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Peramivir Fact Sheet for Health Care Providers (cont.)

CONTRAINDICATIONS

Do not use Peramivir IV in patients with history of severe allergic reaction to any other neuraminidase inhibitors (Relenza or Tamiflu) or any ingredient of Peramivir IV [see Product Description].

WARNINGS AND PRECAUTIONS

Limited multiple dose data are available for Peramivir IV 600 mg. The clinical trial experience for Peramivir IV 600 mg is limited to three clinical trials in which 478 patients received a single 600 mg dose. The Warnings and Precautions described here are based on the limited controlled clinical data. Most of the data are from patients who received either multiple doses less than 600 mg IV or only received single doses of Peramivir [see Limitations of Populations Studied]. Serious and unexpected adverse events may occur that have not been previously reported with Peramivir use.

Completion of FDA MedWatch Form to report all medication errors and selected adverse events occurring during Peramivir IV treatment is mandatory. Please see the Adverse Reactions and Medication Errors Reporting Requirements and Instructions section below for details on FDA MedWatch reporting.

Gastrointestinal Side Effects

Patients should be monitored for development of diarrhea and have appropriate evaluation and/or treatment, as indicated, including evaluation for other causes of diarrhea as clinically warranted.

In Trial BCX1812-201 of hospitalized patients with serious influenza receiving either Peramivir IV 200 mg (n=41) or 400 mg (n=40) for 5 days or oral oseltamivir 75 mg bid (n=41) for 5 days, the following events were observed:

  • Gastrointestinal (GI) adverse events were reported in 33% of patients receiving Peramivir IV 200 mg, 28% of patients receiving Peramivir IV 400 mg, and 15% of patients receiving oseltamivir.
  • Diarrhea was reported in 13% patients receiving Peramivir IV 200 mg or 400 mg compared to 2% patients receiving oseltamivir.
  • One serious adverse event of severe diarrhea was reported by a patient receiving Peramivir IV 400 mg daily and was judged as probably related to Peramivir IV. All diarrhea events resolved.

Similar rates of diarrhea, nausea and vomiting in patients receiving Peramivir and placebo were observed in other phase 1 and 2 trials. All GI events, regardless of causality, were seen in 12.4% of patients receiving Peramivir IV 600 mg compared to 18.1% of patients receiving oseltamivir. In the phase 3 trial, the incidence of diarrhea was similar between Peramivir IV 600 mg and oseltamivir.

Bacterial Infections

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or develop as complications 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 IV. Consult an infectious disease specialist when appropriate.

Allergic Reactions

Serious allergic-like reactions have not been reported in clinical trials in patients receiving Peramivir to date. However, allergic-like reactions, including oropharyngeal edema, serious skin rashes and anaphylaxis have been reported with use of neuraminidase inhibitors including Relenza (zanamivir) and Tamiflu (oseltamivir). Peramivir IV should be stopped and appropriate treatment instituted if an allergic reaction occurs or is suspected.

Neuropsychiatric Events

Influenza infection itself can be associated with a variety of neurologic and behavioral symptoms which can include events such as seizures, 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 without clinically apparent severe disease.

There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury in patients with influenza who were receiving the approved neuraminidase inhibitors, Tamiflu or Relenza. These events appear to be uncommon based on usage data, have been reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. Because Peramivir IV is also a neuraminidase inhibitor, and based on limited data from clinical trials, it is possible that these types of reactions or other types of neurologic and behavior events could occur in patients receiving Peramivir IV. Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient.

In Trial BCX1812-201 of hospitalized patients with serious influenza receiving either Peramivir IV 200 mg (n=41) or 400 mg (n=40) for 5 days or oral oseltamivir 75 mg bid (n= 41) for 5 days, the following events were observed.

  • Psychiatric adverse events were reported in 11% of patients receiving Peramivir IV 200 or 400 mg compared to 4% of patients receiving oseltamivir.
  • Other adverse events reported by patients treated with Peramivir IV were depression (n=2), confusion (n=1), insomnia (n=4), delirium (n=1), restlessness (n=1), anxiety (n=2), nightmare (n=1), and alteration of mood (n=1). Of these adverse events, approximately half were judged as related to study treatment.

Overall Safety Summary

From the available phase 1, 2 and 3 data the more common adverse events related to administration of Peramivir are:

  • diarrhea
  • nause

From the available phase 1 and 2 data, other less common adverse events related to administration of Peramivir are:

Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. The decision to continue or discontinue Peramivir IV therapy after development of an adverse event should be made based on the clinical risk benefit assessment for the individual patient. [See CLINICAL TRIAL RESULTS AND SUPPORTING DATA FOR EUA]

PATIENT MONITORING RECOMMENDATIONS

Given the limited experience with Peramivir IV at the recommended dose and duration, the following procedures for monitoring patients are recommended during Peramivir IV therapy. Additionally, completion of FDA MedWatch Form to report all medication errors and selected adverse events is mandatory.

