Rapivab

Mechanism of Action

Elicits antiviral activity by inhibiting influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells

• BioCryst Pharmaceuticals, Inc.

To make sure peramivir is safe for you, tell your doctor if you have:

• kidney disease (or if you are on dialysis); or

• if you have received a nasal flu vaccine (FluMist) within the past 2 weeks.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether peramivir passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Peramivir is injected into a vein through an IV. A healthcare provider will give you this injection.

Peramivir is usually given as a single dose. The medicine should be given within the first 2 days of when flu symptoms start.

Peramivir will not treat an infection caused by bacteria or fungus.

Call your doctor if your symptoms do not improve, or if they get worse after you have received this medicine.

Antiviral; neuraminidase inhibitor.1 2 3 137 144

Contraindications

• Manufacturer states none.1

Warnings/Precautions

Sensitivity Reactions

Serious dermatologic reactions (Stevens-Johnson syndrome, erythema multiforme) reported.1 Exfoliative dermatitis and rash also reported.1

If hypersensitivity or serious skin reaction occurs or is suspected, 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 children in Japan 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) and fatalities can occur.1 Although such events may occur in the setting of encephalitis or encephalopathy, they can occur without obvious severe disease.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 infection 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 of efficacy in illness caused by any organisms other than influenza A or B.1

Influenza Vaccination

Although antivirals used for treatment of influenza, including peramivir, may be used concomitantly with or at any time before or after influenza virus vaccine inactivated,1 100 these antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal.1 100 (See Specific Drugs under Interactions.)

Specific Populations

Category C.1

No adequate and well-controlled studies using peramivir in pregnant women;1 animal studies revealed evidence of maternal toxicity, developmental toxicity, and some fetal anomalies.1

Pregnant women are at increased risk for severe complications from influenza,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.21

Manufacturer states use peramivir during pregnancy only if clearly needed.1

CDC and ACIP state that pregnancy is not a contraindication to use of antivirals for treatment of influenza;137 142 144 oseltamivir may be preferred when a neuraminidase inhibitor indicated for treatment of influenza in women who are pregnant or up to 2 weeks postpartum.137 142 144

Distributed into milk in rats;1 not known whether distributed into human milk.1

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

Safety and efficacy not established in pediatric patients <18 years of age.1

During the 2009 influenza A (H1N1)pdm09 pandemic (see Pandemic Influenza under Uses), FDA issued an Emergency Use Authorization (EUA) that temporarily allowed use of peramivir for treatment of serious pandemic influenza virus infection in certain hospitalized patients, including infants and children†.10 11 Although the EUA expired in June 2010,11 some information is available regarding safety and efficacy for treatment of influenza virus infection in pediatric patients†.1 5 9 Data from an open-label study evaluating peramivir for treatment of uncomplicated influenza in infants and children 4 weeks to 16 years of age indicated that the safety profile is similar to that reported in adults.5 Most frequently reported adverse effects in pediatric patients are GI effects (diarrhea, vomiting) and decreased neutrophil counts.1 5 9

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

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.)

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

Common Adverse Effects

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

Not metabolized by and does not affect 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

• Advise patients of the risk of serious skin reactions and importance of immediately contacting a clinician if a skin reaction occurs.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.)

A nurse or other trained health professional will give you this medicine in a hospital. This medicine is given through a needle placed in one of your veins. The medicine must be injected slowly, so your IV tube will need to stay in place for 15 to 30 minutes.

This medicine should be given as soon as possible after flu symptoms start or after you are exposed to the flu (within the first 2 days).

Dosage in Acute Uncomplicated Influenza

Administer Rapivab within 2 days of onset of symptoms of influenza.

The recommended dose of Rapivab in adult patients 18 years of age or older with acute uncomplicated influenza is a single 600 mg dose, administered via intravenous infusion for 15 to 30 minutes.

Dosing in Patients with Renal Impairment

Significantly increased drug exposures were observed when Rapivab was administered to subjects with renal dysfunction [see Clinical Pharmacology (12.3)]. Therefore, the Rapivab dose should be reduced for patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 1. No dose adjustment is required for single administration of Rapivab in patients with creatinine clearance of 50 mL/min or higher [see Clinical Pharmacology (12.3)].

In patients with chronic renal impairment maintained on hemodialysis, Rapivab should be administered after dialysis at a dose adjusted based on renal function (Table 1) [see Clinical Pharmacology (12.3)].

Preparation of Rapivab for Intravenous Infusion

Use aseptic technique during the preparation of Rapivab 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 Rapivab:

Once a diluted solution of Rapivab 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 Rapivab to reach room temperature then administer immediately.

Drug Compatibility

Rapivab injection is compatible with 0.9% or 0.45% sodium chloride, 5% dextrose, or lactated Ringer's. Do not mix or co-infuse Rapivab with other intravenous medications.

Rapivab injection is compatible with materials commonly used for administration such as polyvinylchloride (PVC) bags and PVC-free bags, polypropylene syringes, and polyethylene tubing.

None

The following adverse reactions are discussed in other sections of the labeling:

• Serious skin and hypersensitivity reactions [see Warnings and Precautions (5.1)]
• Neuropsychiatric Events [see Warnings and Precautions (5.2)]

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.

In five randomized, double-blind, controlled trials, 1,399 subjects with acute uncomplicated influenza received a single dose of Rapivab, administered intravenously or intramuscularly, at doses up to 600 mg. Among the 664 subjects receiving Rapivab 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 Rapivab 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 2 occurred more frequently in subjects treated with Rapivab 600 mg (intravenous or intramuscular) than placebo. Only events occurring at ≥2% are included.

In a subset of subjects with serious influenza requiring hospitalization treated with Rapivab 600 mg as monotherapy (N=101) the following adverse reactions were also reported more frequently with Rapivab as compared to placebo: constipation (4% versus 2%), insomnia (3% versus 0%), AST increased (3% versus 2%), and hypertension (2% versus 0%).

Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of Rapivab in Japan. 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 [see Warnings and Precautions (5.1)]

Psychiatric: abnormal behavior, hallucination [see Warnings and Precautions (5.2)]

Applies to peramivir: intravenous solution, solution iv (infusion)

Along with its needed effects, peramivir (the active ingredient contained in Rapivab) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking peramivir:

• Blistering, peeling, or loosening of the skin
• chills
• cough
• diarrhea
• fever
• itching
• joint or muscle pain
• red, irritated eyes
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• unusual tiredness or weakness

• Confusion as to time, place, or person
• holding false beliefs that cannot be changed by fact
• red skin lesions, often with a purple center
• seeing, hearing, or feeling things that are not there
• unusual excitement, nervousness, or restlessness

Some side effects of peramivir may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blurred vision
• difficulty having a bowel movement (stool)
• dizziness
• headache
• nervousness
• pounding in the ears
• slow or fast heartbeat
• trouble sleeping