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Peramivir

Class: Neuraminidase Inhibitors
VA Class: AM800
Chemical Name: 3-[(1S)-1-(Acetylamino)-2-ethylbutyl]-4-[(aminoiminomethyl)amino]-2-hydroxy-cyclopentanecarboxylic acid hydrate
Molecular Formula: C15H28N4O4 • 3H2O
CAS Number: 1041434-82-5
Brands: Rapivab

Medically reviewed by Drugs.com. Last updated on Sep 9, 2019.

Introduction

Antiviral; neuraminidase inhibitor active against influenza A and B viruses.1 2 3 137 144

Uses for Peramivir

Treatment of Seasonal Influenza A and B Virus Infections

Treatment of acute, uncomplicated illness caused by influenza A or B viruses in adults, adolescents, and children ≥2 years of age who have been symptomatic for ≤2 days.1 2 3 137

Has been used for treatment of serious influenza in some patients,1 4 137 but efficacy not established in patients with serious influenza requiring hospitalization.1

CDC, Advisory Committee on Immunization Practices (ACIP), IDSA, and AAP recommend that antiviral treatment be initiated as soon as possible in all individuals with suspected or confirmed influenza who require hospitalization or have severe, complicated, or progressive illness (regardless of vaccination status or underlying illness).105 112 116 137 144 Early empiric antiviral treatment also recommended in individuals with suspected or confirmed influenza of any severity if they are at high risk of developing influenza-related complications because of age or underlying medical conditions (regardless of vaccination status).105 112 116 137 144 This includes children <5 years of age (especially those <2 years of age), adults ≥65 years of age, individuals of any age with certain chronic medical or immunosuppressive conditions, women who are pregnant or up to 2 weeks postpartum, individuals <19 years of age receiving long-term aspirin therapy, American Indians, Alaskan natives, morbidly obese individuals with body mass index (BMI) ≥40, and residents of any age in nursing homes or other long-term care facilities.112 116 137 144

CDC, ACIP, IDSA, and AAP also state that empiric antiviral treatment can be considered in previously healthy, symptomatic individuals with suspected or confirmed influenza who are not known to be at increased risk of developing severe or complicated illness (regardless of vaccination status), if such treatment can be initiated within 48 hours of illness onset.105 112 116 137 144 Although these individuals typically do not require treatment, early empiric antiviral treatment might provide some benefit (e.g., shortened duration of illness).112 116 144

If indicated, initiate appropriate antiviral treatment as soon as possible after illness onset (ideally within 48 hours);105 112 116 137 144 do not delay initiation of treatment while waiting for laboratory confirmation.105 112 116 137 144

For treatment of suspected or confirmed severe, complicated influenza in hospitalized patients or outpatients, oseltamivir is the preferred antiviral because of lack of data regarding use of peramivir, zanamivir, or baloxavir marboxil in such patients.137 CDC states that data are insufficient regarding use of peramivir for treatment of severe influenza in hospitalized patients or outpatients;137 however, peramivir should be considered for treatment of severe influenza in patients who cannot tolerate or absorb oral or enterically administered oseltamivir (e.g., because of suspected or known gastric stasis, malabsorption, or GI bleeding).137

For treatment of suspected or confirmed acute, uncomplicated influenza in otherwise healthy outpatients, CDC, IDSA, and other experts state that any age-appropriate influenza antiviral (oseltamivir, peramivir, zanamivir, baloxavir marboxil) can be used if not contraindicated.112 116 137

Consider viral surveillance data available from local and state health departments and CDC when selecting an antiviral for treatment of seasonal influenza.1 116 137 144 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve;1 144 emergence of resistant strains may decrease effectiveness of influenza antivirals.1 Although influenza A and B viruses circulating in US during the last few years generally have been susceptible to peramivir (see Actions and Spectrum),561 567 570 575 consult most recent information.1 137 144

CDC issues recommendations concerning use of antivirals for treatment of influenza, and these recommendations are updated as needed during each influenza season.137 Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at [Web].

