4 mg/kg twice daily for 1 day ranged from 7.7 hours to 20.8 hours. Table 4 shows the summary of the pharmacokinetic parameters of Peramivir at various IV doses across multiple studies.

Table 4: Summary of the PK Parameters of Peramivir after Intravenous (IV) Administration of Peramivir Across Multiple Studies

Study Number Dose(s) Administered Intravenously Number of Patients Mean Cmax ng/mL Mean AUC0-∞ ng*hr/mL
Hi-06-101 0.5 mg/kg single dose 6 1925.8 4975.2
Hi-06-102 0.5 mg/kg BID x one day 6 2549.2a 6035.9a
BCX1812-103 1 mg/kg single dose 6 5531.7 12246.7
2 mg/kg single dose 6 11346.7 22689.7
4 mg/kg single dose 6 20491. 7 49902.2
8 mg/kg single dose 6 44666.7 90666.0
4 mg/kg BID X one day 7 21933.3a 47776.2a
2 mg/kg BID X 10 days 9 12935.6b 26132.1b
4 mg/kg BID X 10 days 9 24533.3b 49272.1b
BCX1812-104 (healthy elderly patients ≥ 65 years of age) 4 mg/kg BID X one day 20 23600.0 ND
4 mg/kg BID X 5 days 6 22608.3c 78950.1c
4 mg/kg BID X 10 days 6 22933.3d 67425.4d
BCX1812-105 (patients with renal impairment) 2.0 mg/kg single dose CrCL > 80 mL/min 6 12775.0 25932.1
2.0 mg/kg single dose CrCL 50-80 mL/min 6 11900.8 32103.4
2.0 mg/kg single dose CrCL 30-49 mL/min 6 13698.3 109233.9
2.0 mg/kg single dose CrCL < 30 mL/min 6 12325.0 136918.3
2.0 mg/kg (pre-dialysis) 6 11020 137819.5e
2.0 mg/kg (after dialysis) 6 15475.0 1013660.9f
BCX1812-111 75 mg single dose 9 4652.2 10843.2
150 mg single dose 9 9400.6 24198
300 mg single dose 9 17166.7 47241.1
a. Cmax and AUC0-12hours after the second infusion
b. AUC0-72hours after the second dose on Day 10
c. Cmax and AUC0-48hours after the second infusion on Day 5
d. Cmax and AUC0-48hours after the second infusion on Day 10
e. PK measurements before dialysis
f. PK measurements after dialysis

The major route of elimination of unchanged Peramivir IV is via the kidney. In patients with normal renal function, the apparent elimination half-life of intravenously administered Peramivir ranged from 7.7 to 20.8 hours.

Special Populations

Gender, Race and Age

Pharmacokinetic differences for gender and race have not been evaluated.

Comparisons of the pharmacokinetics of Peramivir administered intravenously in healthy young volunteers with data from healthy volunteers ( ≥ 65 years of age) suggest patients ≥ 65 years of age group had approximately a 46% increase in dose-normalized AUC and on average, approximately 26% lower clearance of Peramivir IV primarily due to decrease in kidney function. Peramivir IV Cmax was independent of age and dose adjustment is not currently recommended for patients ≥ 65 years of age.

Pediatric Patients

Peramivir has not been administered to any pediatric patients (age < 18 years) in clinical trials.

The pharmacokinetics in pediatric patients have not been studied. Dosing recommendations for pediatric patients (birth to 17 years of age) are based on modeling and simulation of pharmacokinetic data from adult healthy volunteers and adult patients with influenza and patient pharmacokinetic data and information on renal maturation and body weight [see Dose Rationale].

Renal Impairment – Adults

Peramivir pharmacokinetics were studied in healthy adult patients with mild, moderate, and severe renal impairment and patients undergoing hemodialysis. Based on the results of the study the dose of Peramivir IV should be adjusted in adult patients with renal impairment as follows:

Mild Renal Impairment (CrCl 50-80 mL/min)

The mean systemic exposures in patients with mild renal impairment are expected to be approximately 24% higher than the systemic exposures in patients with normal renal function. These higher exposures in patients with mild renal impairment are not expected to be clinically relevant. Therefore, no dose adjustments of Peramivir IV are needed for patients with mild renal impairment.

Moderate Renal Impairment (CrCl 30-49 mL/min)

The mean systemic exposures in patients with moderate renal impairment are expected to be approximately 3.4-fold higher than the exposures in patients with normal renal function. Therefore, the dose of Peramivir IV is reduced to 150 mg in order to achieve exposures similar to the exposures in patients with normal renal function after administration of a single 600 mg IV dose [see DOSAGE AND ADMINISTRATION].

Severe Renal Impairment (CrCl 10-30 mL/min)

The mean systemic exposures in patients with severe renal impairment are expected to be approximately 6-fold higher than the exposures in patients with normal renal function. Therefore, the dose of Peramivir IV is reduced to 100 mg in order to achieve exposures similar to the exposures in patients with normal renal function after administration of a single 600 mg IV dose [see DOSAGE AND ADMINISTRATION].

