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Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 27.03.2022
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Peramiflu is indicated for the treatment of acute uncomplicated influenza in patients 2 years and older who have been symptomatic for no more than 2 days.
Limitations Of Use
- Efficacy of Peramiflu is based on clinical trials of naturally occurring influenza in which the predominant influenza infections were influenza A virus; a limited number of subjects infected with influenza B virus were enrolled.
- Influenza viruses change over time. Emergence of resistance substitutions could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Peramiflu.
- The efficacy of Peramiflu could not be established in patients with serious influenza requiring hospitalization.
Dosage In Acute Uncomplicated Influenza
Administer Peramiflu within 2 days of onset of symptoms of influenza.
Adults And Adolescents (13 Years Of Age And Older)
The recommended dose of Peramiflu in adult and adolescent patients 13 years of age or older with acute uncomplicated influenza is a single 600 mg dose, administered via intravenous infusion for 15 to 30 minutes.
Pediatric Patients (2 To 12 Years Of Age)
The recommended dose of Peramiflu in pediatric patients 2 to 12 years of age with acute uncomplicated influenza is a single 12 mg/kg dose (up to a maximum dose of 600 mg), administered via intravenous infusion for 15 to 30 minutes.
Dosing In Patients With Renal Impairment
Significantly increased drug exposures were observed when Peramiflu was administered to adult subjects with renal dysfunction. Therefore, the Peramiflu dose should be reduced for patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 1 and Table 2. No dose adjustment is required for single administration of Peramiflu in patients with creatinine clearance of 50 mL/min or higher.
In patients with chronic renal impairment maintained on hemodialysis, Peramiflu should be administered after dialysis at a dose adjusted based on renal function (Table 1 and Table 2).
Table 1: Dosage Adjustment for Adults and Adolescents (13 years and older) with Altered Creatinine Clearance
Creatinine Clearance* (mL/min) | |||
≥50 | 30-49 | 10-29 | |
Recommended Dose (mg) | 600 mg | 200 mg | 100 mg |
* Calculated using the Cockcroft and Gault equation. |
Table 2: Dosage Adjustment for Pediatric Patients (2 to 12 years of age) with Altered Creatinine Clearance
Creatinine Clearance* (mL/min) | |||
≥50 | 30-49 | 10-29 | |
Recommended Dose (mg/kg)** | 12 mg/kg | 4 mg/kg | 2 mg/kg |
* Calculated using the Cockcroft and Gault equation. ** Up to maximum dose of 600 m |
Preparation Of Peramiflu For Intravenous Infusion
Use aseptic technique during the preparation of Peramiflu to prevent inadvertent microbial contamination. There is no preservative or bacteriostatic agent present in the solution.
Follow the steps below to prepare a diluted solution of Peramiflu:
- Do not use if seal over bottle opening is broken or missing.
- Visually inspect Peramiflu for particulate matter and discoloration prior to administration.
- Dilute an appropriate dose of Peramiflu 10 mg/mL solution in 0.9% or 0.45% sodium chloride, 5% dextrose, or lactated Ringer’s to a maximum volume of 100 mL.
- Administer the diluted solution via intravenous infusion for 15 to 30 minutes.
- Discard any unused diluted solution of Peramiflu after 24 hours.
Once a diluted solution of Peramiflu has been prepared, administer immediately or store under refrigerated conditions (2° to 8°C or 36° to 46°F) for up to 24 hours. If refrigerated, allow the diluted solution of Peramiflu to reach room temperature then administer immediately.
Drug Compatibility
Peramiflu injection is compatible with 0.9% or 0.45% sodium chloride, 5% dextrose, or lactated Ringer’s. Do not mix or co-infuse Peramiflu with other intravenous medications.
Peramiflu injection is compatible with materials commonly used for administration such as polyvinylchloride (PVC) bags and PVC-free bags, polypropylene syringes, and polyethylene tubing.
Peramiflu is contraindicated in patients with known serious hypersensitivity or anaphylaxis to peramivir or any component of the product. Severe allergic reactions have included anaphylaxis, erythema multiforme and Stevens-Johnson Syndrome.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Serious Skin/Hypersensitivity Reactions
Rare cases of serious skin reactions, including erythema multiforme, have been reported with Peramiflu in clinical studies and in postmarketing experience. Cases of anaphylaxis and Stevens-Johnson Syndrome have been reported in postmarketing experience with Peramiflu. Discontinue Peramiflu and institute appropriate treatment if anaphylaxis or a serious skin reaction occurs or is suspected. The use of Peramiflu is contraindicated in patients with known serious hypersensitivity or anaphylaxis to Peramiflu.
Neuropsychiatric Events
Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur in uncomplicated influenza as well.
There have been postmarketing reports of delirium and abnormal behavior leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including Peramiflu. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made, but they appear to be uncommon. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of Peramiflu to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior.
