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Peramivir

Indications/Dosage

Labeled

  • influenza A virus infection
  • influenza B virus infection

Off-Label

  • avian influenza A virus infection
† Off-label indication

For the treatment of uncomplicated acute influenza (e.g., influenza A virus infection or influenza B virus infection)

Intravenous dosage

Adults

600 mg IV as a single dose within 48 hours of symptom onset.[58671] [62315] [63866]

Adolescents

600 mg IV as a single dose within 48 hours of symptom onset.[58671] [62315] [63866]

Children 2 to 12 years

12 mg/kg/dose (Max: 600 mg/dose) IV as a single dose within 48 hours of symptom onset.[58671] [62315] [63866]

For the treatment of novel influenza A viruses associated with severe human disease†, including avian influenza A virus infection†

Intravenous dosage

Adults

600 mg IV once daily for 5 days as an alternative in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment.[62336]

Children and Adolescents 6 to 17 years

10 mg/kg/dose IV once daily (Max: 600 mg/dose) for 5 days as an alternative in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. This dose was recommended in the Emergency Use Authorization (EUA) for the treatment of hospitalized patients with H1N1 influenza A virus (swine influenza). At the time of the EUA, peramivir had not been administered to pediatric patients in clinical trials; dosing recommendations were based on modeling and simulation of pharmacokinetic data from adult trials, information on renal maturation, and body weight. Peramivir 10 mg/kg/dose IV once daily for up to 5 days was effective and well-tolerated in an open-label, uncontrolled study in 106 children (125 days to 15 years; 79 children 6 years and older) with 2009 pandemic H1N1 influenza virus A infection. Peramivir exposure in children receiving the 10 mg/kg/dose was within the range of concentrations observed in adult patients receiving 300 mg or 600 mg doses.[37099] [58681] [62336]

Infants older than 180 days and Children 1 to 5 years

10 to 12 mg/kg/dose IV once daily for 5 days as an alternative in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. The 12 mg/kg/dose IV once daily was the dosage recommended in the Emergency Use Authorization (EUA) for the treatment of hospitalized patients with H1N1 influenza A virus (swine influenza). At the time of the EUA, peramivir had not been administered to pediatric patients in clinical trials; dosing recommendations were based on modeling and simulation of pharmacokinetic data from adult trials, information on renal maturation, and body weight. Peramivir 10 mg/kg/dose IV once daily for up to 5 days was effective and well-tolerated in an open-label, uncontrolled study in 106 children (125 days to 15 years; 27 children younger than 6 years) with 2009 pandemic H1N1 influenza virus A infection. Peramivir exposure in children receiving the 10 mg/kg/dose was within the range of concentrations observed in adult patients receiving 300 mg or 600 mg doses.[37099] [58681] [62336]

Infants 91 to 180 days

10 mg/kg/dose IV once daily for 5 days as an alternative in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. This dose was recommended in the Emergency Use Authorization (EUA) for the treatment of hospitalized patients with H1N1 influenza A virus (swine influenza). At the time of the EUA, peramivir had not been administered to pediatric patients in clinical trials; dosing recommendations were based on modeling and simulation of pharmacokinetic data from adult trials, information on renal maturation, and body weight. Peramivir 10 mg/kg/dose IV once daily for up to 5 days was effective and well-tolerated in an open-label, uncontrolled study in 106 children (125 days to 15 years; 3 infants younger than 1 year) with 2009 pandemic H1N1 influenza virus A infection. Peramivir exposure in children receiving the 10 mg/kg/dose was within the range of concentrations observed in adult patients receiving 300 mg or 600 mg doses.[37099] [58681] [62336]

Infants 30 to 90 days

8 mg/kg/dose IV once daily for 5 days as an alternative in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir. Consider longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. This dose was recommended in the Emergency Use Authorization (EUA) for the treatment of hospitalized patients with H1N1 influenza A virus (swine influenza). At the time of the EUA, peramivir had not been administered to pediatric patients in clinical trials; dosing recommendations were based on modeling and simulation of pharmacokinetic data from adult trials, information on renal maturation, and body weight.[37099] [58681] [62336]