Patients Undergoing Hemodialysis and CrCl < 10 mL/min

The mean systemic exposure of Peramivir IV in patients on hemodialysis (determined after hemodialysis) was approximately 40-fold higher than the mean systemic exposures of Peramivir IV in patients with normal renal function. Therefore, the dose of Peramivir IV is reduced to 15 mg in order to achieve exposures similar to the exposures in patients with normal renal function after administration of a single 600 mg IV dose. As the dose was derived by using pharmacokinetic data collected after dialysis, Peramivir IV should be administered after dialysis on the dialysis day [see DOSAGE AND ADMINISTRATION].

Renal Impairment – Pediatric Patients

Dose recommendations for pediatric patients with renal impairment are based on modeling pharmacokinetic data from healthy adults with mild, moderate, and severe renal impairment and patients undergoing hemodialysis. [see DOSAGE AND ADMINISTRATION].

Microbiology

Mechanism of Action

Peramivir is a cyclopentane analogue which binds to the active site of influenza virus neuraminidase. It has inhibitory activity against human influenza A and influenza B viruses. Peramivir inhibited the neuraminidase activity of several influenza A and B strains in a biochemical assay with median IC50 values of 0.2 nM (range 0.09 to 1.4 nM, n=15) for influenza A strains and 1.3 nM (range 0.60 to 11 nM, n=8) for influenza B strains. The IC50 values of Peramivir against several 2009 H1N1 influenza A (swine flu) isolates ranged from 0.06-0.26 nM.

Antiviral Activity

The antiviral activity of Peramivir against laboratory strains and clinical isolates of influenza virus was determined in cell culture assays. The 50% effective concentrations (EC50) were 1 然 (range 0.09 to 21 然, n=5) for seasonal influenza A H1N1 isolates, 0.07 然 (range < 0.01 to 0.16 然, n=12) for influenza A H3N2 isolates, and 2.2 然 (range 0.06 to 3.2 然, n=5) for influenza B isolates. The relationship between the antiviral activity in cell culture, the inhibitory activity in neuraminidase assays, and the inhibition of influenza virus replication in humans has not been established. Limited biochemical, cell culture, and animal model data are available on the combination antiviral activity antiviral relationships of Peramivir with oseltamivir. No data are available on the combination activity with zanamivir. In a mouse influenza A virus challenge model study, the combination of Peramivir with oseltamivir demonstrated additive antiviral activity. The clinical significance of this data is currently unknown.

Resistance

No clinical data are available on the development of resistance to Peramivir. Characterization of virus selected in cell culture for resistance to Peramivir identified the H275Y substitution in influenza A/WSN/33 (H1N1). The H1N1 influenza A clinical isolates expressing the oseltamivir resistance-associated substitution H275Y appear to be resistant to Peramivir. The H275Y substitution has been observed in 2009 H1N1 in patients exposed to oseltamivir. As of September 5, 2009, the frequency of resistance in isolates from treated and untreated patients has been < 1% (Source: http://www.cdc.gov/flu/weekly/index.htm#whomap). To date, the resistance pathways for Peramivir have not been fully described.

Cross-Resistance

Cross-resistance has been observed among influenza virus neuraminidase inhibitors. The oseltamivir resistance-associated substitutions E119V (A/H3N2), D198N (B), H275Y (A/H1N1), and R292K (H2N2) conferred 1, 4.8, 100 and 80 fold reductions in susceptibility to Peramivir in a neuraminidase assay, respectively. The zanamivir resistance-associated substitutions E119A (H4N2), E119D (H4N2), E119G (H4N2), R152K (B) conferred 1, 33, 2 and 400 fold reductions in susceptibility to Peramivir, respectively. The relationship between susceptibility to Peramivir inhibition in biochemical assays and clinical efficacy has not been established. Current information on neuraminidase inhibitor resistance-associated substitutions in 2009 H1N1 can be found at www.cdc.gov/h1n1flu/recommendations.htm.

Nonclinical Toxicology

Carcinogenesis

No long-term animal carcinogenicity studies have been conducted with Peramivir.

Animal Studies: Target Organs of Toxicity

In studies of rabbits and rats, kidney related events including increases in creatinine, increases in ALT and AST and hematologic abnormalities including decreased red blood cell counts were observed. The events observed in animals are easily monitored in humans. Based on the limited data, no dose related laboratory abnormalities including proteinuria and other renal abnormalities possibly related to Peramivir were observed.

Clinical Trial Results And Supporting Data For Eua

Peramivir is an unapproved antiviral drug. Limited safety and efficacy data from phase 1, 2 and 3 trials are available to support use for treatment of 2009 H1N1 infection under an EUA. The following table provides the total number of patients who received Peramivir in phase 1, 2 and 3 trials, including available data from the Shionogi development program.

