There is no human experience of acute overdosage with RAPIVAB. Treatment of overdosage with RAPIVAB 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 RAPIVAB.
RAPIVAB is cleared by renal excretion and can be cleared by hemodialysis.
RAPIVAB is contraindicated in patients with known serious hypersensitivity or anaphylaxis to peramivir or any component of the product. Severe allergic reactions have included anaphylaxis, erythema multiforme and Stevens-Johnson Syndrome.
The following adverse reactions are discussed in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions In Adults (18 years of age and older)In five randomized, double-blind, controlled trials, 1,399 subjects with acute uncomplicated influenza received a single dose of RAPIVAB, administered intravenously or intramuscularly, at doses up to 600 mg. Among the 664 subjects receiving RAPIVAB 600 mg (intravenous or intramuscular), the most commonly observed adverse reaction was diarrhea, occurring at a rate of 8% versus 7% in subjects receiving placebo. No subject receiving RAPIVAB 600 mg experienced a serious adverse event and less than 1% discontinued study because of an adverse reaction.
Clinically significant laboratory abnormalities (DAIDS Grade 2-4) listed in Table 3 occurred more frequently in subjects treated with RAPIVAB 600 mg (intravenous or intramuscular) than placebo. Only events occurring at ≥2% are included.
Table 3: Laboratory Abnormalities Occurring in
≥2% of Subjects Treated with RAPIVAB 600 mg
| Laboratory Parameter Abnormality* | RAPIVAB 600 mg | Placebo |
| Alanine Aminotransferase (>2.5 x ULN) | (N=654) | (N=430) |
| 3% | 2% | |
| Serum Glucose (>160 mg/dL) | (N=660) | (N=433) |
| 5% | 3% | |
| Creatine Phosphokinase (≥6.0 x ULN) | (N=654) | (N=431) |
| 4% | 2% | |
| Neutrophils (<1.000 x109/L) | (N=654) | (N=430) |
| 8% | 6% | |
| * Frequencies based on treatment-emergent laboratory abnormalities |
In a subset of subjects with serious influenza requiring hospitalization treated with RAPIVAB 600 mg as monotherapy (N=101), the following adverse reactions were also reported more frequently with RAPIVAB as compared to placebo: constipation (4% versus 2%), insomnia (3% versus 0%), AST increased (3% versus 2%), and hypertension (2% versus 0%).
Adverse Reactions In Adolescent And Pediatric Subjects (2 To 17 Years Of Age)Assessment of adverse reactions is based on a randomized, active-controlled study in which 110 adolescent and pediatric subjects ages 2 to 17 years of age with acute uncomplicated influenza received open-label treatment with a single dose of RAPIVAB (N=88), or 5 days of treatment with oseltamivir (N=22).
The safety profile of RAPIVAB in subjects 2 to 17 years of age was generally similar to that observed in adults. Specific adverse reactions reported in pediatric subjects treated with RAPIVAB (occurring in ≥2% of subjects) and not reported in adults included vomiting (3% versus 9% for oseltamivir), fever and tympanic membrane erythema (2% versus 0%, respectively, for each of these events). The only clinically significant laboratory abnormality (DAIDS Grade 2) occurring in ≥2% of pediatric subjects treated with RAPIVAB was proteinuria by dipstick analysis (3% versus 0% for oseltamivir).
Postmarketing ExperienceThe following additional adverse reactions have been identified during postapproval use of RAPIVAB. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Dermatologic: Stevens-Johnson Syndrome, exfoliative dermatitis, rash
General disorders and administration site conditions: anaphylactic/anaphylactoid reactions
Psychiatric: abnormal behavior, hallucination
RAPIVAB is indicated for the treatment of acute uncomplicated influenza in patients 2 years and older who have been symptomatic for no more than 2 days.
Limitations Of UseThe 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 (Cmax and AUC).
Following intravenous administration of a single dose of RAPIVAB 600 mg over 30 minutes, a maximum serum concentration (Cmax) of 46,800 ng/mL (46.8 μg/mL) was reached at the end of infusion. AUC0-∞ values were 102,700 ng•hr/mL.
DistributionIn 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 EliminationPeramivir 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.
Limited available data with RAPIVAB use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with influenza in pregnancy. In animal reproduction studies, no adverse developmental effects were observed in rats when peramivir was administered by intravenous bolus injection during organogenesis at the maximum feasible dose, resulting in systemic drug exposures (AUC) approximately 8 times those in humans at the recommended dose. However, when peramivir was administered to rats by continuous intravenous infusion during the same gestation period, fetal abnormalities of reduced renal papilla and dilated ureters were observed. In rabbits, administration of peramivir during organogenesis at exposures 8 times those in humans at the recommended dose resulted in developmental toxicity (abortion or premature delivery) at a maternally toxic dose.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical ConsiderationsDisease-Associated Maternal And/Or Embryo/Fetal Risk
Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, stillbirths, birth defects, preterm delivery, low birthweight, and small for gestational age.