Neonates

6 mg/kg/dose IV once daily for 5 days as an alternative in patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. This dose was recommended in the Emergency Use Authorization (EUA) for the treatment of hospitalized patients with H1N1 influenza A virus (swine influenza). At the time of the EUA, peramivir had not been administered to pediatric patients in clinical trials; dosing recommendations were based on modeling and simulation of pharmacokinetic data from adult trials, information on renal maturation, and body weight.[37099] [58681] [62336]

Therapeutic Drug Monitoring

Maximum Dosage Limits

  • Adults

    600 mg/dose IV.

  • Geriatric

    600 mg/dose IV.

  • Adolescents

    600 mg/dose IV.

  • Children

    2 to 12 years: 12 mg/kg/dose (Max: 600 mg/dose) IV.

    1 to 2 years: Safety and efficacy have not been established; however, doses up to 12 mg/kg/dose IV daily have been used off-label.

  • Infants

    181 days and older: Safety and efficacy have not been established; however, doses up to 12 mg/kg/dose IV daily have been used off-label.

    91 to 180 days: Safety and efficacy have not been established; however, doses up to 10 mg/kg/dose IV daily have been used off-label.

    31 to 90 days: Safety and efficacy have not been established; however, doses up to 8 mg/kg/dose IV daily have been used off-label.

  • Neonates

    Safety and efficacy have not been established; however, doses up to 6 mg/kg/dose IV daily have been used off-label.

Patients with Hepatic Impairment Dosing

The pharmacokinetics of peramivir in patients with hepatic impairment have not been studied. Because peramivir is not significantly metabolized by the liver, no dose adjustment is necessary for patients with impaired hepatic function.[58671]

Patients with Renal Impairment Dosing

Adults and Adolescents [58671]:

CrCl 50 mL/minute or more: No dosage adjustment necessary.

CrCl 30 to 49 mL/minute: 200 mg IV as single dose.

CrCl 10 to 29 mL/minute: 100 mg IV as single dose.

 

Children 2 to 12 years [58671]:

CrCl 50 mL/minute or more: No dosage adjustment is necessary.

CrCl 30 to 49 mL/minute: 4 mg/kg (Max: 200 mg/dose) IV as single dose.

CrCl 10 to 29 mL/minute: 2 mg/kg (Max: 100 mg/dose) IV as single dose.

 

NOTE: Dosage recommendations below for pediatric patients younger than 2 years were included in the Emergency Use Authorization (EUA) of peramivir. These recommendations have not been FDA-approved.[37099]

NOTE: In the absence of a measured CrCl, the Schwartz equation may be used to estimate CrCl.

Infants 181 days and older and Children younger than 2 years:

CrCl 50 mL/minute/1.73 m2 or more: No dosage adjustment necessary.

CrCl 31 to 49 mL/minute/1.73 m2: Reduce to 3 mg/kg/dose.

CrCl 10 to 30 mL/minute/1.73 m2: Reduce to 1.9 mg/kg/dose.

CrCl less than 10 mL/minute/1.73 m2 (not on dialysis or CRRT): 1.9 mg/kg IV on day one, then 0.3 mg/kg IV daily. (NOTE: The regimen approved in the EUA was for a 5 to 10 day course.)

 

Infants 91 to 180 days:

CrCl 50 mL/minute/1.73 m2 or more: No dosage adjustment necessary.

CrCl 31 to 49 mL/minute/1.73 m2: Reduce to 2.5 mg/kg/dose.

CrCl 10 to 30 mL/minute/1.73 m2: Reduce to 1.6 mg/kg/dose.