Dose, Formulation, Duration Total Number of Exposed Patients
Any dose, Any formulation, Any Duration 1891
Any Dose, IV Formulation, Any Duration 1213
≥ 600 mg, Any Formulation, Any Duration 847
≥ 600 mg, Intramuscular, Single Dose 287
600 mg, IV, Single Dose 478
600 mg, IV, ≥ 5 Day Duration 33
400 mg, IV, 5 Day Duration 85

Clinical Trial Safety Information
Safety of Intravenous (IV) Peramivir in Hospitalized Patients Treated for 5 Days

Trial BCX1812-201

Trial BCX1812-201 was a phase 2, multicenter, randomized, double-blind trial conducted by BioCryst in the United States, Canada, South Africa, Australia, New Zealand, Hong Kong and Singapore comparing the efficacy and safety of Peramivir administered intravenously once daily for 5 days versus oral oseltamivir 75 mg twice daily for 5 days in adults with acute serious or potentially life-threatening influenza. The doses of Peramivir IV used were 200 mg and 400 mg [see Clinical Trials]. The safety population, consisting of patients who received study drug [Peramivir IV 200 mg (n=45), Peramivir IV 400 mg (n=46), or oseltamivir (n=46)], totaled 137 patients.

Serious adverse events (SAEs) were reported by 10% of all patients; 4% of patients who received Peramivir IV 200 mg; 17% of patients who received Peramivir IV 400 mg; 9% of patients who received oseltamivir. Overall, the most frequently reported SAEs were pneumonia (2%) and chronic obstructive pulmonary disease (COPD)(1%). One patient who received Peramivir IV but was not infected with influenza died during the trial with viral myocarditis confirmed at post-mortem exam.

Three patients withdrew from the trial. The adverse events leading to withdrawal were anxiety and altered mood (Peramivir IV 200 mg), acute respiratory failure (Peramivir IV 400 mg), and angioedema (oseltamivir).

Adverse Events:

  • Overall, 54% of patients treated with Peramivir IV developed an adverse event compared to 41% of patients treated with oral oseltamivir.
  • Diarrhea was reported in 13% of patients receiving Peramivir IV 200 mg or 400 mg compared to 2% of patients receiving oseltamivir.
  • Psychiatric adverse events were reported in 11% of patients receiving Peramivir IV 200 or 400 mg compared to (4%) of patients receiving oseltamivir.
  • Psychiatric adverse events reported by patients treated with Peramivir IV either 200 mg or 400 mg were depression (n=2), confusion (n=1), insomnia (n=4), delirium (n=1), restlessness (n=1), anxiety (n=2), nightmare (n=1), and alteration of mood (n=1). Half the events were judged as related to Peramivir IV.

Laboratory Abnormalities:

At the time of enrollment, lymphopenia and elevated glucose levels were common. Three patients had increases in creatinine over enrollment values during or after the treatment period. Evaluation of 24-hour urine collection for protein and creatinine levels did not reveal a trend for renal toxicity for Peramivir when compared to oseltamivir. No laboratory evidence for hematologic or liver toxicity for patients exposed to Peramivir was seen. The laboratory results for the enrolled patients generally reflected the spectrum of underlying co-morbid conditions and severity of illness in the trial population.

Safety of Intravenous Peramivir in Outpatients Treated with Single Dose

I. A phase 2 trial conducted by Shionogi & Co. Ltd in Japan (Study 0722T0621) was a randomized, multicenter, blinded trial to evaluate a single administration of placebo, Peramivir 300 mg IV, or Peramivir 600 mg IV in patients with acute uncomplicated influenza infection. The overall safety population, consisting of patients administered study drug (Peramivir IV or placebo), totaled 298 patients. The safety population by treatment arm was: Peramivir IV 300 mg (N=99); Peramivir IV 600 mg (N=99); placebo (N=100).

  • No deaths or serious adverse events were reported in this trial.
  • Gastrointestinal Disorders were the most frequently reported adverse events:
    • Peramivir IV 300 mg (19%), Peramivir IV 600 mg (23%), and placebo (22%)
  • Diarrhea accounted for the majority of these adverse events:
    • Peramivir IV 300 mg (14%), Peramivir IV 600 mg (15%), and placebo (17%)
    • Most diarrhea adverse events were reported as mild and 7 cases were reported as moderate. None were reported as severe.
  • Nausea:
    • Ten patients reported nausea: 3 patients receiving Peramivir IV 300 mg, 6 patients receiving Peramivir IV 600 mg and 1 receiving placebo. With the exception of 1 case of moderate nausea in the Peramivir IV 600 mg group, all cases of nausea were reported as mild.
  • Psychiatric events were infrequent
    • 1% Peramivir IV 300 mg (insomnia) and 0 patients in the Peramivir IV 600 mg group
    • 2% placebo (anger (1), insomnia (1))

There was no clinical trend or safety concern observed in the laboratory results for the patients with acute uncomplicated influenza receiving single doses of Peramivir 300 mg or 600 mg intravenously compared with the limited data derived from patients receiving placebo in Study 0722T0621.

