Data from FDA - Curated by EPG Health - Last updated 02 February 2018

Indication(s)

1 INDICATIONS AND USAGE Oral transmucosal fentanyl citrate is indicated for the management of breakthrough pain in cancer patients 16 years of age and older 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, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids when taking oral transmucosal fentanyl citrate. Limitations of Use: Not for use in opioid non-tolerant patients. Not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see Contraindications (4)]. As a part of the TIRF REMS Access program, oral transmucosal fentanyl citrate may be dispensed only to outpatients enrolled in the program [see Warnings and Precautions (5.7)]. For inpatient administration of oral transmucosal fentanyl citrate (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required. Oral transmucosal fentanyl citrate is an opioid agonist indicated for the management of breakthrough pain in cancer patients 16 years of age and older 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, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids while taking oral transmucosal fentanyl citrate. Limitations of Use Not for use in opioid non-tolerant patients. Not for use in the management of acute or postoperative pain, including headache/migraine or dental pain. (4) As a part of the TIRF REMS Access program, oral transmucosal fentanyl citrate may be dispensed only to outpatients enrolled in the program. (5.7) For inpatient administration of oral transmucosal fentanyl citrate (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.

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Advisory information

contraindications
4 CONTRAINDICATIONS Oral transmucosal fentanyl citrate is contraindicated in: Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see Indications and Usage (1)]; Warnings and Precautions (5.1) [see Indications and Usage (1)]. Significant respiratory depression [see Warnings and Precautions (5.1)]. Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department. Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9)]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14)]. Known hypersensitivity to fentanyl or components of oral transmucosal fentanyl citrate (e.g., anaphylaxis, hypersensitivity) [see Adverse Reactions (6.2)]. Opioid non-tolerant patients. (4) Significant respiratory depression. (4) Management of acute or postoperative pain including headache/migraines and dental pain. (4) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. (4) Known or suspected gastrointestinal obstruction, including paralytic ileus. (4) Known hypersensitivity to fentanyl or components of oral transmucosal fentanyl citrate. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Life-Threatening Respiratory Depression [see Warnings and Precautions (5.1)] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4)] Addiction, Abuse, and Misuse [see Warnings and Precautions (5.6)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.8)] Serotonin Syndrome [see Warnings and Precautions (5.10)] Adrenal Insufficiency [see Warnings and Precautions (5.11)] Severe Hypotension [see Warnings and Precautions (5.12)] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14)] Seizures [see Warnings and Precautions (5.15)] Most common (frequency ≥5%): nausea, dizziness, somnolence, vomiting, asthenia, and headache, dyspnea, constipation, anxiety, confusion, depression, rash, and insomnia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact SpecGx LLC, at 1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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. The safety of oral transmucosal fentanyl citrate has been evaluated in 257 opioid-tolerant chronic cancer pain patients. The duration of oral transmucosal fentanyl citrate use varied during the open-label study. Some patients were followed for over 21 months. The average duration of therapy in the open-label study was 129 days. The most serious adverse reactions associated with oral transmucosal fentanyl citrate are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Because the clinical trials of oral transmucosal fentanyl citrate were designed to evaluate safety and efficacy in treating breakthrough cancer pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received oral transmucosal fentanyl citrate for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of oral transmucosal fentanyl citrate therapy, or cancer-related symptoms. Three short-term clinical trials with similar titration schemes were conducted in 257 patients with malignancy and breakthrough cancer pain. Data are available for 254 of these patients. Table 1 lists, by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during titration. The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schemes used in these studies. Adverse reactions are listed in descending order of frequency within each body system. Table 1. Percent of Patients with Specific Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Titration (Events