DataAnimal Data
Reproductive toxicity studies have been performed in rats and rabbits. In rats, peramivir was administered once daily by intravenous bolus injection at doses of 200, 400, and 600 mg/kg/day on gestational days 6-17. No treatment-related fetal toxicities were observed when peramivir was administered by intravenous bolus injection at the maximum feasible dose of 600 mg/kg, resulting in exposures approximately 8 times those in humans at the recommended dose.
Peramivir was also administered by continuous intravenous infusion to rats at daily doses of 50, 400, and 1000 mg/kg/day on gestational days 6-17. Dose related increases in the incidence of fetal abnormalities of reduced renal papilla and dilated ureters were observed at 400 and 1000 mg/kg/day. The systemic drug exposure in rats at a dose without fetal effects was less than the exposures in humans at the recommended dose.
In rabbits, peramivir was administered once daily by intravenous bolus injection at doses of 25, 50, 100, and 200 mg/kg/day on gestational days 7-19. Developmental toxicity (abortion or premature delivery) was observed at maternally toxic dose levels (100 and 200 mg/kg/day) resulting in exposures approximately 8 times those in humans at the recommended dose. The exposure in rabbits at doses without developmental toxicity was less than the exposure in humans at the recommended dose.
A pre/post-natal developmental toxicity study was performed in pregnant rats administered peramivir once daily by intravenous infusion at doses of 50, 200, 400 and 600 mg/kg/day on gestational day 6 through lactation day 20. No significant effects of peramivir on developmental outcomes were observed in nursing pups at up to the highest dose tested.
Each vial of RAPIVAB injection contains 200 mg per 20 mL (10 mg per mL) as a clear, colorless solution.
Storage And HandlingRAPIVAB 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 # 61364-181-01). RAPIVAB injection is supplied in cartons containing three single-use vials (NDC # 61364-181-03).
Store vials of RAPIVAB injection in original cartons at 20° to 25°C (68° to 77°F). Excursions are permitted to 15° to 30°C (59° to 86°F).
Do not use if seal over bottle opening is broken or missing.
Manufactured for and distributed by: BioCryst Pharmaceuticals, Inc. Durham, NC 27703. Revised: Apr 2018
Included as part of the PRECAUTIONS section.
PRECAUTIONS Serious Skin/Hypersensitivity ReactionsRare cases of serious skin reactions, including erythema multiforme, have been reported with RAPIVAB in clinical studies and in postmarketing experience. Cases of anaphylaxis and Stevens-Johnson Syndrome have been reported in postmarketing experience with RAPIVAB. Discontinue RAPIVAB and institute appropriate treatment if anaphylaxis or a serious skin reaction occurs or is suspected. The use of RAPIVAB is contraindicated in patients with known serious hypersensitivity or anaphylaxis to RAPIVAB.
Neuropsychiatric EventsInfluenza 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 events may occur in the setting of encephalitis or encephalopathy but can occur in uncomplicated influenza as well.
There have been postmarketing reports of delirium and abnormal behavior leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including RAPIVAB. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made, but they appear to be uncommon. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of RAPIVAB to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior.
Risk Of Bacterial InfectionsThere is no evidence for efficacy of RAPIVAB in any illness caused by agents other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. RAPIVAB has not been shown to prevent such complications.
Prescribers should be alert to the potential for secondary bacterial infections and treat with antibiotics as appropriate.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisCarcinogenicity 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.
MutagenesisPeramivir 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 FertilityPeramivir 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.
Use In Specific Populations Pregnancy Risk SummaryLimited available data with RAPIVAB use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with influenza in pregnancy. In animal reproduction studies, no adverse developmental effects were observed in rats when peramivir was administered by intravenous bolus injection during organogenesis at the maximum feasible dose, resulting in systemic drug exposures (AUC) approximately 8 times those in humans at the recommended dose. However, when peramivir was administered to rats by continuous intravenous infusion during the same gestation period, fetal abnormalities of reduced renal papilla and dilated ureters were observed. In rabbits, administration of peramivir during organogenesis at exposures 8 times those in humans at the recommended dose resulted in developmental toxicity (abortion or premature delivery) at a maternally toxic dose.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical ConsiderationsDisease-Associated Maternal And/Or Embryo/Fetal Risk
Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, stillbirths, birth defects, preterm delivery, low birthweight, and small for gestational age.
DataAnimal Data
Reproductive toxicity studies have been performed in rats and rabbits. In rats, peramivir was administered once daily by intravenous bolus injection at doses of 200, 400, and 600 mg/kg/day on gestational days 6-17. No treatment-related fetal toxicities were observed when peramivir was administered by intravenous bolus injection at the maximum feasible dose of 600 mg/kg, resulting in exposures approximately 8 times those in humans at the recommended dose.