Avian Influenza A Virus Infections

Has been used for treatment of infections caused by susceptible avian influenza A viruses.50 178 556

For treatment of severe, complicated, or progressive avian influenza A infections in hospitalized patients or outpatients, including infections caused by avian influenza A (H7N9), avian influenza A (H5N1), or novel avian influenza A H5 viruses, CDC recommends oseltamivir as antiviral of choice.178 CDC states peramivir may be considered for treatment of hospitalized patients with severe avian influenza A infection who cannot tolerate or absorb oseltamivir (e.g., because of suspected or known gastric stasis, malabsorption, or GI bleeding).178

For treatment of uncomplicated avian influenza A infections in outpatients, CDC states oseltamivir, zanamivir, or peramivir may be used.178

When antiviral prophylaxis indicated in close contacts of individuals with confirmed or probable infection with avian influenza A viruses associated with severe disease or with potential to cause severe disease, CDC recommends oseltamivir or zanamivir.179

Most recent information regarding treatment and prevention of avian influenza A infections is available from CDC at [Web] or WHO at [Web].

Pandemic Influenza

Alternative for treatment of pandemic influenza caused by susceptible strains of influenza virus.5 9 52 151

Influenza viruses can cause pandemics, during which rates of illness and death from influenza-related complications can increase dramatically worldwide.52 488

Most recent influenza pandemic occurred during 2009 and was related to a novel influenza A (H1N1) strain, influenza A (H1N1)pdm09.52 135 144 151 488 In the US, the pandemic was characterized by a substantial increase in influenza activity that peaked in late October and early November 2009 and returned to seasonal baseline levels by January 2010.123 488 During that time, ≥99% of influenza viruses circulating in the US were influenza A (H1N1)pdm09.123 488 In August 2010, the WHO declared that the world was in a post-pandemic period;148 influenza A (H1N1)pdm09 had become a seasonal influenza virus and still continues to circulate with other seasonal viruses.144 551 553 561 562 567 570 575

The spread of the highly pathogenic Asian strain of avian influenza A (H5N1) in poultry in Asia and other countries that has been occurring since 2003 and has caused human infections represents a potential future pandemic threat.50 52 54 55 56 104 147 The novel avian influenza A (H7N9) virus first identified in China in March 2013 that has been causing sporadic human infections also has pandemic potential.50 104 182 555 556

Peramivir Dosage and Administration

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Commercially available injection concentrate containing 10 mg/mL must be diluted prior to administration.1

Do not mix with or administer simultaneously with other drugs.1

Compatible with materials commonly used for administration (e.g., polyvinyl chloride and polyvinyl chloride-free infusion bags, polypropylene syringes, polyethylene tubing).1

Vials contain no preservatives or bacteriostatic agents and are for single use only.1

Dilution

Withdraw appropriate dose of peramivir injection concentrate containing 10 mg/mL and dilute in 0.9 or 0.45% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to achieve a maximum total volume of 100 mL.1

Administer immediately after dilution.1 If not used immediately, diluted solution may be stored for ≤24 hours at 2–8°C.1 Allow refrigerated solution to reach room temperature and administer immediately.1

Discard unused portions of diluted solution 24 hours after dilution.1

Rate of Administration

Administer by IV infusion over 15–30 minutes.1

Dosage

Pediatric Patients

Treatment of Seasonal Influenza A and B Virus Infections
Acute, Uncomplicated Seasonal Influenza A or B Virus Infections
IV

Children 2–12 years of age: Single dose of 12 mg/kg (up to 600 mg) given within 2 days of symptom onset.1

Adolescents ≥13 years of age: Single 600-mg dose given within 2 days of symptom onset.1

Treatment of Avian Influenza A Virus Infections
Avian Influenza A (H7N9), Avian Influenza A (H5N1), and Novel Avian Influenza A H5 Viruses
IV

Children: 10 mg/kg (up to 600 mg) once daily for ≥5 days.178 Only limited data available regarding use for these infections.178

Adults

Treatment of Seasonal Influenza A and B Virus Infections
Acute, Uncomplicated Seasonal Influenza A or B Virus Infections
IV

Single 600-mg dose given within 2 days of symptom onset.1

Treatment of Avian Influenza A Virus Infections
Avian Influenza A (H7N9), Avian Influenza A (H5N1), and Novel Avian Influenza A H5 Viruses
IV

600 mg once daily for ≥5 days.178 Only limited data available regarding use for these infections.178

Special Populations

Hepatic Impairment

Not studied in patients with hepatic impairment;1 clinically important alterations in pharmacokinetics not expected.1