The most common laboratory abnormalities were an increased monocyte percentage: 20% in the Peramivir IV 300 mg group, 18% in the Peramivir IV 600 mg group and 31% in the placebo group.

Also increased lymphocyte percentage was commonly seen: 4% in the Peramivir IV 300 mg group, 14% in the Peramivir IV 600 mg group and 5% in the placebo group.

Because renal abnormalities were observed in animal studies, renal parameters including proteinuria were closely monitored in phase 1 and 2 studies. Based on the limited data, no dose related proteinuria or other renal abnormalities possibly related to Peramivir IV were observed.

Proteinuria:

  • 9% for the Peramivir IV 300 mg group, 11% for the Peramivir IV 600 mg group, and 18% for the placebo group

No cases of hypersensitivity reaction, septic phlebitis, necrosis of IV administration site or other serious local skin reactions have been reported during the clinical trials.

II. A phase 3 trial conducted by Shionogi & Co. Ltd in Japan, Korea and Taiwan (Trial 0815T0631) was a randomized, multicenter, double-blinded comparative trial to evaluate a single administration of Peramivir 300 mg IV, or Peramivir 600 mg IV and Tamiflu 75 mg twice daily for five days in patients with acute uncomplicated influenza infection. A total of 1093 subjects were included in the safety analyses.

The safety findings include the following:

Preliminary Safety Findings From Phase 3 Trial (0815T0631)

System Organ Class _Preferred Term Peramivir 300 mg
N=364
Peramivir 600 mg
N=364
Oseltamivir
N=365
Adverse Events – More than 10 cases [number of patients (cases) incidence]
Gastrointestinal disorders 41 (44) 11.3% 45 (49) 12.4% 66 (79) 18.1%
  Diarrhea 24 (24) 6.6% 30 (30) 8.2% 27 (27) 7.4%
  Nausea 8 (8) 2.2% 8 (8) 2.2% 20 (20) 5.5%
  Vomiting 2 (2) 0.5% 6 (6) 1.6% 15 (15) 4.1%
Investigations 112 (153) 30.8% 111 (155) 30.5% 109 (139) 29.9%
   Alanine amino transferase increased 10 (10) 2.7% 10 (10) 2.7% 5 (5) 1.4%
   Blood glucose increased 11 (11) 3% 14 (14) 3.8% 12 (12) 3.3%
   Electrocardiogram QT prolonged 5 (5) 1.4% 8 (8) 2.2% 10 (10) 2.7%
   Neutrophil count decreased 39 (39) 10.7% 38 (38) 10.4% 34 (34) 9.3%
   White blood cells urine positive 14 (14) 3.8% 8 (8) 2.2% 16 (16) 4.4%
   Protein urine present 17 (17) 4.7% 16 (16) 4.4% 22 (22) 6%
Gastrointestinal disorders 18 (19) 4.9% 28 (37) 7.7% 42 (51) 11.5%
   Diarrhea 14 (14) 3.8% 20 (20) 5.5% 19 (19) 5.2%
   Nausea 2 (2) 0.5% 7 (7) 1.9% 16 (16) 4.4%
Investigations 32 (47) 8.8% 30 (48) 8.2% 33 (43) 9%
   Neutrophil count decreased 9 (9) 2.5% 14 (14) 3.8% 13 (13) 3.6%
   Protein urine present 7 (7) 1.9% 4 (4) 1.1% 10 (10) 2.7%

III. Shionogi & Co., Ltd. provided preliminary results on a trial in patients at high-risk for serious influenza complications. The trial enrolled 42 patients with either poorly controlled diabetes, chronic respiratory disease requiring pharmacotherapy or patients who were currently on immunosuppressant medication. Patients were randomized to receive 300 mg IV or 600 mg IV for one to five days depending on clinical criteria. Only the incidences of adverse events and adverse drug reactions were provided. No individual cases reporting significant events were observed. The incidence of adverse events and adverse drug reactions were as follows:

Preliminary Safety Summary from Trial in Patients at High Risk for Serious Influenza Complications

  Combined
N=42
Peramivir 300 mg
N=21
Peramivir 600 mg
N=21
Adverse Events
  Number of Patients 31 15 16
  Number of Events (82) (44) (38)
  Percentage of Patients 73.8% 71.4% 76.2%
Adverse Drug Reactions
  Number of Patients 14 6 8
  Number of Events (21) (11) (10)
  Percentage of Patients 33.3% 28.6% 38.1%

Phase 1 Safety Data

No serious adverse events and no adverse events leading to discontinuation have been reported from any phase 1 study for either IV or intramuscular formulation.

Overall, 133 patients were exposed to Peramivir IV during the phase 1 studies and 29 patients (22%) reported adverse events. The most commonly reported adverse event was somnolence experienced by 6% of patients receiving Peramivir IV and no placebo patients. Hematuria was reported by 3% of patients receiving Peramivir IV and 7% of patients receiving placebo. Proteinuria was reported by 1% of patients receiving Peramivir IV. There were no dose related trends in the incidence of reported adverse events. Of note, there were no increased reports of adverse events in the trials conducted in the special populations of renal insufficiency and elderly patients.