CrCl less than 10 mL/minute/1.73 m2 (not on dialysis or CRRT): 1.6 mg/kg IV on day one, then 0.25 mg/kg IV daily. (NOTE: The regimen approved in the EUA was for a 5 to 10 day course.)

 

Infants 31 to 90 days:

CrCl 50 mL/minute/1.73 m2 or more: No dosage adjustment necessary.

CrCl 31 to 49 mL/minute/1.73 m2: Reduce to 2 mg/kg/dose.

CrCl 10 to 30 mL/minute/1.73 m2: Reduce to 1.3 mg/kg/dose.

CrCl less than 10 mL/minute/1.73 m2 (not on dialysis or CRRT): 1.3 mg/kg IV on day one, then 0.2 mg/kg IV daily. (NOTE: The regimen approved in the EUA was for a 5 to 10 day course.)

 

Neonates:

CrCl 50 mL/minute/1.73 m2 or more: No dosage adjustment necessary.

CrCl 31 to 49 mL/minute/1.73 m2: Reduce to 1.5 mg/kg/dose.

CrCl 10 to 30 mL/minute/1.73 m2: Reduce to 1 mg/kg/dose.

CrCl less than 10 mL/minute/1.73 m2 (not on dialysis or CRRT): 1 mg/kg IV on day one, then 0.15 mg/kg IV daily. (NOTE: The regimen approved in the EUA was for a 5 to 10 day course.)

 

 

Intermittent Hemodialysis:

Peramivir is removed by hemodialysis. In patients with chronic renal impairment maintained on hemodialysis, peramivir should be administered after dialysis at a dose adjusted on renal function.[58671]

† Off-label indication
Revision Date: 11/11/2020, 11:26:40 AM

References

37099 - Food and Drug Administration Emergency Use Authorization Fact Sheet for Heath Care Providers. Peramivir injection. Retrieved Nov. 20, 2009. Available on the World Wide Web at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187811.pdf.58671 - Rapivab (peramivir injection) package insert. Durham, NC: BioCryst Pharmacetuicals, Inc; 2020 Aug.58681 - Sugaya N, Kohno S, Ishibashi T, et al. Efficacy, safety, and pharmacokinetics of intravenous peramivir in children with 2009 pandemia H1N1 influenza A virus infection. Antimicrob Agents Chemother 2012;56:369-377.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm62336 - Centers for Disease Control and Prevention (CDC). Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/novel-av-treatment-guidance.htm63520 - American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2020-2021. Pediatrics. 2020;146(4):e202002458863866 - Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Management of Seasonal Influenza. Clin Infect Dis 2018 Dec 19 [Epub ahead of print].

How Supplied

Peramivir Solution for injection

Rapivab 200mg/20mL Solution for Injection (61364-0181) (BioCryst Pharmaceuticals, Inc.) null

Description/Classification

Description

Peramivir is an intravenous neuraminidase inhibitor indicated for the treatment of acute uncomplicated influenza in patients 2 years and older who have been symptomatic for no more than 48 hours. The efficacy is based on clinical trials in which the predominant influenza virus type was influenza A; only a limited number of patients infected with influenza B virus were enrolled.[58671] Peramivir is not a substitute for annual influenza virus vaccination. Instead, antiviral drugs are considered adjuncts to the prevention and control of influenza; annual influenza vaccination remains the main option for reducing the impact of influenza.[62315] [63866] An Emergency Use Authorization (EUA) was previously issued for peramivir in which the dosage regimen approved was a daily infusion for 5 to 10 days; however, the FDA-approved regimen is a single infusion for patients with uncomplicated influenza only. An interim analysis of a phase 3 study failed to show a significant difference in efficacy of peramivir (5-day course) and standard of care vs. placebo and standard of care in patients with serious influenza requiring hospitalization.[41176] [58671]

Classifications

  • General Anti-infectives Systemic
    • Antivirals For Systemic Use
      • Neuraminidase Inhibitor Antivirals
Revision Date: 03/14/2019, 11:47:25 AM

References

41176 - Food and Drug Administration. Peramivir emergency use authorization disposition letter and question and answer attachment. Retrieved June 30, 2010. Available on the World Wide Web at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm216252.htm.58671 - Rapivab (peramivir injection) package insert. Durham, NC: BioCryst Pharmacetuicals, Inc; 2020 Aug.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm63866 - Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Management of Seasonal Influenza. Clin Infect Dis 2018 Dec 19 [Epub ahead of print].