in 1% or More of Patients) Percentage of Patients Reporting Event Dose Group 200-600 mcg (n =230) 800-1400 mcg (n =138) 1600 mcg (n =54) >1600 mcg (n =41) Any Dose* (n =254) Body As A Whole Asthenia 6 4 0 7 9 Headache 3 4 6 5 6 Accidental Injury 1 1 4 0 2 Digestive Nausea 14 15 11 22 23 Vomiting 7 6 6 15 12 Constipation 1 4 2 0 4 Nervous Dizziness 10 16 6 15 17 Somnolence 9 9 11 20 17 Confusion 1 6 2 0 4 Anxiety 3 0 2 0 3 Abnormal Gait 0 1 4 0 2 Dry Mouth 1 1 2 0 2 Nervousness 1 1 0 0 2 Vasodilatation 2 0 2 0 2 Hallucinations 0 1 2 2 1 Insomnia 0 1 2 0 1 Thinking Abnormal 0 1 2 0 1 Vertigo 1 0 0 0 1 Respiratory Dyspnea 2 3 6 5 4 Skin Pruritus 1 0 0 5 2 Rash 1 1 0 2 2 Sweating 1 1 2 2 2 Special Senses Abnormal Vision 1 0 2 0 2 * Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once. The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system. Body as a Whole: Pain, fever, abdominal pain, chills, back pain, chest pain, infection Digestive: Diarrhea, dyspepsia, flatulence Metabolic and Nutritional: Peripheral edema, dehydration Nervous: Hypesthesia, migraine Respiratory: Pharyngitis, cough increased The following reactions occurred during titration with an overall frequency of less than 1% and are listed in descending order of frequency within each body system. Body as a Whole: bone pain Cardiovascular: Deep thrombophlebitis, hypertension, hypotension Digestive: Anorexia, eructation, fecal impaction, gum hemorrhage, mouth ulceration, oral moniliasis Hemic and Lymphatic: Anemia, leukopenia Metabolic and Nutritional: Edema, hypercalcemia, weight loss Musculoskeletal: Myalgia, pathological fracture, myasthenia Nervous: Abnormal dreams, urinary retention, agitation, amnesia, emotional lability, euphoria, incoordination, libido decreased, neuropathy, paresthesia, speech disorder Respiratory: Hemoptysis, pleural effusion, rhinitis, asthma, hiccup, pneumonia, respiratory insufficiency, sputum increased Skin and Appendages: Alopecia, exfoliative dermatitis Special Senses: Taste perversion Urogenital: Vaginal hemorrhage, dysuria, hematuria, urinary incontinence, urinary tract infection A long-term extension study was conducted in 156 patients with malignancy and breakthrough cancer pain who were treated for an average of 129 days. Data are available for 152 of these patients. Table 2 lists by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during the long-term extension study. Adverse reactions are listed in descending order of frequency within each body system. Table 2. Percent of Patients with Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Long Term Treatment (Events in 1% or More of Patients) Percentage of Patients Reporting Event Dose Group 200-600 mcg (n=98) 800-1400 mcg (n=83) 1600 mcg (n=53) >1600 mcg (n=27) Any Dose* (n=152) Body As A Whole Asthenia 25 30 17 15 38 Headache 12 17 13 4 20 Accidental Injury 4 6 4 7 9 Hypertonia 2 2 2 0 3 Digestive Nausea 31 36 25 26 45 Vomiting 21 28 15 7 31 Constipation 14 11 13 4 20 Intestinal Obstruction 0 2 4 0 3 Cardiovascular Hypertension 1 1 0 0 1 Nervous Dizziness 12 10 9 0 16 Anxiety 9 8 8 7 15 Somnolence 8 13 8 7 15 Confusion 2 5 13 7 10 Depression 9 4 2 7 9 Insomnia 5 1 8 4 7 Abnormal Gait 5 1 0 0 4 Dry Mouth 3 1 2 4 4 Nervousness 2 2 0 4 3 Stupor 4 1 0 0 3 Vasodilatation 1 1 4 0 3 Thinking Abnormal 2 1 0 0 2 Abnormal Dreams 1 1 0 0 1 Convulsion 0 1 2 0 1 Myoclonus 0 0 4 0 1 Tremor 0 1 2 0 1 Vertigo 0 0 4 0 1 Respiratory Dyspnea 15 16 8 7 22 Skin Rash 3 5 8 4 8 Sweating 3 2 2 0 4 Pruritus 2 0 2 0 2 Special Senses Abnormal Vision 2 2 0 0 3 Urogenital Urinary Retention 1 2 0 0 2 * Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once. The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system. Body as a Whole: Pain, fever, back pain, abdominal pain, chest pain, flu syndrome, chills, infection, abdomen enlarged, bone pain, ascites, sepsis, neck pain, viral infection, fungal infection, cachexia, cellulitis, malaise, pelvic pain Cardiovascular: Deep thrombophlebitis, palpitation, vascular disorder Digestive: Diarrhea, anorexia, dyspepsia, dysphagia, oral moniliasis, mouth ulceration, rectal disorder, stomatitis, flatulence, gastrointestinal hemorrhage, gingivitis, jaundice, periodontal abscess, eructation, glossitis, rectal hemorrhage Hemic and Lymphatic: Anemia, leukopenia, thrombocytopenia, ecchymosis, lymphadenopathy, lymphedema, pancytopenia Metabolic and Nutritional: Peripheral edema, edema, dehydration, weight loss, hyperglycemia, hypokalemia, hypercalcemia, hypomagnesemia Musculoskeletal: Myalgia, pathological fracture, joint disorder, leg cramps, arthralgia, bone disorder Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech disorder, migraine Respiratory: Cough increased, pharyngitis, pneumonia, rhinitis, sinusitis, bronchitis, epistaxis, asthma, hemoptysis, sputum increased Skin and Appendages: Skin ulcer, alopecia Special Senses: Tinnitus, conjunctivitis, ear disorder, taste perversion Urogenital: Urinary tract infection, urinary incontinence, breast pain, dysuria, hematuria, scrotal edema, hydronephrosis, kidney