Besides reports of adverse events related to the injection site (injection site anesthesia, discomfort, irritation, pain), there were no other clinically significant safety findings or trends observed in the phase 1 or phase 2 trials of the intramuscular formulation of Peramivir that were not described above.

Clinical Trial Efficacy Information

Four IV trials were completed, three single dose trials in acute uncomplicated influenza and one multiple dose trial in hospitalized patients. Additionally, two single dose intramuscular trials were completed. The following table summarizes the phase 2 and 3 trials of Peramivir administered intravenously or intramuscularly. The table below includes the number of patients who completed the trial and are included in the safety analyses and the number of patients evaluable for efficacy. Because only patients who have laboratory confirmed influenza infection are included for evaluation of efficacy, the number of patients evaluated for efficacy differs from the number of patients evaluated for safety (which includes all subjects who had a least one dose of study drug). Additionally, the sections below provide the preliminary efficacy results:

Table 5: Phase 2 and 3 Trials with Peramivir Administered Intravenously or Intramuscularly

Type of Trial Trial Identifier Population (N) Trial Design and Type of Control Dosage Regimen Route of Administration Duration; Test Product(s) Trial Results
Intravenous Trials – Acute Uncomplicated Influenza
Phase 2 Shionogi Trial 0722T0621 Patients aged 20 to 65 years of age with symptoms of influenza A double-blind, placebo-controlled multicenter with dynamic allocation using the minimization method Peramivir 300 mg or 600 mg IV, single dose, compared to placebo Completed(n=298; n=296 efficacy analyses) A statistically significant difference for both doses of Peramivir compared with placebo was observed for time to alleviation of symptoms
Phase 3 Shionogi Trial 0815T0631 Patients with symptoms of influenza Double blind, randomized Single IV dose Peramivir 300 mg or 600 mg compared to oseltamivir 75 mg twice daily for 5 days Completed(n=1093; n=1091 efficacy analyses)The time to alleviation of symptoms, the primary endpoint, was similar for all 3 treatment groups, but a non-inferiority margin has not been established for acute uncomplicated influenza, so the results cannot be interpreted.
Phase 2 Efficacy and Safety BCX1812-201 Hospitalized men and women, 18 years or older, with RAT + test for acute influenza infection, and complications of influenza. Randomized, double-mask, double-dummy comparing the efficacy and safety of Peramivir 200mg or 400mg administered intravenously QD for 5 days v. oseltamivir administered orally BID x 5 days in adults hospitalized with acute serious or potentially life-threatening influenza. Adaptive study design with interim analysis. Each patient receives IV study drug (Peramivir or placebo) QD for 5 days and receives oral suspension study drug (oseltamivir or placebo) BID for 5 days. completed(n=137; n=122 efficacy analyses) The results of this trial did not show superiority of either Peramivir dose over oseltamivir or a dose response for Peramivir for the primary endpoint.
Phase 2 Efficacy and Safety BCX1812-211 Men and women, 18 years or older, with RAT + test for acute uncomplicated influenza infection. Multicenter, Double-blind, randomized, placebo-controlled 150 mg, 300 mg, placebo Intramuscular injection, single dose completed (n=344) no statistically significant differences between treatment groups were observed for the primary efficacy endpoint of time to alleviation of symptoms.
Phase 2 BCX1812-212 The study was planned to include 320 to treatment to ensureenrollment of a minimum of 252 patients who were positive for influenza A (by RT-PCR) and up to 50 patients who were positive for influenza B. Multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a single dose of intramuscular Peramivir (600 mg) versus placebo in adults with uncomplicated acute influenza. Patients received a single dose intramuscular of Peramivir 600 mg or placebo Completed (n=402; n=334 for efficacy) no statistically significant differences between treatment groups were observed for the primary efficacy endpoint of time to alleviation of symptoms.

The efficacy of Peramivir has not been established in adequate and well-controlled studies.

Four trials are available to evaluate the efficacy of Peramivir IV. Three of the trials were completed in the outpatient setting and a fourth trial was completed in hospitalized patients. The first trial evaluated a single dose of Peramivir (300 mg and 600 mg) administered intravenously compared to placebo in 298 patients with acute uncomplicated influenza. The second trial evaluated a single dose of Peramivir (300 mg and 600 mg) administered intravenously compared to Tamiflu 75 mg twice daily for five days in 1,093 patients with acute uncomplicated influenza. The third trial provides limited preliminary data in patients at high-risk for serious influenza complications (poorly controlled diabetes, chronic respiratory disease requiring pharmacotherapy or currently on drug medication which suppresses the patient's natural immune responses). Patients were randomized to receive Peramivir IV 300 mg or 600 mg for one to five days depending on clinical criteria.