Administration Information

General Administration Information

For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration

  • For intravenous use only. Do not administer as an intramuscular (IM) injection.
  • Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if seal over the bottle opening is broken or missing.[58671]

Intravenous Administration

Preparation

  • Use aseptic technique during the preparation process, as the solution does not contain a preservative or bacteriostatic agent.
  • Dilute the appropriate dose of peramivir 10 mg/mL solution to a maximum volume of 100 mL. Acceptable diluents include 0.9% or 0.45% Sodium Chloride for Injection, 5% Dextrose for Injection, or Lactated Ringer's.
  • Storage of diluted solution: Administer immediately or store under refrigeration 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours. Refrigerated solution should be allowed to reach room temperature prior to administration. Discard any unused diluted solution after 24 hours.[58671]

 

Intravenous (IV) Administration

  • Infuse over 15 to 30 minutes.
  • Do not mix or administer concurrently with other intravenous medications.[58671]

Clinical Pharmaceutics Information

From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

Peramivir

pH Range
pH 5.5 to 8.5
ReferencesRapivab (peramivir injection), for intravenous use. Durham, NC. BioCryst Pharmaceuticals, Inc. 2016; Aug
    Revision Date: 11/06/2020, 02:39:52 PMCopyright 2004-2021 by Lawrence A. Trissel. All Rights Reserved.

    References

    58671 - Rapivab (peramivir injection) package insert. Durham, NC: BioCryst Pharmacetuicals, Inc; 2020 Aug.

    Adverse Reactions

    Moderate

    • constipation
    • delirium
    • elevated hepatic enzymes
    • erythema
    • hallucinations
    • hyperglycemia
    • hypertension
    • neutropenia
    • proteinuria
    • psychosis

    Mild

    • diarrhea
    • fever
    • insomnia
    • rash
    • vomiting

    Severe

    • anaphylactoid reactions
    • erythema multiforme
    • exfoliative dermatitis
    • Stevens-Johnson syndrome

    Gastrointestinal effects are among the most frequently reported adverse reactions to peramivir in clinical trials. Diarrhea (8% peramivir vs. 7% placebo) was the most common adverse event. Constipation (4% vs. 2% placebo) was reported in a subset of patients (n = 101) with serious influenza requiring hospitalization who were treated with peramivir 600 mg as monotherapy. Vomiting was reported in 3% of pediatric patients (age 2 to 17 years) receiving peramivir (n = 88) compared with 9% of patients receiving oseltamivir (n = 22) in clinical trials.[58671]

    Anaphylactoid reactions and cases of serious dermatologic adverse events have been reported in clinical trials and international postmarketing experience, including anaphylaxis, Stevens-Johnson syndrome, exfoliative dermatitis, and erythema multiforme. Rash has also been reported.[58671]

    Neuropsychiatric adverse events, including delirium (psychosis), abnormal behavior, and hallucinations, have been reported with neuraminidase inhibitors, including peramivir. Some cases have been severe; fatalities have been reported. These reactions were primarily reported in pediatric patients and often occurred abruptly and resolved rapidly. Because influenza infection itself can be associated with a variety of neurologic and behavioral symptoms, particularly in children, the relative contribution of neuraminidase inhibitors to these adverse reactions is not known. Regardless, all patients with influenza should be closely monitored for signs of abnormal behavior. Insomnia (3% peramivir vs. 0% placebo) was also reported in a subset of patients (n = 101) with serious influenza requiring hospitalization.[58671]