Renal Impairment

Pediatric Patients
Treatment of Acute, Uncomplicated Seasonal Influenza A or B Virus Infections
IV

Children 2–12 years of age with Clcr 30–49 mL/minute: Single dose of 4 mg/kg.1

Children 2–12 years of age with Clcr 10–29 mL/minute: Single dose of 2 mg/kg.1

Adolescents ≥13 years of age with Clcr 30–49 mL/minute: Single 200-mg dose.1

Adolescents ≥13 years of age with Clcr 10–29 mL/minute: Single 100-mg dose.1

Chronic renal disease maintained on hemodialysis: Adjust dosage based on renal function;1 give dose after dialysis.1

Adults
Treatment of Acute, Uncomplicated Seasonal Influenza A or B Virus Infections
IV

Clcr 30–49 mL/minute: Single 200-mg dose.1

Clcr 10–29 mL/minute: Single 100-mg dose.1

Chronic renal disease maintained on hemodialysis: Adjust dosage based on renal function;1 give dose after dialysis.1

Geriatric Patients

Dosage adjustments based solely on age not needed.1

Cautions for Peramivir

Contraindications

  • Known serious hypersensitivity (e.g., anaphylaxis, erythema multiforme, Stevens-Johnson syndrome) to the drug or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Serious dermatologic reactions (Stevens-Johnson syndrome, erythema multiforme) reported.1

Anaphylactic/anaphylactoid reactions, exfoliative dermatitis, and rash also reported.1

If anaphylaxis or serious skin reaction occurs or is suspected, discontinue peramivir and initiate appropriate treatment.1

Neuropsychiatric and CNS Effects

Postmarketing cases of delirium and abnormal behavior leading to injury reported in patients with influenza receiving neuraminidase inhibitors, including peramivir.1 Most cases involved pediatric patients and generally had abrupt onset and rapid resolution.1 Role of peramivir not established.1

Influenza itself can be associated with a variety of neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior) that sometimes result in fatalities.1 Although such events may occur in the setting of encephalitis or encephalopathy, they can occur in patients with uncomplicated influenza.1

Closely monitor patients with influenza for signs of abnormal behavior.1

Differential Diagnosis

When making treatment decisions in patients with suspected influenza, consider possibility of primary or concomitant bacterial infections for which peramivir would be ineffective.1

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza.1 No evidence that peramivir prevents such complications.1

No evidence that peramivir is effective for illness caused by any organisms other than influenza A or B.1

Influenza Vaccination

Influenza antivirals are not a substitute for annual vaccination with a seasonal influenza vaccine (influenza virus vaccine inactivated, influenza vaccine live intranasal, influenza vaccine recombinant).112 116 144

Although influenza antivirals, including peramivir, may be used concomitantly with or any time before or after influenza virus vaccine inactivated or influenza vaccine recombinant,1 100 134 such antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal and decrease efficacy of this vaccine.1 100 (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Data regarding use of peramivir in pregnant women are insufficient to determine whether there is a risk of adverse developmental outcomes.1

In pregnant rats, no adverse embryofetal effects observed when peramivir was given by IV injection once daily at maximum feasible dosage; however, fetal abnormalities (reduced renal papilla, dilated ureters) observed when administered to rats by continuous IV infusion.1 In rabbits, developmental toxicity (abortion or premature delivery) observed when peramivir given by IV injection once daily at maternally toxic doses.1

Pregnant women are at increased risk for severe complications from influenza,1 142 144 which may lead to adverse pregnancy and/or fetal outcomes including maternal death, stillbirths, birth defects, preterm delivery, low birthweight, and small size for gestational age.1

CDC states that only limited data available regarding use of peramivir for treatment of influenza in pregnant women.142 These experts state oseltamivir is the preferred antiviral for treatment of suspected or confirmed influenza in women who are pregnant or ≤2 weeks postpartum.116 137 142

Lactation

Not known whether peramivir distributes into human milk, affects milk production, or has any effects on breast-fed infants.1 Distributed into milk in rats.1

Consider benefits of breast-feeding and importance of peramivir to the woman; also consider potential adverse effects on breast-fed child from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients <2 years of age.1

Safety and efficacy for treatment of acute, uncomplicated influenza in pediatric patients 2–17 years of age established and supported by evidence from adequate and well-controlled trials of the drug in adults and additional data from a randomized, open-label, active-controlled trial in pediatric patients in this age group.1

Safety profile in pediatric patients 2–17 years of age generally similar to that reported in adults.1 Adverse effects reported in ≥2% of pediatric patients and not reported in adults include vomiting, fever, and tympanic membrane erythema.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

Not studied in patients with hepatic impairment;1 clinically important alterations in pharmacokinetics not expected since the drug does not undergo clinically important metabolism.1 (See Elimination under Pharmacokinetics.)