The fourth trial enrolled hospitalized patients infected with influenza and compared Peramivir IV 200 mg and 400 mg once daily for five days to oral oseltamivir 75 mg twice daily for five days. The results of this trial are not interpretable because the treatment effect of oseltamivir for the primary endpoint of time to clinical stability has not been established for the treatment of influenza in hospitalized patients and the results did not show superiority of either Peramivir IV dose over oseltamivir or a dose response for Peramivir IV for the primary endpoint.

Experience with Peramivir IV at the 600 mg once daily dose for five days in clinical trials is limited to 33 adult patients [see WARNINGS and PRECAUTIONS, Limitations of Populations Studied]. However, limited use of Peramivir IV in adults and children has been allowed for Peramivir IV 600 mg once daily for 5 to 10 days under emergency IND procedures

Acute Uncomplicated Influenza

A randomized, multicenter, blinded trial was conducted in Japan to evaluate a single IV treatment with either Peramivir 300 mg, Peramivir 600 mg, or placebo in 298 patients with acute uncomplicated influenza. A total of 296 patients had influenza confirmed by virus culture or PCR assay. The inclusion criteria required that patients be enrolled in the trial within 2 days of symptom onset.

The primary endpoint was time to alleviation of symptoms and 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 24 hours.

A statistically significant difference for both doses of Peramivir IV compared with placebo was observed for time to alleviation of symptoms. An approximately one day treatment benefit was observed. The trial results are as follows:

Trial 0722T0621 Results – Time to Alleviation of Symptoms

Kaplan-Meier Estimates Peramivir 300 mg
(n=99)
Peramivir 600 mg
(n=97)
Placebo
(n=100)
Median (hours) 59.1 59.9 81.8
95% CI 50.9, 72.4 54.4, 68.1 68.0, 101.5
Median Improvement over placebo (hours) 22.7 21.1  
95% CI* (2.75, 43.492) (4.233, 41.442)  
one sided P value 0.0046 0.0030  
Cox Proportional hazards model
Hazard ratio 0.681 0.666 --
(95% CI) (0.511, 0.909) (0.499, 0.890) --
* Based on bootstrap estimation of 7500 samples

A phase 3 trial conducted by Shionogi & Co. Ltd in Japan, Korea and Taiwan (Trial 0815T0631) was a randomized, multicenter, double-blinded comparative trial to evaluate a single administration of Peramivir IV 300 mg, or Peramivir IV 600 mg and Tamiflu 75 mg twice daily for five days in 1093 patients with acute uncomplicated influenza infection. A total of 1091 patients were included in the efficacy analyses.

The primary endpoint was time to alleviation of symptoms. BioCryst recently provided preliminary results via a slide set and press release. The final study report is being drafted. The time to alleviation of symptoms was similar for all three treatment groups as shown below.

Trial 0722T0631 Time to Alleviation of Symptoms (Hours) – ITTI Population

  Peramivir 300 mg
(n=364)
Peramivir 600 mg
(n=362)
Tamiflu
(n=365)
Median (hours) 78.0 81.0 81.8
95% CI (68.4, 88.6) 72.7, 91.5) (73.2, 91.1)
Improvement over Tamiflu (hours) -3.8 -0.8 --
Cox Proportional hazards model
Hazard ratio 0.946 0.970 --
(97.5% CI) (0.793, 1.129) (0.814, 1.157) --
P value 0.4836 0.7015 --

The overall trial results are challenging to interpret because appropriate non-inferiority margins have not been established in trials of acute uncomplicated influenza. Placebo-controlled rather than noninferiority designs are preferred for studies evaluating treatment of uncomplicated mild to moderate influenza because the risks of receiving placebo are low and the efficacy of available treatment is modest (1-day difference in time-to-alleviation of symptoms), variable, and cannot be predicted well enough to support a noninferiority margin. Additionally, BioCryst provided preliminary results of a trial conducted by Shionogi in patients at high-risk for serious influenza complications. Trial 0816T0632 enrolled 42 patients with either poorly controlled diabetes, chronic respiratory disease requiring pharmacotherapy or currently on drug medication which suppresses the patient's natural immune responses. Patients were randomized to receive 300 mg IV or 600 mg IV for one to five days depending on clinical criteria. The primary endpoint was time to alleviation of symptoms. The table below summarizes how many doses were administered by dose group. Thirty seven patients were included in the efficacy analyses.

Trial 0816T0632 Number of Peramivir IV Doses Received by Dose Group

# of doses Combined
N=37
300 mg
N=18
600 mg
N=19
1 10 7 3
2 23 9 14
3 2 1 1
4 1 0 1
5 1 1 0

The following results were presented in a slide set and press release. The results are presented for all patients combined, comparison between single-dose and multiple-dose groups and comparison between doses.