failure, urinary urgency, urination impaired, breast neoplasm, vaginal hemorrhage, vaginitis The following reactions occurred with a frequency of less than 1% in the long-term extension study and are listed in descending order of frequency within each body system. Body as a Whole: Allergic reaction, cyst, face edema, flank pain, granuloma, bacterial infection, mucous membrane disorder, neck rigidity Cardiovascular: Angina pectoris, hemorrhage, hypotension, peripheral vascular disorder, postural hypotension, tachycardia Digestive: Cheilitis, esophagitis, fecal incontinence, gastroenteritis, gastrointestinal disorder, gum hemorrhage, hemorrhage of colon, hepatorenal syndrome, liver tenderness, tooth caries, tooth disorder Hemic and Lymphatic: Bleeding time increased Metabolic and Nutritional: Acidosis, generalized edema, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, thirst Musculoskeletal: Arthritis, muscle atrophy, myopathy, synovitis, tendon disorder Nervous: Acute brain syndrome, agitation, cerebral ischemia, facial paralysis, foot drop, hallucinations, hemiplegia, miosis, subdural hematoma Respiratory: Hiccup, hyperventilation, lung disorder, pneumothorax, respiratory failure, voice alteration Skin and Appendages: Herpes zoster, maculopapular rash, skin discoloration, urticaria, vesiculobullous rash Special Senses: Ear pain, eye hemorrhage, lacrimation disorder, partial permanent deafness, partial transitory deafness Urogenital: Kidney pain, nocturia, oliguria, polyuria, pyelonephritis 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oral transmucosal fentanyl citrate. Because these 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. Digestive: - Dental decay: Dental decay, including dental caries, tooth loss, and gum line erosion. Nervous System Disorders: - Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Endocrine Disorders: - Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. - Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids. Immune System Disorders: - Anaphylaxis: Anaphylaxis has been reported with ingredients contained in oral transmucosal fentanyl citrate. General Disorders and Administration Site Conditions: Application site reactions including irritation, pain, and ulcer, and drug withdrawal syndrome.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Patients must require and use around-the-clock opioids when taking oral transmucosal fentanyl citrate. (1) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2.1) Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1) Initial dose of oral transmucosal fentanyl citrate: 200 mcg. Prescribe an initial supply of six 200 mcg oral transmucosal fentanyl citrate units. (2.2) Individually titrate to a tolerable dose that provides adequate analgesia using single oral transmucosal fentanyl citrate dosage unit per breakthrough cancer pain episode. (2.3) No more than two doses can be taken per breakthrough pain episode. (2.3, 2.4) Wait at least 4 hours before treating another episode of breakthrough pain with oral transmucosal fentanyl citrate. (2.3, 2.4) Limit consumption to four or fewer units per day once successful dose is found. (2.4) When opioid therapy is no longer required, consider discontinuing oral transmucosal fentanyl citrate along with a gradual downward of other opioids to minimize possible withdrawal effects. (2.6) 2.1 Important Dosage and Administration Instructions Healthcare professionals who prescribe oral transmucosal fentanyl citrate on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of oral transmucosal fentanyl citrate [see Warnings and Precautions (5.7)]. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with oral transmucosal fentanyl citrate and adjust the dosage accordingly [see Warnings and Precautions (5.1)]. Instruct patients and caregivers to take steps to store oral transmucosal fentanyl citrate securely and to properly dispose of unused oral transmucosal fentanyl citrate as soon as no longer needed [see Warnings and Precautions (5.1, 5.2), Patient Counseling Information (17)]. Other TIRF formulations and oral transmucosal fentanyl citrate are not equivalent. DO NOT substitute an oral transmucosal fentanyl citrate prescription for any other TIRF formulation under any circumstances. Do not convert patients on a mcg per mcg basis from any other fentanyl product to oral transmucosal fentanyl citrate [see Warnings and Precautions (5.5)]. 2.2 Initial Dosage Individually titrate oral transmucosal fentanyl citrate to a dose that provides adequate analgesia and minimizes side effects. The initial dose of oral transmucosal fentanyl citrate to treat episodes of breakthrough cancer pain is always 200 mcg. The oral transmucosal fentanyl citrate unit should be consumed over 15 minutes. Patients should be prescribed an initial titration supply of six 200 mcg oral transmucosal fentanyl citrate units, thus limiting the number of units in the home during titration. Patients should use up all units before increasing to a higher dose to prevent confusion and possible overdose. Repeat Dosing a. In cases where the breakthrough pain episode is not relieved after 15 minutes after completion of the oral transmucosal fentanyl citrate unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of oral transmucosal fentanyl citrate for any episode of breakthrough pain. b. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with oral transmucosal fentanyl citrate. 2.3 Dose Titration From an initial dose, closely follow patients and change the dosage strength until the patient reaches a dose that provides adequate analgesia using a single oral transmucosal fentanyl citrate dosage unit per breakthrough cancer pain episode. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should be removed from the patient’s mouth immediately, disposed of properly, and subsequent doses should be decreased. Patients should record their use of oral transmucosal fentanyl citrate over several episodes of breakthrough cancer pain and review their experience with their physicians to determine if a dosage adjustment is warranted. In cases where the breakthrough pain episode is not relieved 15 minutes after completion of the oral transmucosal fentanyl citrate unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose of the same strength for that episode. Thus, patients should take a maximum of two doses of oral transmucosal fentanyl citrate for any breakthrough pain episode. Patients must wait at least 4 hours before treating another episode of breakthrough pain with oral transmucosal fentanyl citrate. To reduce the risk of overdosing during titration, patients should have only one strength of oral transmucosal fentanyl citrate available at any one time. Figure 1 2.4 Maintenance Dosing a. Once titrated to an effective dose, patients should generally use ONLY ONE oral transmucosal fentanyl citrate unit of the appropriate strength per breakthrough pain episode. b. On those occasions when the breakthrough pain episode is not relieved 15 minutes after completion of the oral transmucosal fentanyl citrate unit, patient may take ONLY ONE additional dose using the same strength for that episode. c. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with oral transmucosal fentanyl citrate. Once a successful dose has been found (i.e., an average episode is treated with a single unit), patients should limit consumption to four or fewer units per day. d. Dosage adjustment of oral transmucosal fentanyl citrate may be required in some patients in order to continue to provide adequate relief of breakthrough pain. e. Generally, the oral transmucosal fentanyl citrate dose should be increased only when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes. f. If the patient experiences greater than four breakthrough pain episodes per day, the dose of the maintenance (around-the-clock) opioid used for persistent pain should be re-evaluated. 2.5 Administration of Oral Transmucosal Fentanyl Citrate Open the blister package with scissors immediately prior to product use. The patient should place the oral transmucosal fentanyl citrate unit in his or her mouth between the cheek and lower gum, occasionally moving the drug matrix from one side to the other using the handle. The oral transmucosal fentanyl citrate unit should be sucked, not chewed. A unit dose of oral transmucosal fentanyl citrate, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed [see Clinical Pharmacology (12.3)]. The oral transmucosal fentanyl citrate unit should be consumed over a 15-minute period. Longer or shorter consumption times may produce less efficacy than reported in oral transmucosal fentanyl citrate clinical trials. If signs of excessive opioid effects appear before the unit is consumed, remove the drug matrix from the patient’s mouth immediately and decrease future doses. 2.6 Discontinuation of Oral Transmucosal Fentanyl Citrate When opioid therapy is no longer required, consider discontinuing oral transmucosal fentanyl citrate along with a gradual downward of other opioids to minimize possible withdrawal effects. 2.7 Disposal of Oral Transmucosal Fentanyl Citrate After consumption of the unit is complete and the matrix is totally dissolved, throw away the handle in a trash container that is out of the reach of children. If any of the drug matrix remains on the handle, place the handle under hot running tap water until all of the drug matrix is dissolved, and then dispose of the handle in a place that is out of the reach of children. Dispose of handles in the child-resistant container (as described in steps 1 and 2) at least once a day. If the temporary storage bottle provided as part of the oral transmucosal fentanyl citrate Child Safety Kit is available, partially consumed units may be stored in the specially provided child-resistant container out of the reach of children until proper disposal is possible. Unopened units remaining from a prescription must be properly disposed as soon as they are no longer needed. To dispose of the unused oral transmucosal fentanyl citrate units: Remove the oral transmucosal fentanyl citrate unit from its blister package using scissors, and hold oral transmucosal fentanyl citrate by its handle over the toilet bowl. Using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet. Dispose of the handle in a place that is out of the reach of children. Repeat steps 1, 2, and 3 for each oral transmucosal fentanyl citrate unit. Flush the toilet twice after 5 units have been cut and deposited into the toilet. Do not flush the entire oral transmucosal fentanyl citrate units, oral transmucosal fentanyl citrate handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it. In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for SpecGx LLC (1-800-778-7898) or seek assistance from their local DEA office.