Renal Impairment

Increased AUC.1 Reduce dosage in patients with Clcr <50 mL/minute.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea,1 constipation,1 insomnia,1 hypertension.1

Interactions for Peramivir

Not metabolized by and does not induce or inhibit CYP isoenzymes.1 Drug interactions with drugs that are substrates or inhibitors of these enzymes unlikely.1

Not a substrate for and does not inhibit P-glycoprotein (P-gp).1

Specific Drugs

Drug

Interaction

Comments

Estrogens/progestins

Oral contraceptives containing ethinyl estradiol and levonorgestrel: No pharmacokinetic interactions1 6

Influenza vaccines

Influenza virus vaccine inactivated or influenza vaccine recombinant: Influenza antivirals not expected to affect vaccine efficacy;100 134 no specific studies1

Influenza vaccine live intranasal: Peramivir may inhibit the vaccine virus;1 100 137 no specific studies1

Influenza virus vaccine inactivated or influenza vaccine recombinant: May administer concomitantly with or any time before or after influenza antivirals100 134

Influenza vaccine live intranasal: Do not administer until ≥48 hours after peramivir discontinued;1 100 134 137 if feasible, do not administer peramivir until ≥14 days after the live vaccine;1 134 137 if peramivir administered within 2 weeks after the live vaccine, repeat vaccine dose ≥48 hours after the antiviral;134 alternatively, if peramivir given 2 days before to 14 days after the live vaccine, revaccinate using age-appropriate inactivated or recombinant influenza vaccine100 134

Oseltamivir

No pharmacokinetic interactions1 6

No in vitro evidence of antagonistic antiviral effects against influenza A (H1N1)8

Probenecid

No pharmacokinetic interactions1 6

Rimantadine

No pharmacokinetic interactions1 6

No in vitro evidence of antagonistic antiviral effects against influenza A (H1N1) or influenza A (H3N2)8

Zanamivir

Concomitant use not recommended178

Peramivir Pharmacokinetics

Absorption

Bioavailability

Following IV infusion over 30 minutes, peak serum concentrations attained at end of the infusion.1 Negligible accumulation following multiple doses for up to 10 days.1

Linear relationship between dose and exposure parameters (peak plasma concentrations, AUC).1

Distribution

Extent

Well distributed within extracellular fluid spaces, including nose and throat, following IV administration.6

Not known whether distributed into human milk.1 Distributed into milk in rats1 (peak milk concentrations attained 0.75 hours after an IV dose and milk to plasma AUC ratio approximately 0.5).1

Plasma Protein Binding

<30%.1

Elimination

Metabolism

Does not undergo clinically important metabolism.1

Not a substrate for and does not affect CYP isoenzymes.1

Elimination Route

Following IV administration, approximately 90% of dose eliminated unchanged in urine, principally by glomerular filtration.1

Removed by hemodialysis.1

Half-life

Adults: Approximately 20 hours following single 600-mg IV dose.1

Special Populations

Children 2–12 years of age: Pharmacokinetics following single 12-mg/kg IV dose similar to pharmacokinetics reported in adults following single 600-mg IV dose.1

Adolescents 13–17 years of age: Pharmacokinetics following single 600-mg IV dose similar to pharmacokinetics reported in adults following single 600-mg IV dose.1

Pediatric patients with renal impairment: Pharmacokinetics not evaluated.1

Adults with renal Impairment: AUC increased by 28, 302, or 412% in patients with Clcr of 50–79, 30–49, or <30 mL/minute, respectively, compared with those with normal renal function.1 Systemic exposure decreased by 73–81% in patients undergoing hemodialysis.1

Hepatic impairment: Pharmacokinetics not studied, but substantial alterations not expected since the drug does not undergo clinically important metabolism.1