    Neutropenia (neutrophils less than 1 x 109/L) occurred more frequently in patients receiving peramivir (8%) than placebo (6%) in clinical trials. Neutropenia was the most frequent laboratory adverse event in a single arm trial of 117 Japanese pediatric patients (aged 28 days to 16 years) with uncomplicated influenza who received a single dose of peramivir 10 mg/kg. Proteinuria (Grade 2) was reported in 3% of pediatric patients receiving peramivir (n = 88) compared with 0% of patients receiving oseltamivir (n = 22) in clinical trials. Other laboratory abnormalities reported in placebo-controlled trials include the following: creatinine phosphokinase of at least 6 times upper limit of normal (4% peramivir vs. 2% placebo), elevated hepatic enzymes (specifically increased ALT/AST; 3% peramivir vs. 2% placebo), and hyperglycemia (serum glucose more than 160 mg/dL; 5% peramivir vs. 3% placebo).[58671]

    Hypertension was noted in 2% of patients receiving peramivir compared to 0% of placebo patients in clinical trials.[58671]

    Fever and tympanic membrane erythema were reported in 2% of pediatric patients receiving peramivir (n = 88) compared with 0% of patients receiving oseltamivir (n = 22) in clinical trials.[58671]

    Revision Date: 11/11/2020, 11:13:32 AM

    References

    58671 - Rapivab (peramivir injection) package insert. Durham, NC: BioCryst Pharmacetuicals, Inc; 2020 Aug.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • serious hypersensitivity reactions or anaphylaxis
    • serious rash
    • breast-feeding
    • children
    • dialysis
    • infection
    • pregnancy
    • psychosis
    • renal failure
    • renal impairment

    The use of peramivir has not been shown to provide benefit in patients with serious influenza requiring hospitalization. In a randomized, double-blind, multicenter, placebo-controlled trial of 398 patients with serious influenza requiring hospitalization, peramivir plus standard care did not improve median time to clinical resolution vs. standard of care alone.[58671]

    A serious bacterial infection may begin with influenza-like symptoms or may coexist with or develop as a complication during the course of influenza illness. Patients should be monitored, evaluated, and treated for suspected bacterial infections as clinically warranted while being treated with peramivir.[58671]

    Peramivir is renally eliminated. The dosage of peramivir should be adjusted in patients with renal impairment defined as a creatinine clearance of less than 50 mL/min, renal failure, and in patients receiving hemodialysis (dialysis). Peramivir should be administered after dialysis at a dose adjusted based on renal function. Peramivir has not been studied in patients receiving peritoneal dialysis or continuous renal replacement therapies.[58671]

    Neuropsychiatric adverse reactions of self-injury and delirium (psychosis) have been reported during postmarketing use of peramivir; some cases resulted in fatal outcomes. These reactions were primarily reported in pediatric patients and often occurred abruptly and resolved rapidly.[58671] In a trial of hospitalized adult patients with serious influenza, 11% of patients who received peramivir 200 to 400 mg IV daily (n = 81) experienced psychiatric adverse events compared to 4% of patients who received oseltamivir (n = 41).[37099] Since influenza infection itself is associated with a variety of neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior), the role of peramivir in causing these reactions is unclear. Patients with influenza who are receiving peramivir, particularly children and adolescents, should be closely monitored for signs of abnormal behavior. The risks and benefits of continuing peramivir should be evaluated if neuropsychiatric events occur.[58671]

    Limited available data with peramivir use in pregnancy 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 given during organogenesis by IV bolus at 600 mg/kg, representing exposures approximately 8-fold that in humans at the recommended dose. However, when peramivir was administered by continuous IV infusion, fetal anomalies of reduced renal papilla and dilated ureters were observed. In rabbits, maternal toxicity and developmental toxicity (abortion or premature delivery) were observed with administration of peramivir during organogenesis at exposures 8-times those in humans.[58671]