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. (8.1) Lactation: Not recommended. Renal and Hepatic Impairment: Administer oral transmucosal fentanyl citrate with caution. (8.6) 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.8)]. Available data with oral transmucosal fentanyl citrate in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data]. 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 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.8)]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Oral transmucosal fentanyl citrate is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including oral transmucosal fentanyl citrate, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Animal Data Fentanyl (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6 to 17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison). Fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (GD 6 to 18). Maternal toxicity was noted at doses >100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison). Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.2 times the 1600 mcg dose of oral transmucosal fentanyl citrate on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of oral transmucosal fentanyl citrate based on a mg/m2 basis). No evidence of teratogenicity was reported. No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 3 times the human dose of 1600 mcg oral transmucosal fentanyl citrate per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean Cmax observed following administration of 1600 mcg dose of oral transmucosal fentanyl citrate in humans. In a postnatal development study, pregnant rats were treated from GD 6 through Lactation Day (LD) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). Maternal toxicity was noted at doses >100 mcg/kg. A reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. No difference in the number of live pups/litter was seen at birth, however, pup survival at LD 4 was reduced to 48% at 400 mcg/kg and by LD 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. During lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg group. Pups from this group also had significantly reduced body weights throughout the lactation period. The dose of fentanyl administered to rats at which no developmental toxicity in the F1 generation was seen was 50 mcg/kg which is 0.6 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison. 8.2 Lactation Risk Summary Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with oral transmucosal fentanyl citrate. Clinical Considerations Monitor infants exposed to oral transmucosal fentanyl citrate through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below 16 years of age have not been established. In a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with oral transmucosal fentanyl citrate. The study was too small to allow conclusions on safety and efficacy in this patient population. Twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received oral transmucosal fentanyl citrate at doses ranging from 200 mcg to 600 mcg. The mean (CV%; range) dose-normalized (to 200 mcg) Cmax and AUC0-8 values were 0.87 ng/mL (51%; 0.42-1.30) and 4.54 ng•h/mL (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (N = 3) and 0.68 ng/mL (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (N = 9). 8.5 Geriatric Use Of the 257 patients in clinical studies of oral transmucosal fentanyl citrate in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. Those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. No difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in oral transmucosal fentanyl citrate clinical trials. Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. Therefore, exercise caution when individually titrating oral transmucosal fentanyl citrate in elderly patients to provide adequate efficacy while minimizing risk. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of oral transmucosal fentanyl citrate slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9)]. Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Patients with Renal or Hepatic Impairment Insufficient information exists to make recommendations regarding the use of oral transmucosal fentanyl citrate in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. 8.7 Sex Both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions.