Risk Of Bacterial Infections
There is no evidence for efficacy of Peramiflu in any illness caused by agents other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Peramiflu has not been shown to prevent such complications.
Prescribers should be alert to the potential for secondary bacterial infections and treat with antibiotics as appropriate.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
Carcinogenicity studies by intravenous injection of peramivir were not performed. However, in an oral carcinogenicity study in Sprague-Dawley rats no drug-related neoplasms were observed at drug exposures 0.2-to 0.5-fold that of humans at the clinically recommended dose of 600 mg/day.
Mutagenesis
Peramivir was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay, the Chinese hamster ovary chromosomal aberration test, and the in vivo mouse micronucleus test with intravenous administration.
Impairment Of Fertility
Peramivir had no effects on mating or fertility in rats up to 600 mg/kg/day, at which exposures were approximately 8-fold of those in humans at the clinically recommended dose.
Use In Specific Populations
Pregnancy
Risk Summary
Limited available data with Peramiflu use in pregnant women 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 administered by intravenous bolus injection during organogenesis at the maximum feasible dose, resulting in systemic drug exposures (AUC) approximately 8 times those in humans at the recommended dose. However, when peramivir was administered to rats by continuous intravenous infusion during the same gestation period, fetal abnormalities of reduced renal papilla and dilated ureters were observed. In rabbits, administration of peramivir during organogenesis at exposures 8 times those in humans at the recommended dose resulted in developmental toxicity (abortion or premature delivery) at a maternally toxic dose.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, stillbirths, birth defects, preterm delivery, low birthweight, and small for gestational age.
Data
Animal Data
Reproductive toxicity studies have been performed in rats and rabbits. In rats, peramivir was administered once daily by intravenous bolus injection at doses of 200, 400, and 600 mg/kg/day on gestational days 6-17. No treatment-related fetal toxicities were observed when peramivir was administered by intravenous bolus injection at the maximum feasible dose of 600 mg/kg, resulting in exposures approximately 8 times those in humans at the recommended dose.
Peramivir was also administered by continuous intravenous infusion to rats at daily doses of 50, 400, and 1000 mg/kg/day on gestational days 6-17. Dose related increases in the incidence of fetal abnormalities of reduced renal papilla and dilated ureters were observed at 400 and 1000 mg/kg/day. The systemic drug exposure in rats at a dose without fetal effects was less than the exposures in humans at the recommended dose.
In rabbits, peramivir was administered once daily by intravenous bolus injection at doses of 25, 50, 100, and 200 mg/kg/day on gestational days 7-19. Developmental toxicity (abortion or premature delivery) was observed at maternally toxic dose levels (100 and 200 mg/kg/day) resulting in exposures approximately 8 times those in humans at the recommended dose. The exposure in rabbits at doses without developmental toxicity was less than the exposure in humans at the recommended dose.
A pre/post-natal developmental toxicity study was performed in pregnant rats administered peramivir once daily by intravenous infusion at doses of 50, 200, 400 and 600 mg/kg/day on gestational day 6 through lactation day 20. No significant effects of peramivir on developmental outcomes were observed in nursing pups at up to the highest dose tested.
Lactation
Risk Summary
There are no data on the presence of Peramiflu in human milk, the effects on the breastfed infant, or the effects on milk production. Peramivir is present in rat milk. Limited clinical data during lactation preclude a clear determination of the risk of Peramiflu to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Peramiflu and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.
Data
A pharmacokinetic study was performed in lactating rats administered a single intravenous dose of peramivir (10 mg/kg) on lactation/postpartum days 11-13. The maximum concentration of peramivir in milk was reached at 0.75 hours post-dose. The milk to plasma AUC ratio of peramivir was approximately 0.5.
Pediatric Use
The safety and effectiveness of Peramiflu for the treatment of influenza has been established in pediatric patients 2 to 17 years of age. Use of Peramiflu for this indication is supported by evidence from adequate and well-controlled trials of Peramiflu in adults with additional data from Study 305, a randomized, active-controlled trial of 110 adolescent and pediatric subjects with acute uncomplicated influenza who received open-label treatment with a single dose of Peramiflu or 5 days of treatment with oseltamivir administered within 48 hours of onset of symptoms of influenza. Study 305 included:
- 13 to 17 years of age: 21 subjects treated with Peramiflu 600 mg
- 2 to 12 years of age: 67 subjects treated with Peramiflu 12 mg/kg (up to a maximum dose of 600 mg)
Safety and effectiveness of Peramiflu in pediatric patients less than 2 years of age have not been established.
Geriatric Use
Clinical trials of Peramiflu did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in exposures between the elderly and younger subjects.
Patients With Impaired Renal Function
A reduced dose of Peramiflu is recommended for patients with creatinine clearance below 50 mL/min. Dose adjustment is not required for a single administration of Peramiflu for patients with creatinine clearance 50 mL/min or higher.
In patients with chronic renal impairment maintained on hemodialysis, Peramiflu should be administered after dialysis at a dose adjusted based on renal function.