    There are no data on the presence of peramivir in breast milk, the effects on the breast-fed infant, or the effects on milk production. Limited clinical data during breast-feeding preclude a clear determination of the risk of peramivir to a breast-feeding infant. Consider the benefits of breast-feeding along with the mother's clinical need for peramivir and any potential adverse effects on the breast-fed infant from peramivir or the underlying maternal condition. A pharmacokinetic study in rats demonstrated that peramivir is excreted in milk at concentrations below the mother's plasma drug concentrations; the milk to plasma AUC ratio of peramivir was approximately 0.5.[58671]

    Due to the risk of serious hypersensitivity reactions or anaphylaxis, peramivir is contraindicated for use in patients with a known allergic reaction to the drug or any of its components. Cases of anaphylaxis, Stevens-Johnson Syndrome (SJS), and erythema multiforme have been reported during postmarketing use of the drug. If anaphylaxis or a serious rash develops during treatment, immediately discontinue peramivir and institute appropriate treatment.[58671]

    Revision Date: 11/11/2020, 10:54:11 AM

    References

    37099 - Food and Drug Administration Emergency Use Authorization Fact Sheet for Heath Care Providers. Peramivir injection. Retrieved Nov. 20, 2009. Available on the World Wide Web at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187811.pdf.58671 - Rapivab (peramivir injection) package insert. Durham, NC: BioCryst Pharmacetuicals, Inc; 2020 Aug.

    Mechanism of Action

    Peramivir is a cyclopentane analogue that competitively binds to the active site of the influenza virus neuraminidase. Peramivir inhibits the neuraminidase activity of strains of influenza A and B viruses.[58671] Influenza virus neuraminidase is a surface glycoprotein that catalyzes the cleavage of the linkage between a terminal sialic acid and adjacent sugar residue. This action promotes the spread of virus in the respiratory tract by several mechanisms. Viral neuraminidase promotes the release of virions from infected cells; promotes the penetration of virus into respiratory epithelial cells; prevents the formation of viral aggregates; prevents viral inactivation by respiratory mucus; induces cellular apoptosis by activating transforming growth factor beta; and induces cytokines including interleukin-1 and tumor necrosis factor.

     

    Influenza viruses are classified into 3 distinct types, influenza A, influenza B, and influenza C. Influenza A is further divided into subtypes based on their hemagglutinin (H or HA) and neuraminidase (N or NA) activity. At least 16 distinct HAs (H1 to H16) and 9 NAs (N1 to N9) have been described. Influenza infection may be attributed to either influenza A virus or influenza B virus. Influenza A virus subtypes include H1N1 and H3N2. In 2009, a novel influenza A H1N1 virus (previously referred to as swine influenza) was identified; this virus is included in season influenza A viruses. Human cases of influenza illness from the avian H5N1 virus (commonly known as avian flu) have been reported since 1997. Human infections with avian H7N9, H5N2, H5N8, H9N2, H7N7, and H7N3 viruses have also been described.[36906][62337]

    Revision Date: 09/25/2017, 10:01:37 AM

    References

    36906 - Treanor JJ. Influenza viruses (including avian influenza and swine influenza). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 8th ed. New York: Churchhill Livingstone; 2015:2000-2024.58671 - Rapivab (peramivir injection) package insert. Durham, NC: BioCryst Pharmacetuicals, Inc; 2020 Aug.62337 - Centers for Disease Control and Prevention (CDC). Interim guidance on influenza antiviral chemoprophylaxis of persons exposed to birds with avian influenza A viruses associated with severe human disease or with the potential to cause severe human disease. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/guidance-exposed-persons.htm

    Pharmacokinetics

    Peramivir is administered intravenously. Protein binding is less than 30%, and the central volume of distribution was found to be 12.56 L in population pharmacokinetic analysis. Peramivir is not significantly metabolized and is eliminated renally with a half-life of approximately 20 hours in adults with normal renal function after a single 600 mg dose. Renal clearance accounts for about 90% of total clearance. Negligible accumulation was observed after multiple dose administration.[37099][58671]