Trial 0816T0632 Time to Alleviation of Symptoms

  All Patients Combined Single Dose Multiple Dose 300 mg 600 mg
N 37 10 27 18 19
Median (hrs) 68.6 92 64.1 114.4 42.3
(90% confidence interval) (41.5, 113.4) (14.6, 235.3) 41.5, 111.2) (40.2, 235.3) (30, 82.7)

Shionogi states time to alleviation of symptoms was shorter for the 600mg IV group than the 300 mg IV group. In addition, time to alleviation of symptoms was shorter in multiple-dosed patients than single-dosed patients based on time to alleviation of symptoms. Of note, an imbalance in the number of patients receiving single or multiple doses within a dose cohort was seen. More patients received single IV administration in the 300 mg group compared to the 600 mg group (7 versus 3) and more patients received multiple doses in the 600 mg group compared to the 300 mg group (16 versus 11). Based on the limited data, the impact of this imbalance on the overall results is unknown and we await the individual data to verify the overall study results.

Intramuscular Administration for Acute Uncomplicated Influenza

A single dose intramuscular trial (Trial 211) was conducted to compare Peramivir 150 mg and 300 mg and placebo in adult patients with acute uncomplicated influenza. The primary efficacy endpoint was time to alleviation of symptoms 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 24 hours. The results from the intent-to-treat infected (ITTI) population are shown in the table below.

Trial BCX1812-211 Time to Alleviation of Symptoms (Hours) – ITTI Population

Kaplan–Meier Estimates Placebo
(N=108)
Peramivir 150 mg
(N=104)
Peramivir 300 mg
(N=105)
Mean (SD) 150.3 (7.91) 136.2 (8.15) 131.0 (8.79)
Median 136.2 114.1 117.4
95% CI 114.3, 165.8 95.2, 145.5 78.0, 135.9
MedianImprovement over placebo (Hrs)   22.1 18.8
95% CI1 (-19.5, 63.3) (-14.3, 63.7)
Cox Proportional hazards model2
Hazard ratio -- 0.859 0.816
(95% CI) -- (0.606, 1.156) (0.606, 1.098)
P value -- 0.315 0.180
1 Based on bootstrap estimation of 7500 samples
2 Cox proportional hazard model with factors for treatment, influenza season, and smoking status

While there were differences in the point estimates for the Peramivir treatment groups compared to placebo, no statistically significant differences between treatment groups were observed for the primary efficacy endpoint of time to alleviation of symptoms.

In another phase 2 trial (Trial 212) of intramuscular Peramivir 600 mg compared to placebo in patients with acute uncomplicated influenza, a statistically significant treatment effect was not observed for the primary endpoint (time to alleviation of symptoms) or secondary endpoints. Potential reasons for the lack of treatment difference are the circulating virus in the community during this trial and the single dose design. All seasonal influenza A H1N1 viruses tested had the H275Y mutation. Current data supports the conclusion that a single administration of Peramivir will not have adequate activity against viruses with H275Y substitution. No clinical data are available on the development of resistance to Peramivir.

Hospitalized Patients

A double-blind, randomized, multinational trial was conducted to compare two IV doses of Peramivir (200 mg once daily and 400 mg once daily) and oral oseltamivir 75 mg twice daily for five days in hospitalized adults with serious or potentially life-threatening influenza.

No difference between the three treatment groups was reported for the primary endpoint of time to clinical stability or for the secondary endpoints. Clinical stability was defined as:

Sign of Clinical Resolution Normalization Criteria
Temperature ≤ 37.2° C ( ≤ 99° F) oral
Oxygen saturation ≥ 92%
Respiration rate ≤ 24/minute
Heart rate ≤ 100/minute
Systolic BP ≥ 90 mm Hg

Note: Both temperature and oxygen saturation must meet Normalization Criteria in order for the clinical stability endpoint to be met in the clinical trial

The following table summarizes the results.

BCX1812-201 Trial Results

Parameter Peramivir 200 mg
(n=41)
Peramivir 400 mg
(n=40)
Oseltamivir
(n=41)
Time to Clinical Stability 23.7 hours 37 hours 28.1 hours
Time to Resumption of Usual Activities (days) 8.2 days 9.2 days 13.2 days
Clinical Relapse None None None
Time to Hospital Discharge (days) 6.3 days 4.5 days 4.3 days
Overall mean change log10 in viral load from nasopharyngeal specimens at 48 hours -2.3 -2.5 -2.2
Influenza A subgroup:Mean change log10 in viral load fromnasopharyngeal specimens at 48hours -2.0 (n=24) -2.3 (n=28) -2.2 (n=28)
Influenza B subgroup: Overall mean change log10 in viral load from nasopharyngeal specimens at 48 hours -2.7 (n=15) -3.3 (n=6) -2.2 (n=11)

Based on the results of this trial FDA cannot conclude Peramivir IV demonstrated a clinical effect in this population for several reasons:

  • The treatment effect of oseltamivir in hospitalized patients with serious influenza has not been established. Therefore, findings for the primary endpoint of time to clinical stability for all treatment groups are inconclusive.
  • The results did not show superiority of either Peramivir IV dose over oseltamivir for the primary endpoint nor did it show a dose-response for Peramivir IV 200 mg over Peramivir IV 400 mg.

