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  • CLASSES

    Neuraminidase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous neuraminidase inhibitor
    Used for for the treatment of acute uncomplicated influenza
    Administer within 48 hours of symptom onset

    COMMON BRAND NAMES

    Rapivab

    HOW SUPPLIED

    Rapivab Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    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. Administer within 48 hours of onset of influenza symptoms.

    Adolescents

    600 mg IV as a single dose. Administer within 48 hours of onset of influenza symptoms.

    Children 2 to 12 years

    12 mg/kg/dose (Max: 600 mg/dose) IV as a single dose. Administer within 48 hours of onset of influenza symptoms.

    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.

    Children 6 years and older and Adolescents

    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.

    Infants older than 180 days and Children up 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.

    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.

    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.

    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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    Adults and Adolescents :
    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 :
    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.
    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.

    ADMINISTRATION

    Injectable Administration

    Peramivir is 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.

    Intravenous Administration

    Preparation
    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, 5% dextrose, or Lactated Ringer's.
    Storage of diluted solution: Peramivir should be administered immediately or stored under refrigeration 2—8 degrees C (36—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.
     
    Intravenous (IV) Administration
    Infuse over 15—30 minutes.
    Do not mix or co-administer with other intravenous medications.

    STORAGE

    Rapivab:
    - Diluted product if not used immediately can be stored at 36 to 46 degrees F for up to 24 hours
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Infection

    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.

    Dialysis, renal failure, renal impairment

    Peramivir is renally eliminated. The dosage of peramivir should be adjusted in patients with renal impairment defined as a creatinine clearance of < 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 continuos renal replacement therapies.

    Children, infants, psychosis

    Neuraminidase inhibitors, including peramivir, have been associated with neuropsychiatric adverse reactions, including self-injury and delirium (psychosis). Some cases of neuropsychiatric events resulted in fatal outcomes. These reactions were primarily reported in Japanese pediatric patients and often occurred abruptly and resolved rapidly. In a trial of hospitalized 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). Because influenza infection is associated with a variety of neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior), the role of neuraminidase inhibitors in causing these reactions is unclear. Patients with influenza who are receiving neuraminidase inhibitors, particularly infants, children, and adolescents, should be closely monitored for signs of abnormal behavior. The risks and benefits of continuing the neuraminidase inhibitor should be evaluated if neuropsychiatric events occur.

    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.

    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.

    Risk of serious hypersensitivity reactions or anaphylaxis, serious rash

    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 post-marketing use of the drug. If anaphylaxis or a serious rash develops during treatment, immediately discontinue peramivir and institute appropriate treatment.

    ADVERSE REACTIONS

    Severe

    exfoliative dermatitis / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    neutropenia / Delayed / 8.0-8.0
    hyperglycemia / Delayed / 5.0-5.0
    constipation / Delayed / 4.0-4.0
    elevated hepatic enzymes / Delayed / 3.0-3.0
    proteinuria / Delayed / 3.0-3.0
    hypertension / Early / 2.0-2.0
    erythema / Early / 2.0-2.0
    delirium / Early / 0-1.0
    psychosis / Early / Incidence not known
    hallucinations / Early / Incidence not known

    Mild

    diarrhea / Early / 8.0-8.0
    insomnia / Early / 3.0-3.0
    fever / Early / 2.0-2.0
    vomiting / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Peramivir products.

    PREGNANCY AND LACTATION

    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.

    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.

    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. 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.

    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.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    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.