Geriatric individuals: Pharmacokinetics similar to that in younger adults.1

Stability

Storage

Parenteral

Solution for IV Use

20–25°C (may be exposed to 15–30°C).1

Following dilution, use immediately or store for ≤24 hours at 2–8°C.1 Discard unused portions 24 hours after dilution.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1 HID

Compatible

Dextrose 5%

Ringer’s injection, lactated

Sodium chloride 0.45 or 0.9%

Actions and Spectrum

  • Peramivir is a neuraminidase inhibitor antiviral1 2 5 6 pharmacologically related to other neuraminidase inhibitors (e.g., oseltamivir, zanamivir).137

  • Potent selective competitive inhibitor of influenza virus neuraminidase, an enzyme essential for viral replication; possibly alters virus particle aggregation and release.1 2 3 6 9

  • Active in vitro against both influenza A and B viruses.1 2 3 6 137 Majority of seasonal influenza A (H3N2), influenza A (H1N1)pdm09, and influenza B viruses circulating worldwide, including in the US, during recent influenza seasons have been susceptible to neuraminidase inhibitors (oseltamivir, peramivir, zanamivir) in vitro;551 552 561 562 567 568 570 571 575 576 resistance to peramivir reported only rarely.123 144 551 552 561 562 567 568 571 575 576

  • Active against some avian influenza A viruses, including some strains of avian influenza A (H5N1) and (H7N9).6 181

  • Influenza viruses with decreased susceptibility to peramivir have been produced in vitro1 6 and observed rarely in clinical isolates.1 181 561 567 568 571 575 576 Clinical importance of decreased in vitro susceptibility not known.1

  • Major mechanisms of resistance to neuraminidase inhibitors are viral neuraminidase mutations that affect ability of the drugs to inhibit the enzyme and hemagglutinin mutations that reduce viral dependence on neuraminidase activity.1 6 14

  • Cross-resistance between peramivir and other neuraminidase inhibitors (e.g., oseltamivir, zanamivir) reported in influenza A and B viruses.1 6 14 21 137 172 173 175 181 567 568 571 575 576 However, because oseltamivir, peramivir, and zanamivir bind to different sites on the neuraminidase enzyme or interact differently with binding sites, cross-resistance among the drugs is variable.173 175 Some influenza A or B strains have reduced in vitro susceptibility to peramivir and/or oseltamivir, but are susceptible to zanamivir;1 14 137 144 181 552 562 567 other strains have reduced in vitro susceptibility to zanamivir, but are susceptible to peramivir and/or oseltamivir.1 14 21 181 562 Reduced in vitro susceptibility to all 3 drugs (oseltamivir, peramivir, zanamivir) reported in some influenza A and B strains with certain resistance-associated neuraminidase substitutions.1 21 562 To date, influenza A (H1N1)pdm09 isolates with the H275Y mutation are cross-resistant to oseltamivir and peramivir, but susceptible to zanamivir in vitro.172 174 181 562

  • Cross-resistance between peramivir and baloxavir (a polymerase acidic [PA] endonuclease inhibitor antiviral) not expected since the drugs have different mechanisms of action against influenza viruses.22 However, influenza viruses with substitutions that confer resistance to neuraminidase inhibitors may also have amino acid substitutions in the PA protein that confer resistance to baloxavir.22

Advice to Patients

  • Advise patients of the risk of severe allergic reactions (including anaphylaxis) or serious skin reactions with peramivir and importance of immediately seeking medical attention if an allergic-like reaction occurs or is suspected.1

  • Advise patients of the risk of neuropsychiatric reactions in patients with influenza and importance of immediately contacting a clinician if they experience signs of abnormal behavior after receiving peramivir.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Peramivir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Concentrate, for injection, for IV use

10 mg/mL

Rapivab

Seqirus

AHFS DI Essentials™. © Copyright 2020, Selected Revisions September 9, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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3. Kohno S, Yen MY, Cheong HJ et al. Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection. Antimicrob Agents Chemother. 2011; 55:5267-76. http://www.ncbi.nlm.nih.gov/pubmed/21825298?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3195028&blobtype=pdf

4. de Jong MD, Ison MG, Monto AS et al. Evaluation of intravenous peramivir for treatment of influenza in hospitalized patients. Clin Infect Dis. 2014; 59:e172-85. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4200045&blobtype=pdf

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