Transmucosal Immediate Release Fentanyl (TIRF)
Risk Evaluation and Mitigation Strategy

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Selected Important Safety Information

IMPORTANCE OF PROPER PATIENT SELECTION, DOSING, and POTENTIAL FOR ABUSE

TIRF medicines contain fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. TIRF medicines can be abused in a manner similar to other opioid agonists, legal or illicit. Consider the potential for abuse when prescribing or dispensing TIRF medicines in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, hydrocodone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Serious adverse events, including deaths, in patients treated with some oral transmucosal fentanyl medicines have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of a TIRF medicine for any other fentanyl medicine, including another TIRF medicine, may result in fatal overdose.

TIRF medicines are indicated only for the management of breakthrough pain in adult cancer patients 18 years of age and older (16 years of age and older for Actiq® brand and generic equivalents), who are already receiving, and who are tolerant to, around-the-clock opioid therapy for their underlying persistent cancer pain.

Patients considered opioid-tolerant are those who are taking:

•    at least 60 mg of oral morphone/daily
•    at least 25 mg transdermal fentanyl/hour
•    at least 30 mg of oral oxycodone/daily
•    at least 8 mg of oral hydromorphone/daily
•    at least 25 mg of oral oxymorphone/daily
•    at least 60 mg oral hydrocodone/daily
•    or an equianalgesic dose of another opiod/daily

Patients must remain on around-the-clock opioids when taking a TIRF medicine.

TIRF medicines are contraindicated in opioid non-tolerant patients and in:

  • the management of acute or postoperative pain, including headache/migraine, dental pain, or in use in the emergency department,
  • in acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment,
  • known or suspected gastrointestinal obstruction, including paralytic ileus,
  • known hypersensitivity to fentanyl, or components of the TIRF medicine.

Please see each TIRF medicine's Full Prescribing Information for a full list of specific situations in which TIRF medicines are not indicated or are contraindicated. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with fentanyl products.

When prescribing, do not convert patients on a mcg per mcg basis from another fentanyl medicine to a TIRF medicine, except for substitutions between a branded TIRF medicine and its generic equivalent. Patients beginning treatment with TIRF medicines must begin with titration from the lowest available dose for that specific medicine. Carefully consult the Initial Dosing Instructions in the TIRF medicine-specific Full Prescribing Information.

When dispensing, TIRF medicines are not interchangeable with each other, regardless of route of administration. Differences exist in the pharmacokinetics of TIRF medicines resulting in clinically important differences in the amount of fentanyl absorbed that could cause a fatal overdose. Converting patients from one TIRF medicine to a different TIRF medicine must not be done on a microgram-per-microgram basis, and must be titrated according to the labeled dosing instructions each time they begin use of a new TIRF medicine. The only exception is for substitution between a branded TIRF medicine and its specific generic equivalent.

Special care must be used when dosing TIRF medicines. Refer to the Full Prescribing Information for the individual TIRF medicine for guidance on the maximum number of doses that can be taken per breakthrough pain episode and the time that patients must wait before treating another episode of breakthrough pain with the TIRF medicine.

TIRF medicines are intended to be used only in the care of opioid-tolerant cancer patients and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain.

Patients and their caregivers must be instructed that TIRF medicines contain fentanyl in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid-tolerant. All TIRF medicines must be kept in a safe place out of reach of children.

Drug Interactions:

    1. Fentanyl is metabolized mainly via the human cytochrome P450 (CYP3A4) isoenzyme system; therefore, potential drug interactions may occur when TIRF medicines are given concurrently with agents that affect CPY3A4 activity.
    2. Concomitant use of TIRF medicines with CYP3A4 inhibitors (e.g., certain protease inhibitors, ketoconazole, fluconazole, diltiazem, erythromycin, verapamil) may result in potentially dangerous increases in fentanyl plasma concentrations, which could increase or prolong the drug effects and may cause potentially fatal respiratory depression.
    3. Patients receiving TIRF medicines who begin therapy with, or increase the dose of, CYP3A4 inhibitors are to be carefully monitored for signs of opioid toxicity over an extended period of time. Dosage increases should be done conservatively.
    4. Due to the additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma and death.
    5. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    6. Monoamine Oxidase Inhibitors (MAOIs) interactions with opioids may manifest as serotonin syndrome.
    7. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics may reduce the analgesic effect of TIRF medicines and/or precipitate withdrawal symptoms.
    8. Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
    9. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
    10. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Prolonged use of TIRF medicines during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Adverse Reactions
The most commonly observed adverse reactions with TIRF medicines include typical opioid adverse reactions, such as nausea, vomiting, constipation, somnolence, dizziness, and headache. Refer to individual medicine prescribing information for all adverse reactions. Expect opioid side effects and manage them accordingly.

Please see the individual Full Prescribing Information for each TIRF medicine for all information including boxed warnings, and Medication Guide for important safety information for each TIRF medicine.

Adverse Event Reporting
Promptly report suspected adverse events including misuse, abuse, addiction and overdoses directly to the TIRF REMS Access program at 1-866-822-1483. You also may report adverse event information to the FDA MedWatch Reporting System by telephone at 1-800-FDA-1088 or by mail using Form 3500, available at www.fda.gov/medwatch.

Medication Guide
It is important that you discuss the risks of TIRF medicines with your patients and encourage them to read the relevant Medication Guide. The Medication Guide provides important information on the safe and effective use of TIRF medicine and you will need to review the appropriate Medication Guide for the TIRF medicines you prescribe to your patient. Patients should be counseled on the need to store TIRF medicines safely out of the reach of children and other persons for whom the medicine is not prescribed.

You must provide your patient with a copy of the appropriate Medication Guide for the TIRF medicine you prescribe. Medication Guides will be provided to you by the manufacturers of individual TIRF medicines. If you require additional Medication Guides you can:
•   Print copies from the TIRF REMS Access program website at www.TIRFREMSaccess.com.
•   Contact the TIRF REMS Access program at 1-866-822-1483.

For assistance, please call the TIRF REMS Access program at 1-866-822-1483.