Peramivir was also administered by continuous intravenous infusion to rats at daily doses of 50, 400, and 1000 mg/kg/day on gestational days 6-17. Dose related increases in the incidence of fetal abnormalities of reduced renal papilla and dilated ureters were observed at 400 and 1000 mg/kg/day. The systemic drug exposure in rats at a dose without fetal effects was less than the exposures in humans at the recommended dose.
In rabbits, peramivir was administered once daily by intravenous bolus injection at doses of 25, 50, 100, and 200 mg/kg/day on gestational days 7-19. Developmental toxicity (abortion or premature delivery) was observed at maternally toxic dose levels (100 and 200 mg/kg/day) resulting in exposures approximately 8 times those in humans at the recommended dose. The exposure in rabbits at doses without developmental toxicity was less than the exposure in humans at the recommended dose.
A pre/post-natal developmental toxicity study was performed in pregnant rats administered peramivir once daily by intravenous infusion at doses of 50, 200, 400 and 600 mg/kg/day on gestational day 6 through lactation day 20. No significant effects of peramivir on developmental outcomes were observed in nursing pups at up to the highest dose tested.
Lactation Risk SummaryThere are no data on the presence of RAPIVAB in human milk, the effects on the breastfed infant, or the effects on milk production. Peramivir is present in rat milk. Limited clinical data during lactation preclude a clear determination of the risk of RAPIVAB to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RAPIVAB and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
DataA pharmacokinetic study was performed in lactating rats administered a single intravenous dose of peramivir (10 mg/kg) on lactation/postpartum days 11-13. The maximum concentration of peramivir in milk was reached at 0.75 hours post-dose. The milk to plasma AUC ratio of peramivir was approximately 0.5.
Pediatric UseThe safety and effectiveness of RAPIVAB for the treatment of influenza has been established in pediatric patients 2 to 17 years of age. Use of RAPIVAB for this indication is supported by evidence from adequate and well-controlled trials of RAPIVAB in adults with additional data from Study 305, a randomized, active-controlled trial of 110 adolescent and pediatric subjects with acute uncomplicated influenza who received open-label treatment with a single dose of RAPIVAB or 5 days of treatment with oseltamivir administered within 48 hours of onset of symptoms of influenza. Study 305 included:
Safety and effectiveness of RAPIVAB in pediatric patients less than 2 years of age have not been established.
Geriatric UseClinical trials of RAPIVAB did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in exposures between the elderly and younger subjects.
Patients With Impaired Renal FunctionA reduced dose of RAPIVAB is recommended for patients with creatinine clearance below 50 mL/min. Dose adjustment is not required for a single administration of RAPIVAB for patients with creatinine clearance 50 mL/min or higher.
In patients with chronic renal impairment maintained on hemodialysis, RAPIVAB should be administered after dialysis at a dose adjusted based on renal function.
Patients With Serious Influenza Requiring HospitalizationThe use of RAPIVAB was not shown to provide benefit in patients with serious influenza requiring hospitalization.
Administer RAPIVAB within 2 days of onset of symptoms of influenza.
Adults And Adolescents (13 Years Of Age And Older)The recommended dose of RAPIVAB in adult and adolescent patients 13 years of age or older with acute uncomplicated influenza is a single 600 mg dose, administered via intravenous infusion for 15 to 30 minutes.
Pediatric Patients (2 To 12 Years Of Age)The recommended dose of RAPIVAB in pediatric patients 2 to 12 years of age with acute uncomplicated influenza is a single 12 mg/kg dose (up to a maximum dose of 600 mg), administered via intravenous infusion for 15 to 30 minutes.
Dosing In Patients With Renal ImpairmentSignificantly increased drug exposures were observed when RAPIVAB was administered to adult subjects with renal dysfunction. Therefore, the RAPIVAB dose should be reduced for patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 1 and Table 2. No dose adjustment is required for single administration of RAPIVAB in patients with creatinine clearance of 50 mL/min or higher.
In patients with chronic renal impairment maintained on hemodialysis, RAPIVAB should be administered after dialysis at a dose adjusted based on renal function (Table 1 and Table 2).
Table 1: Dosage Adjustment for Adults and Adolescents
(13 years and older) with Altered Creatinine Clearance
| Creatinine Clearance* (mL/min) | |||
| ≥50 | 30-49 | 10-29 | |
| Recommended Dose (mg) | 600 mg | 200 mg | 100 mg |
| * Calculated using the Cockcroft and Gault equation. |
Table 2: Dosage Adjustment for Pediatric Patients (2
to 12 years of age) with Altered Creatinine Clearance
| Creatinine Clearance* (mL/min) | |||
| ≥50 | 30-49 | 10-29 | |
| Recommended Dose (mg/kg)** | 12 mg/kg | 4 mg/kg | 2 mg/kg |
| * Calculated using the Cockcroft and Gault equation. ** Up to maximum dose of 600 m |
Use aseptic technique during the preparation of RAPIVAB to prevent inadvertent microbial contamination. There is no preservative or bacteriostatic agent present in the solution.