     

    Affected cytochrome P450 isoenzymes and drug transporters: none

    Route-Specific Pharmacokinetics

    Intravenous Route

    The pharmacokinetic parameters after IV administration of peramivir to adult subjects showed a linear relationship between dose and the exposure parameters (Cmax and AUC). After a single IV dose of 600 mg infused over 30 minutes, Cmax was 46,800 ng/mL at the end of the infusion and AUC was 102,700 ng x hour/mL.[58671]

    Special Populations

    Hepatic Impairment

    Although the pharmacokinetics of peramivir have not been specifically studied in patients with hepatic impairment, clinically relevant alterations are not expected.[58671]

    Renal Impairment

    Peramivir pharmacokinetics have been studied in otherwise healthy adult subjects with various degrees of renal impairment. When compared to a concurrent cohort with normal renal function, no change in mean Cmax was observed (6 subjects per cohort). However, the mean AUC after a single 2 mg/kg IV dose was increased by 28%, 302%, and 412% in patients with creatinine clearance 50 to 79, 30 to 49, and 10 to 29 mL/minute, respectively. Dose adjustments are recommended in patients with renal impairment. The pharmacokinetics of peramivir have not been evaluated in pediatric patients with renal impairment. However, given that the pharmacokinetics of peramivir in pediatric patients are comparable to those observed in adults, the same proportional dose reductions in pediatric patients are recommended.[58671]

     

    Hemodialysis is effective in reducing systemic exposure of peramivir by 73% to 81%. Because peramivir is removed by hemodialysis, the dose should be given after hemodialysis.[58671]

     

    Very limited information on peramivir in the setting of continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodialysis (CVVHD) in adults indicates that peramivir is efficiently cleared by CRRT. The pharmacokinetic sampling was sparse (2 to 4 samples/patient) and the timing of the samples is not well documented. No information is provided regarding filter type, flow rate, or duration of renal replacement therapy. Ultrafiltrate concentrations from a single adult patient on CVVH revealed a high sieving coefficient (about 80%), which is consistent with peramivir's low protein binding. There is no information available specific to patients receiving extracorporeal membrane oxygenation (ECMO) on peramivir exposure or pharmacokinetics.[37099]

    Pediatrics

    The pharmacokinetics of peramivir were evaluated in a study of 88 pediatric patients (2 to 17 years) with acute uncomplicated influenza who received a single IV dose of peramivir 12 mg/kg/dose (children 2 to 12 years) or 600 mg (adolescents). The pharmacokinetics of peramivir in children 2 to 12 years (Cmax 61,300 ng/mL and AUC 81,700 ng x hour/mL) and adolescents (Cmax 54,300 ng/mL and AUC 72,400 ng x hour/mL) were similar to those seen in adult patients administered a single 600 mg dose.[58671]

    In another small pharmacokinetic study in 11 critically ill pediatric patients (9 months to 12 years) receiving peramivir (9.8 to 12.7 mg/kg/dose IV every 24 hours) for influenza infections, peramivir pharmacokinetics differed significantly compared with previous pediatric studies and product labeling data in healthy patients. The Vd of peramivir was larger in 10 patients (median 0.58 L/kg; interquartile range, 0.35 to 1.47) and all 11 patients demonstrated an increase in clearance (median 5.1 mL/minute/kg; interquartile range, 2.5 to 11.2 mL/minute/kg) and shorter elimination half-life (median 1.7 hours; interquartile range, 1.25 to 1.95). This compares with previous data in healthy pediatric patients of an elimination half-life of 20 hours, Vd of 0.18 L/kg, and clearance of 0.1 mL/minute/kg. All patients required dosing adjustments to a more frequent dosing interval to attain AUC targets; 10 patients required an every 12-hour regimen and 1 patient required an every 8-hour regimen.[64737]