Overall, because of the trial design, valid conclusions cannot be determined regarding whether Peramivir IV had a clinically meaningful impact on clinical disease in hospitalized patients infected with influenza virus.

Dose Rationale

Adults

Peramivir administered intravenously at a dose of 600 mg once daily for 5 to 10 days is recommended for the emergency use of Peramivir IV under EUA based on the following available data and assumptions.

  • A treatment benefit was observed in a phase 2 trial (0722T0621) conducted by Shionogi & Co. Ltd in Japan. The results showed 300 mg and 600 mg single doses of Peramivir given intravenously to patients with acute uncomplicated influenza had statistically significant shorter time to alleviation of symptoms compared to placebo (approximately one day treatment benefit).
  • The results from two other trials (one in hospitalized patients and one in outpatients with acute uncomplicated influenza) are challenging to interpret, in part, because oseltamivir was the comparator. The treatment effect of oseltamivir in hospitalized patients has not been established and insufficient information is available to establish a noninferiority margin for the acute uncomplicated influenza trial. In the phase 2 trial in hospitalized patients and the phase 3 trial in outpatients with acute uncomplicated influenza, the individual study results did not show superiority of either Peramivir IV dose over oseltamivir for the primary endpoint nor did it show a dose-response for either Peramivir IV dose (200 mg versus 400 mg and 300 mg versus 600 mg, respectively).
  • Safety data from phase 1, 2, and 3 clinical trials support emergency use under EUA.
  • Pharmacokinetic data suggest Peramivir will show a dose proportional increase in exposures when the dose is increased from 300 mg to 600 mg. Dose proportional increases in exposures were observed at single IV doses from 75 to 300 mg and from 1 mg/kg to 8 mg/kg (560 mg for a 70 kg patient).
  • No accumulation of Peramivir was observed after multiple dose administration.
  • The exposure parameter that correlates with antiviral activity is not known for Peramivir or for the other approved neuraminidase inhibitors. Data for antiviral products indicated to treat viral infections show that maintaining sufficient exposures throughout the dosing interval is important for antiviral activity and minimizes development of resistance.

The objective is to provide a sufficient Peramivir IV dose and exposure throughout the course of infection in an attempt to improve clinical outcome. A treatment benefit was observed with single doses of IV administration of Peramivir in patients with acute uncomplicated influenza. It is reasonable to expect a proportional increase in exposure when the Peramivir IV dose is increased from 300 mg to 600 mg once daily. Therefore, a longer duration of therapy at the 600 mg IV dose which already showed a treatment benefit, albeit in a different population, is reasonable for certain hospitalized patients infected with 2009 H1N1 infection.

The information presented above along with the currently available safety information support the use of Peramivir IV under EUA. The 600 mg daily dose of Peramivir IV for 5 to 10 days is being evaluated in phase 3 clinical development. Given the currently available safety and pharmacokinetic data for Peramivir IV, FDA believes the 600 mg dose once daily is appropriate for treating certain patients with 2009 H1N1 infection under EUA. Initial treatment courses of 5 days or 10 days are permitted. Patients with critical illness (such as those with respiratory failure or those requiring intensive care unit admission) might benefit from a longer treatment course, although there are no available data demonstrating that longer treatment courses are more effective. Limited data are available on the use of Peramivir IV for up to 10 days or longer. Additional treatment beyond 10 days is permitted depending on clinical presentation such as continued viral shedding or unresolved clinical influenza illness.

Pediatrics

No patients less than 18 years of age have received Peramivir IV in clinical trials. However, limited use of Peramivir IV in children has been allowed for Peramivir IV 600 mg once daily for 5 to 10 days under emergency IND procedures. The pediatric dosing recommendations are derived from a model based analysis of data available from 36 healthy adults (age: 18-46 yrs; weight: 49-113 kg; females: 12) and 198 acute uncomplicated influenza infected patients (age: 20-62 yrs; weight: 39-109 kg; females: 97). In the absence of pharmacokinetic (PK) data in pediatric patients (17 years and younger), the model for pediatric patients was derived from the published literature on renal function maturation and the knowledge of other renally eliminated drugs.3. The estimated exposures of the recommended doses for pediatric patients reasonably approximate the exposures in adults.

Peramivir clearance was found to be 7.58 L/hr/70 kg in influenza infected patients and 6.19 L/hr/70 kg in healthy adults. The effect of body size on Peramivir clearance was described using an allometric function with an exponent of ¾. The effect of renal maturation on Peramivir clearance was described with a sigmoid hyperbolic model described by Rhodin et. al. 3.

Based on the adult data (body size model) and pediatric model (renal function maturation), the proposed dosing recommendations were derived to reasonably match exposures (AUC = 80 µg*hr/mL) in adult influenza patients. The target exposures were defined from an AUC for a typical 70 kg patient from the 0722T0621 study after 600 mg IV dose of Peramivir. The dose of 600 mg IV for 5 days will be administered in phase 3 trials in adults.



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