Interactions

7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with oral transmucosal fentanyl citrate. Table 3: Clinically Significant Drug Interactions with Oral Transmucosal Fentanyl Citrate Inhibitors of CYP3A4 Clinical Impact: The concomitant use of oral transmucosal fentanyl citrate and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of oral transmucosal fentanyl citrate is achieved [see Warnings and Precautions (5.3)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. Intervention: If concomitant use is necessary, consider dosage reduction of oral transmucosal fentanyl citrate until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the oral transmucosal fentanyl citrate dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice CYP3A4 Inducers Clinical Impact: The concomitant use of oral transmucosal fentanyl citrate and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.3)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the oral transmucosal fentanyl citrate dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oral transmucosal fentanyl citrate dosage reduction and monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to 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. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.10)]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oral transmucosal fentanyl citrate if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.1)]. Intervention: The use of oral transmucosal fentanyl citrate is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of oral transmucosal fentanyl citrate and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphrine Muscle Relaxants Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oral transmucosal fentanyl citrate and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when oral transmucosal fentanyl citrate is used concomitantly with anticholinergic drugs. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid the use of mixed agonist/antagonist or partial agonist analgesics in patients who are already receiving a full opioid agonist analgesic (including oral transmucosal fentanyl citrate) because they may reduce analgesic effect of oral transmucosal fentanyl citrate or precipitate withdrawal symptoms. (7)

More information

Category Value
Authorisation number ANDA078907
Agency product number MUN5LYG46H
Orphan designation No
Product NDC 0406-9202,0406-9216,0406-9206,0406-9212,0406-9204,0406-9208
Date Last Revised 18-01-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 310293
Marketing authorisation holder SpecGx LLC
Warnings WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME Life-Threatening Respiratory Depression Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with oral transmucosal fentanyl citrate, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of oral transmucosal fentanyl citrate or following a dose increase [see Warnings and Precautions (5.1)]. The substitution of oral transmucosal fentanyl citrate for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.2)]. Due to the risk of respiratory depression, oral transmucosal fentanyl citrate is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients [see Contraindications (4)]. Accidental Ingestion Accidental ingestion of even one dose of oral transmucosal fentanyl citrate, especially by children, can result in a fatal overdose of fentanyl [see Warnings and Precautions (5.2)]. Death has been reported in children who have accidentally ingested oral transmucosal fentanyl citrate. Oral transmucosal fentanyl citrate must be kept out of reach of children [see Patient Counseling Information and How Supplied/Storage and Handling (16)]. Cytochrome P450 3A4 Interaction The concomitant use of oral transmucosal fentanyl citrate with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving oral transmucosal fentanyl citrate and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.3), Drug Interactions (7), Clinical Pharmacology (12.3)]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.4), Drug Interactions (7)]. Reserve concomitant prescribing of oral transmucosal fentanyl citrate and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. Risk of Medication Errors Substantial differences exist in the pharmacokinetic profile of oral transmucosal fentanyl citrate compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl and that could result in fatal overdose [see Dosage and Administration (2.1), Warnings and Precautions (5.5)]. When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to oral transmucosal fentanyl citrate [see Dosage and Administration (2.1)]. When dispensing, do not substitute an oral transmucosal fentanyl citrate prescription for other fentanyl products. Addiction, Abuse, and Misuse Oral transmucosal fentanyl citrate exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing oral transmucosal fentanyl citrate, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.6)]. Risk Evaluation and Mitigation Strategy (REMS) Access Program Because of the risk for misuse, abuse, addiction, and overdose, oral transmucosal fentanyl citrate is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program [see Warnings and Precautions (5.7)]. Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483. Neonatal Opioid Withdrawal Syndrome Prolonged use of oral transmucosal fentanyl citrate 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 [see Warnings and Precautions (5.8)]. WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME See full prescribing information for complete boxed warning. Serious, life-threatening, and/or fatal respiratory depression has occurred. Monitor closely, especially upon initiation or following a dose increase. Due to the risk of fatal respiratory depression, oral transmucosal fentanyl citrate is contraindicated in opioid non-tolerant patients (1) and in management of acute or postoperative pain, including headache/migraines. (5.1) Accidental ingestion of oral transmucosal fentanyl citrate, especially by children, can result in a fatal overdose of fentanyl. Keep out of reach of children. Ensure proper storage and disposal. (2.7, 5.2) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of fentanyl. (5.3, 7, 12.3) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4, 7) When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to oral transmucosal fentanyl citrate. (5.5) When dispensing, do not substitute with any other fentanyl products. (5.5) Oral transmucosal fentanyl citrate exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor closely for these behaviors and conditions. (5.6) Oral transmucosal fentanyl citrate is available only through a restricted program called the TIRF REMS Access program. Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors are required to enroll in the program. (5.7) Prolonged use of oral transmucosal fentanyl citrate during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.8)