Please see the ADVERSE REACTIONS and Medication Errors Reporting Requirements and Instructions section 9 for details on submitting MedWatch Forms.

Assessment Laboratory Parameter Timing
Complete blood count with differential and a basic metabolic profile glucose, calcium, sodium, potassium, chloride, serum bicarbonate, creatinine, and blood urea nitrogen On initiation, Day 3 of therapy and end of therapy
Liver associated tests alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase,and total and directbilirubin On initiation and conclusion of therapy and during therapy if clinically indicated
Urinalysis*   On initiation and conclusion of therapy and during therapy, if clinically indicated.
If significant proteinuria develops while on therapy then appropriate further evaluation including laboratory testing, 24-hour urine collection and possible nephrology consultation should be considered
Assessment of renal function serum creatinine (at a minimum) completed prior to initiation of dosing and followed carefully throughout dosing as clinically appropriate
Vital Signs body temperature, noninvasive blood pressure, heart rate, respiratory rate, and oxygen saturation Daily (at a minimum)
*[Note: Because renal abnormalities were observed in animal studies, renal parameters including proteinuria were closely monitored in phase 1 and 2 studies. Based on the limited data, no dose related proteinuria and other renal abnormalities possibly related to Peramivir were observed; however, monitoring is recommended].

  • It is especially important for patients in whom abnormal laboratory values are noted at the time Peramivir IV treatment is initiated to be monitored through the duration of therapy for worsening.
  • Patients with significant or serious metabolic abnormalities should be assessed continually with regard to the risks and potential benefits of continued Peramivir IV therapy.
  • Patients with abnormal laboratory parameters should have careful follow-up and, at a minimum, repeat assessment within 1-2 weeks of the conclusion of therapy to assess normalization.

ADVERSE REACTIONS AND MEDICATION ERRORS REPORTING REQUIREMENTS AND INSTRUCTIONS

See WARNINGS AND PRECAUTIONS for information about risk of serious adverse events such as gastrointestinal events, bacterial infections, allergic-like reactions, and neuropsychiatric events.

The prescribing health care provider and/or their designee is/are responsible for the mandatory reporting of all medication errors and the following selected adverse events occurring during Peramivir IV treatment within 7 calendar days from the onset of the event:

  1. Deaths
  2. Neuropsychiatric Events
  3. Renal Adverse Events
  4. Serious Skin Adverse Events (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)
  5. Hypersensitivity Reactions Adverse Events (e.g., anaphylaxis, urticaria, angioedema)
  6. Severe Intravenous site or Intravenous Administration Adverse Events (e.g. septic phlebitis, infiltrated IV)
  7. Other Serious Adverse Events*

*Serious Adverse Event defined as: any life-threatening adverse drug experience that may prolong existing hospitalization, result in a persistent or significant disability/incapacity or a congenital anomaly or birth defect or an event that may jeopardize the patient to an extent that may require medical/surgical intervention to prevent one of the outcomes above including death.

The MedWatch FDA Form 3500 must be completed either online at www.fda.gov/medwatch/report.htm or by using a postage-paid FDA Form 3500 (available at http://www.fda.gov/medwatch/safety/FDA-3500_fillable.pdf) and returning by fax (1-800-FDA-0178) or by mail (MedWatch, 5600 Fishers Lane,

Rockville, MD 20852-9787). If you do not have online internet access call 1-800-FDA-1088. Audits for compliance for completion and return of the MedWatch Form will be performed. FDA or their designee may contact health care providers for additional information about the adverse events or medication errors. In addition, response to follow-up inquiries requesting information regarding selected adverse events and medication errors associated with Peramivir IV administration is mandatory.

IMPORTANT: When reporting adverse events or medication errors to MedWatch, please complete the entire form with detailed information It is important that the information reported to FDA be as detailed and complete as possible. Information to include:

  • Patient Demographics (e.g., Peramivir Request number, patient initials, date of birth)
  • Pertinent medical history
  • Pertinent details regarding admission and course of illness
  • Concomitant medications
  • Timing of adverse event(s) in relationship to administration of Peramivir IV
  • Pertinent laboratory and virology information
  • Outcome of the event and any additional follow-up information if it is available at the time of the MedWatch report. Subsequent reporting of follow-up information should be completed if additional details become available (use the same Peramivir Request number when completing the report).

The following steps are highlighted to provide the necessary information for safety tracking:

  1. In section A, box 1 provide the Peramivir Request number and the patient's initials in the Patient Identifier
  2. In section A, box 2 provide the patient's date of birth
  3. In section B, box 5 description of the event provide:
    1. Write “Peramivir IV EUA” as the first line
    2. Provide a detailed report of medication error and/or adverse event. It is important to provide detailed information regarding the patient and adverse event/medication error for ongoing safety evaluation of this unapproved drug. Please see information to include listed above.
  4. In section G, box 1 name and address:
    1. Provide the name and contact information of the prescribing health care provider or institutional designee who is responsible for the report
    2. Provide the address of the treating institution (NOT the health care provider's office address).


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