    Geriatric

    Peramivir pharmacokinetics in geriatric patients were similar to younger patients. Peak concentrations of peramivir after a single 4 mg/kg IV dose were approximately 10% higher in geriatric patients compared to young adults. Additionally, geriatric patients have an approximately 34% increase in dose-normalized AUC. Dose adjustments are not required for geriatric patients without reduced renal function.[58671]

    Gender Differences

    Peramivir pharmacokinetics were similar in male and female subjects.[58671]

    Ethnic Differences

    Peramivir pharmacokinetics were primarily evaluated in Caucasian and Asian patients. Based on a population pharmacokinetic analysis including race as a covariate, volume of distribution was dependent on weight and Asian race. No dosage adjustment is required based on weight or Asian race.[58671]

    Revision Date: 11/11/2020, 12:08:07 PM

    References

    37099 - Food and Drug Administration Emergency Use Authorization Fact Sheet for Heath Care Providers. Peramivir injection. Retrieved Nov. 20, 2009. Available on the World Wide Web at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187811.pdf.58671 - Rapivab (peramivir injection) package insert. Durham, NC: BioCryst Pharmacetuicals, Inc; 2020 Aug.64737 - Cies JJ, Moore WS, Enache A, et al. Peramivir for influenza A and B viral infections: A pharmacokinetic case series. Pharmacotherapy 2019 Sept 12; doi: 10.1002/phar.2330. [Epub ahead of print]

    Pregnancy/Breast-feeding

    pregnancy

    Limited available data with peramivir use in pregnancy 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 given during organogenesis by IV bolus at 600 mg/kg, representing exposures approximately 8-fold that in humans at the recommended dose. However, when peramivir was administered by continuous IV infusion, fetal anomalies of reduced renal papilla and dilated ureters were observed. In rabbits, maternal toxicity and developmental toxicity (abortion or premature delivery) were observed with administration of peramivir during organogenesis at exposures 8-times those in humans.[58671]

    breast-feeding

    There are no data on the presence of peramivir in breast milk, the effects on the breast-fed infant, or the effects on milk production. Limited clinical data during breast-feeding preclude a clear determination of the risk of peramivir to a breast-feeding infant. Consider the benefits of breast-feeding along with the mother's clinical need for peramivir and any potential adverse effects on the breast-fed infant from peramivir or the underlying maternal condition. A pharmacokinetic study in rats demonstrated that peramivir is excreted in milk at concentrations below the mother's plasma drug concentrations; the milk to plasma AUC ratio of peramivir was approximately 0.5.[58671]

    Revision Date: 09/22/2017, 02:17:17 PM

    References

    58671 - Rapivab (peramivir injection) package insert. Durham, NC: BioCryst Pharmacetuicals, Inc; 2020 Aug.

    Interactions

    Level 2 (Major)

    • Live Attenuated Influenza Vaccine (intranasal)
    Live Attenuated Influenza Vaccine (intranasal): (Major) Do not administer the intranasal live attenuated influenza vaccine (LAIV) 2 weeks before or 5 days after administration of peramivir, unless medically indicated. Inactivated influenza vaccines may be used, as appropriate. Because of its antiviral properties, peramivir may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live influenza virus vaccines are not recommended during treatment with peramivir. Consult currently recommended guidance on the use of antiviral drugs against influenza. [58671] [63436]
    Revision Date: 10/14/2020, 02:50:00 AM

    References

    58671 - Rapivab (peramivir injection) package insert. Durham, NC: BioCryst Pharmacetuicals, Inc; 2020 Aug.63436 - Grohskopf LA, Alyanak E, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2020-2021 Influenza Season. MMWR 2020;69(No. RR-8):1-24.

    Monitoring Parameters

    • CBC
    • LFTs
    • serum creatinine/BUN
    • urinalysis

    US Drug Names

    • Rapivab