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Peramivir
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Seasonal influenza virus:
Novel influenza A viruses associated with severe human disease, including avian influenza virus:
Limitations of Use:
600 mg IV as a single dose within 48 hours of symptom onset.[58671] [62315] [63866]
600 mg IV as a single dose within 48 hours of symptom onset.[58671] [62315] [63866]
12 mg/kg/dose (Max: 600 mg/dose) IV as a single dose within 48 hours of symptom onset.[58671] [62315] [63866]
600 mg IV as a single dose within 48 hours of symptom onset.[62336] [62315]
600 mg IV once daily for a minimum of 5 days may be used as an alternative. 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] [62315]
600 mg IV as a single dose within 48 hours of symptom onset.[62336] [62315]
600 mg IV once daily for a minimum of 5 days may be used as an alternative. 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] [62315]
12 mg/kg (Max: 600 mg) IV as a single dose within 48 hours of symptom onset.[62336] [62315]
12 mg/kg/dose (Max: 600 mg/dose) IV once daily for a minimum of 5 days may be used as an alternative. 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] [62315]
600 mg/day IV.
600 mg/day IV.
600 mg/day IV.
12 mg/kg/day (Max: 600 mg/day) IV.
6 months and older: 12 mg/kg/day IV.
younger than 6 months: Safety and efficacy have not been established.
Safety and efficacy have not been established.
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]
Adults [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.
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.
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 indicationPeramivir is an intravenous neuraminidase inhibitor indicated for the treatment of acute uncomplicated influenza in patients 6 months 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] The FDA-approved regimen is a single infusion for patients with uncomplicated influenza. 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.[58671]
For storage information, see the specific product information within the How Supplied section.
Dilution
Intermittent IV Infusion
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 (6 months to 17 years of age) receiving peramivir (n = 107) compared with 9% of patients receiving oseltamivir (n = 23) 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. If anaphylaxis or a serious rash develops during treatment, immediately discontinue peramivir and institute appropriate treatment.[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.[58671] 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.[58681] Proteinuria (Grade 2) was reported in 3% of pediatric patients receiving peramivir (n = 107) compared with 0% of patients receiving oseltamivir (n = 23) 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 a subset of adult patients (n = 101) with serious influenza requiring hospitalization.[58671]
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]
Pregnant and postpartum patients are at significantly higher risk for serious complications from influenza infection as compared with nonpregnant people; therefore, timely use of antiviral therapy is recommended for the treatment of influenza. The American College of Obstetricians and Gynecologists (ACOG) consider peramivir an alternative antiviral for treatment of influenza in pregnant patients. Limited available data with peramivir use in pregnancy are insufficient to determine a drug-associated risk of adverse developmental outcomes. 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] [70419]
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]
Serious rash, including Stevens-Johnson Syndrome (SJS) and erythema multiforme, have been reported during postmarketing use of peramivir.[58671]
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: 04/12/2024, 12:16:56 PMPeramivir 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.[58671]
Affected cytochrome P450 isoenzymes and drug transporters: none
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]
Although the pharmacokinetics of peramivir have not been specifically studied in patients with hepatic impairment, clinically relevant alterations are not expected.[58671]
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. The pharmacokinetics of peramivir have not been evaluated in pediatric patients with renal impairment.[58671]
Hemodialysis is effective in reducing systemic exposure of peramivir by 73% to 81%.[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]
The pharmacokinetics of peramivir were evaluated in a study of 107 pediatric patients (6 months to 17 years) with acute uncomplicated influenza who received a single IV dose of peramivir 12 mg/kg/dose (children 6 months to 12 years) or 600 mg (adolescents). The pharmacokinetics of peramivir in children 2 to 6 years (Cmax 47,400 ng/mL and AUC 62,700 ng x hour/mL), children 7 to 12 years (Cmax 61,200 ng/mL and AUC 76,300 ng x hour/mL), and adolescents (Cmax 51,500 ng/mL and AUC 65,500 ng x hour/mL) were similar to those seen in healthy adults administered a single 600 mg dose (Cmax 45,700 ng/mL and AUC 68,500 ng x hour/mL). The pharmacokinetics of peramivir in children 6 months to younger than 2 years (Cmax 38,000 ng/mL and AUC 46,200 ng x hour/mL) were lower than that of healthy adults, with geometric mean ratios of 0.68 (0.52 to 0.88) for AUC and 0.83 (0.59 to 1.18) for Cmax; however, the difference in exposure was not considered to be clinically significant.[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]
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]
Peramivir pharmacokinetics were similar in male and female subjects.[58671]
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]
Pregnant and postpartum patients are at significantly higher risk for serious complications from influenza infection as compared with nonpregnant people; therefore, timely use of antiviral therapy is recommended for the treatment of influenza. The American College of Obstetricians and Gynecologists (ACOG) consider peramivir an alternative antiviral for treatment of influenza in pregnant patients. Limited available data with peramivir use in pregnancy are insufficient to determine a drug-associated risk of adverse developmental outcomes. 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] [70419]
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]
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