Follow the steps below to prepare a diluted solution of RAPIVAB:
Once a diluted solution of RAPIVAB has been prepared, administer immediately or store under refrigerated conditions (2° to 8°C or 36° to 46°F) for up to 24 hours. If refrigerated, allow the diluted solution of RAPIVAB to reach room temperature then administer immediately.
Drug CompatibilityRAPIVAB injection is compatible with 0.9% or 0.45% sodium chloride, 5% dextrose, or lactated Ringer’s. Do not mix or co-infuse RAPIVAB with other intravenous medications.
RAPIVAB injection is compatible with materials commonly used for administration such as polyvinylchloride (PVC) bags and PVC-free bags, polypropylene syringes, and polyethylene tubing.
The following adverse reactions are discussed in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions In Adults (18 years of age and older)In five randomized, double-blind, controlled trials, 1,399 subjects with acute uncomplicated influenza received a single dose of RAPIVAB, administered intravenously or intramuscularly, at doses up to 600 mg. Among the 664 subjects receiving RAPIVAB 600 mg (intravenous or intramuscular), the most commonly observed adverse reaction was diarrhea, occurring at a rate of 8% versus 7% in subjects receiving placebo. No subject receiving RAPIVAB 600 mg experienced a serious adverse event and less than 1% discontinued study because of an adverse reaction.
Clinically significant laboratory abnormalities (DAIDS Grade 2-4) listed in Table 3 occurred more frequently in subjects treated with RAPIVAB 600 mg (intravenous or intramuscular) than placebo. Only events occurring at ≥2% are included.
Table 3: Laboratory Abnormalities Occurring in
≥2% of Subjects Treated with RAPIVAB 600 mg
| Laboratory Parameter Abnormality* | RAPIVAB 600 mg | Placebo |
| Alanine Aminotransferase (>2.5 x ULN) | (N=654) | (N=430) |
| 3% | 2% | |
| Serum Glucose (>160 mg/dL) | (N=660) | (N=433) |
| 5% | 3% | |
| Creatine Phosphokinase (≥6.0 x ULN) | (N=654) | (N=431) |
| 4% | 2% | |
| Neutrophils (<1.000 x109/L) | (N=654) | (N=430) |
| 8% | 6% | |
| * Frequencies based on treatment-emergent laboratory abnormalities |
In a subset of subjects with serious influenza requiring hospitalization treated with RAPIVAB 600 mg as monotherapy (N=101), the following adverse reactions were also reported more frequently with RAPIVAB as compared to placebo: constipation (4% versus 2%), insomnia (3% versus 0%), AST increased (3% versus 2%), and hypertension (2% versus 0%).
Adverse Reactions In Adolescent And Pediatric Subjects (2 To 17 Years Of Age)Assessment of adverse reactions is based on a randomized, active-controlled study in which 110 adolescent and pediatric subjects ages 2 to 17 years of age with acute uncomplicated influenza received open-label treatment with a single dose of RAPIVAB (N=88), or 5 days of treatment with oseltamivir (N=22).
The safety profile of RAPIVAB in subjects 2 to 17 years of age was generally similar to that observed in adults. Specific adverse reactions reported in pediatric subjects treated with RAPIVAB (occurring in ≥2% of subjects) and not reported in adults included vomiting (3% versus 9% for oseltamivir), fever and tympanic membrane erythema (2% versus 0%, respectively, for each of these events). The only clinically significant laboratory abnormality (DAIDS Grade 2) occurring in ≥2% of pediatric subjects treated with RAPIVAB was proteinuria by dipstick analysis (3% versus 0% for oseltamivir).
Postmarketing ExperienceThe following additional adverse reactions have been identified during postapproval use of RAPIVAB. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Dermatologic: Stevens-Johnson Syndrome, exfoliative dermatitis, rash
General disorders and administration site conditions: anaphylactic/anaphylactoid reactions
Psychiatric: abnormal behavior, hallucination
DRUG INTERACTIONSThis section describes clinically relevant drug interactions with RAPIVAB. Drug-drug interaction studies are described elsewhere in the labeling.
Influenza VaccinesInactivated influenza vaccine can be administered at any time relative to use of RAPIVAB. For live attenuated influenza vaccine (LAIV), antiviral drugs may inhibit viral replication and thus may reduce vaccine efficacy. The concurrent use of RAPIVAB with LAIV intranasal has not been evaluated. Because of the potential for interference between these two products, avoid use of LAIV within 2 weeks before or 48 hours after administration of RAPIVAB unless medically indicated.
