Indications & Usage
1 INDICATIONS AND USAGE Oral Transmucosal Fentanyl Citrate (OTFC) 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. Patients must remain on around-the-clock opioids when taking OTFC. 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, OTFC may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see Warnings and Precautions ( 5.7 )] . For inpatient administration of OTFC, patient and prescriber enrollment are not required. OTFC 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. ( 1 ) 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. Patients must remain on around-the-clock opioids while taking OTFC. 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, OTFC may be dispensed by outpatient pharmacies only to outpatients enrolled in the program. ( 5.7 ) For inpatient administration of OTFC, patient and prescriber enrollment are not required.
Contraindications
4 CONTRAINDICATIONS Oral Transmucosal Fentanyl Citrate (OTFC) 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 ( 5.2 )]. Significant respiratory depression [see Warnings and Precautions ( 5.2 )]. Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department [see Indications and Usage ( 1 )] . Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.11 )]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.15 )]. Known hypersensitivity to fentanyl or components of OTFC (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/migraine 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 OTFC. ( 4 )
Warnings & Precautions
5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.9 ) Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue OTFC if serotonin syndrome is suspected. ( 5.10 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate patients, particularly during initiation and titration. ( 5.11 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.12 ) Severe Hypotension : Regularly evaluate patients during dosage initiation and titration. Avoid use of OTFC in patients with circulatory shock. ( 5.13 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of OTFC in patients with impaired consciousness or coma. ( 5.14 ) 5.1 Addiction, Abuse, and Misuse Oral Transmucosal Fentanyl Citrate (OTFC) contains fentanyl, a Schedule II controlled substance. As an opioid, OTFC exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OTFC. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6.2 )] . Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OTFC, and reassess all patients receiving OTFC for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as OTFC, but use in such patients necessitates intensive counseling about the risks and proper use of OTFC along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing OTFC. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents , depending on the patient’s clinical status [see Overdosage ( 10 )] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of OTFC, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of OTFC are essential [see Dosage and Administration ( 2 )] . Overestimating the OTFC dosage can result in a fatal overdose with the first dose. The substitution of OTFC for any other fentanyl product may result in fatal overdose [see Warnings and Precautions ( 5.5 )]. OTFC could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant. Accidental ingestion of even one dose of OTFC, especially by children, can result in respiratory depression and death due to an overdose of fentanyl [see Warnings and Precautions ( 5.3 )] . Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.7 )]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.4 )]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.4 ), Overdosage ( 10 )]. 5.3 Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure Death has been reported in children who have accidentally ingested OTFC. Patients and their caregivers must be informed that OTFC contains a medicine in an amount which can be fatal to a child. Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure. Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible. Detailed instructions for the proper storage, administrat
Adverse Reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.4 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.8 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.9 )] Serotonin Syndrome [see Warnings and Precautions ( 5.10 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.12 )] Severe Hypotension [see Warnings and Precautions ( 5.13 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.15 )] Seizures [see Warnings and Precautions ( 5.16 )] 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 Teva Pharmaceuticals at 1-888-483-8279 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 (OTFC) has been evaluated in 257 opioid-tolerant chronic cancer pain patients. The duration of OTFC 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 OTFC are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Because the clinical trials of OTFC 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 OTFC 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 OTFC 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) Dose Group Percentage of Patients Reporting Event 200- 600 mcg (n=230) 800- 1400 mcg (n=138) 1600 mcg (n=54) >1600 mcg (n=41) Any Dose Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once. (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 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) Dose Group Percentage of Patients Reporting Event 200- 600 mcg (n=98) 800- 1400 mcg (n=83) 1600 mcg (n=53) >1600 mcg (n=27) Any Dose Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once. (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 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 hemorr
Drug Interactions
7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with Oral Transmucosal Fentanyl Citrate (OTFC). Table 3: Clinically Significant Drug Interactions with OTFC Inhibitors of CYP3A4 Clinical Impact: The concomitant use of OTFC 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 OTFC is achieved [see Warnings and Precautions ( 5.6 )] . 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 OTFC until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the OTFC dosage until stable drug effects are achieved. Evaluate 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 OTFC 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 ( 5.6 )] . 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 OTFC dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OTFC dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. 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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.4 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), 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, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue OTFC 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), 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 ( 5.2 )]. Intervention: The use of OTFC 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 OTFC and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of OTFC and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.4 )]. Examples: Cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate 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: Evaluate patients for signs of urinary retention or reduced gastric motility when OTFC 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 OTFC) because they may reduce analgesic effect of OTFC or precipitate withdrawal symptoms. ( 7 )
Use in Pregnancy & Lactation
8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.8 )] . Available data with Oral Transmucosal Fentanyl Citrate (OTFC) in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and infant associated with use of OTFC for an extended period of time during pregnancy (see Clinical Considerations). 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 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 Use of opioid analgesics for an extended period of time 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 overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. OTFC is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including OTFC, 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 6-18). 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 be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.2 times the 1600 mcg dose of OTFC on a mg/m 2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of OTFC based on a mg/m 2 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 OTFC per pain episode on a mg/m 2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean C max observed following administration of 1600 mcg dose of OTFC 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.
Active Ingredients
FENTANYL CITRATE EQ 0.4MG BASE
AI Drug & Interaction Analysis
Free account required
Ask Prognia AI about ACTIQ — check interactions with your patient's full medication list, get dosing recommendations with renal/hepatic adjustments, and explore guideline-cited evidence.
Medical disclaimer: This drug information is intended for qualified healthcare professionals only. Always verify with the official FDA prescribing information before clinical use.