Patients With Serious Influenza Requiring Hospitalization
The use of Peramiflu was not shown to provide benefit in patients with serious influenza requiring hospitalization.
The following adverse reactions are discussed in other sections of the labeling:
- Serious skin and hypersensitivity reactions
- Neuropsychiatric Events
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions In Adults (18 years of age and older)
In five randomized, double-blind, controlled trials, 1,399 subjects with acute uncomplicated influenza received a single dose of Peramiflu, administered intravenously or intramuscularly, at doses up to 600 mg. Among the 664 subjects receiving Peramiflu 600 mg (intravenous or intramuscular), the most commonly observed adverse reaction was diarrhea, occurring at a rate of 8% versus 7% in subjects receiving placebo. No subject receiving Peramiflu 600 mg experienced a serious adverse event and less than 1% discontinued study because of an adverse reaction.
Clinically significant laboratory abnormalities (DAIDS Grade 2-4) listed in Table 3 occurred more frequently in subjects treated with Peramiflu 600 mg (intravenous or intramuscular) than placebo. Only events occurring at ≥2% are included.
Table 3: Laboratory Abnormalities Occurring in ≥2% of Subjects Treated with Peramiflu 600 mg
Laboratory Parameter Abnormality* | Peramiflu 600 mg | Placebo |
Alanine Aminotransferase (>2.5 x ULN) | (N=654) | (N=430) |
3% | 2% | |
Serum Glucose (>160 mg/dL) | (N=660) | (N=433) |
5% | 3% | |
Creatine Phosphokinase (≥6.0 x ULN) | (N=654) | (N=431) |
4% | 2% | |
Neutrophils (<1.000 x109/L) | (N=654) | (N=430) |
8% | 6% | |
* Frequencies based on treatment-emergent laboratory abnormalities |
In a subset of subjects with serious influenza requiring hospitalization treated with Peramiflu 600 mg as monotherapy (N=101), the following adverse reactions were also reported more frequently with Peramiflu as compared to placebo: constipation (4% versus 2%), insomnia (3% versus 0%), AST increased (3% versus 2%), and hypertension (2% versus 0%).
Adverse Reactions In Adolescent And Pediatric Subjects (2 To 17 Years Of Age)
Assessment of adverse reactions is based on a randomized, active-controlled study in which 110 adolescent and pediatric subjects ages 2 to 17 years of age with acute uncomplicated influenza received open-label treatment with a single dose of Peramiflu (N=88), or 5 days of treatment with oseltamivir (N=22).
The safety profile of Peramiflu in subjects 2 to 17 years of age was generally similar to that observed in adults. Specific adverse reactions reported in pediatric subjects treated with Peramiflu (occurring in ≥2% of subjects) and not reported in adults included vomiting (3% versus 9% for oseltamivir), fever and tympanic membrane erythema (2% versus 0%, respectively, for each of these events). The only clinically significant laboratory abnormality (DAIDS Grade 2) occurring in ≥2% of pediatric subjects treated with Peramiflu was proteinuria by dipstick analysis (3% versus 0% for oseltamivir).
Postmarketing Experience
The following additional adverse reactions have been identified during postapproval use of Peramiflu. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Dermatologic: Stevens-Johnson Syndrome, exfoliative dermatitis, rash
General disorders and administration site conditions: anaphylactic/anaphylactoid reactions
Psychiatric: abnormal behavior, hallucination
There is no human experience of acute overdosage with Peramiflu. Treatment of overdosage with Peramiflu should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with Peramiflu.
Peramiflu is cleared by renal excretion and can be cleared by hemodialysis.
The pharmacokinetics of Peramiflu was evaluated in Phase 1 trials in adults. The pharmacokinetic parameters following intravenous administration of Peramiflu (0.17 to 2 times the recommended dose) showed a linear relationship between dose and exposure parameters (Cmax and AUC).
Following intravenous administration of a single dose of Peramiflu 600 mg over 30 minutes, a maximum serum concentration (Cmax) of 46,800 ng/mL (46.8 μg/mL) was reached at the end of infusion. AUC0-∞ values were 102,700 ng•hr/mL.
Distribution
In vitro binding of peramivir to human plasma proteins is less than 30%.
Based on a population pharmacokinetic analysis, the central volume of distribution was 12.56 L.
Metabolism And Elimination
Peramivir is not a substrate for CYP enzymes, does not affect glucuronidation, and is not a substrate or inhibitor of P-glycoprotein mediated transport.
Peramivir is not significantly metabolized in humans.
The elimination half-life of Peramiflu following IV administration to healthy subjects of 600 mg as a single dose is approximately 20 hours. The major route of elimination of Peramiflu is via the kidney. Renal clearance of unchanged peramivir accounts for approximately 90% of total clearance. Negligible accumulation was observed following multiple doses, either once or twice daily, for up to 10 days.