CLASSES

Neuraminidase Inhibitor Antivirals

DEA CLASS

Rx

DESCRIPTION

Intravenous neuraminidase inhibitor
Used for the treatment of acute uncomplicated influenza in patients 6 months and older
Administer within 48 hours of symptom onset

COMMON BRAND NAMES

Rapivab

HOW SUPPLIED

Rapivab Intravenous Inj Sol: 1mL, 10mg

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

600 mg/day IV.

600 mg/day IV.

600 mg/day IV.

12 mg/kg/day (Max: 600 mg/day) IV.

181 days and older: 12 mg/kg/day IV.
31 to 180 days: Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

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.

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

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.

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
- Store in original container

CONTRAINDICATIONS / PRECAUTIONS

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.

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.

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.

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. 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). 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.

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.

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.

ADVERSE REACTIONS

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

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

diarrhea / Early / 8.0-8.0
vomiting / Early / 3.0-3.0
insomnia / Early / 3.0-3.0
rash / Early / Incidence not known

DRUG INTERACTIONS

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.

PREGNANCY AND LACTATION

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