Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2178
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FENTORA (Tablet)
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Physicians should individualize treatment using a progressive plan of pain management. Healthcare professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring.<br/>Patients With Hepatic and/or Renal Impairment: Caution should be exercised for patients with hepatic and/or renal impairment, and the lowest possible dose should be used in these patients.<br/>Patients Receiving CYP3A4 Inhibitors: Particular caution should be exercised for patients receiving CYP3A4 inhibitors, and the lowest possible dose should be used in these patients.<br/>Patients With Mucositis: No dose adjustment appears necessary in patients with Grade 1 mucositis. The safety and efficacy of FENTORA when used in patients with mucositis more severe than Grade 1 have not been studied.<br/>Administration of FENTORA:<br/>Dose Titration:: Patients should be titrated to a dose of FENTORA that provides adequate analgesia with tolerable side effects.<br/>Starting Dose:: The initial dose of FENTORA should be 100 mcg. For patients switching from oral transmucosal fentanyl citrate to FENTORA, the starting dose of FENTORA should be initiated as shown in Table 7 below.<br/>Re-dosing Patients Within a Single Episode:: Dosing may be repeated once during a single episode of breakthrough pain if pain is not adequately relieved by one FENTORA dose. Re-dosing may occur 30 minutes after the start of administration of FENTORA and the same dosage strength should be used.<br/>Increasing the Dose:: From an initial dose, patients should be closely followed and the dosage strength changed until the patient reaches a dose that provides adequate analgesia with tolerable side effects using a single FENTORA tablet. Patients should record their use of FENTORA over several episodes of breakthrough pain and discuss their experience with their physician to determine if a dosage adjustment is warranted. Titration should be initiated using multiples of the 100 mcg FENTORA tablet. Patients needing to titrate above 100 mcg can be instructed to use two 100 mcg tablets (one on each side of the mouth in the buccal cavity). If this dose is not successful in controlling the breakthrough pain episode, the patient may be instructed to place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Although not bioequivalent, four 100 mcg FENTORA tablets were found to deliver approximately 12% and 13% higher values for Cand AUC, respectively, compared to one 400 mcg FENTORA tablet. Consequently, patients converting from four 100 mcg tablets to one 400 mcg FENTORA tablet would be expected to experience a decrease in plasma concentration. The impact of this decrease on pain relief has not been evaluated clinically. Titrate above 400 mcg by 200 mcg increments bearing in mind (1) Using more than 4 tablets simultaneously has not been studied and (2) It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. To reduce the risk of overdose during titration, patients should have only one strength FENTORA tablet available at any one time. Patients should be strongly encouraged to use all of their FENTORA tablets of one strength prior to being prescribed the next strength. If this is not practical, unused FENTORA should be disposed of safely. Dispose of any unopened FENTORA tablets remaining from a prescription as soon as they are no longer needed. Once a successful dose has been established, 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.<br/>Dosage Adjustment:: Dosage adjustment of both FENTORA and the maintenance (around-the-clock) opioid analgesic may be required in some patients in order to continue to provide adequate relief of breakthrough pain. Generally, the FENTORA dose should be increased when patients require more than one dose per breakthrough pain episode for several consecutive episodes.<br/>Opening the Blister Package: Patients should be instructed not to open the blister until ready to administer. A single blister unit should be separated from the blister card by tearing it apart at the perforations. The blister unit should then be bent along the line where indicated. The blister backing should then be peeled back to expose the tablet. Patients should NOT attempt to push the tablet through the blister as this may cause damage to the tablet. The tablet should not be stored once it has been removed from the blister package as the tablet integrity may be compromised and because this increases the risk of accidental exposure to the tablet.<br/>Tablet Administration: Patients should remove the tablet from the blister unit and immediately place the entire FENTORA tablet in the buccal cavity (above a rear molar, between the upper cheek and gum). Patients should not attempt to split the tablet. The FENTORA tablet should not be sucked, chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed. The FENTORA tablet should be left between the cheek and gum until it has disintegrated, which usually takes approximately 14-25 minutes. After 30 minutes, if remnants from the FENTORA tablet remain, they may be swallowed with a glass of water. Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not appear to affect early systemic exposure to fentanyl.
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FENTORA (fentanyl buccal tablet) is a potent opioid analgesic, intended for buccal mucosal administration. FENTORA is formulated as a flat-faced, round, beveled-edge white tablet. FENTORA is designed to be placed and retained within the buccal cavity for a period sufficient to allow disintegration of the tablet and absorption of fentanyl across the oral mucosa. FENTORA employs the OraVescent drug delivery technology, which generates a reaction that releases carbon dioxide when the tablet comes in contact with saliva. It is believed that transient pH changes accompanying the effervescent reaction may optimize dissolution (at a lower pH) and membrane permeation (at a higher pH) of fentanyl through the buccal mucosa. Active Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula: All tablet strengths are expressed as the amount of fentanyl free base, e.g., the 100 microgram strength tablet contains 100 micrograms of fentanyl free base. Inactive Ingredients: Mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.
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Pharmacology: Fentanyl is a pure opioid agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, hydromorphone, codeine, and hydrocodone. Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, cough suppression, and analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression.<br/>Analgesia: The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3-to-5-minute half-life). In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals. As a result, the dose of FENTORA should be individually titrated to achieve the desired effect. .<br/>Central Nervous System: The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem to increases in carbon dioxide and to electrical stimulation. Fentanyl depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).<br/>Gastrointestinal System: Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.<br/>Cardiovascular System: Fentanyl may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.<br/>Endocrine System: Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.<br/>Respiratory System: All opioid mu-receptor agonists, including fentanyl, produce dose dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. During the titration phase of the clinical trials, somnolence, which may be a precursor to respiratory depression, did increase in patients who were treated with higher doses of another oral transmucosal fentanyl citrate (Actiq). Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral transmucosal fentanyl citrate product administration and may persist for several hours. Serious or fatal respiratory depression can occur even at recommended doses. Fentanyl depresses the cough reflex as a result of its CNS activity. Although not observed with oral transmucosal fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration. Therefore, physicians and other healthcare providers should be aware of this potential complication.<br/>Pharmacokinetics: Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of FENTORA increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range.<br/>Absorption:: Following buccal administration of FENTORA, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of FENTORA is largely the result of an initial absorption from the buccal mucosa, with peak plasma concentrations following venous sampling generally attained within an hour after buccal administration. Approximately 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorptionfrom the gastrointestinal tract. In a study that compared the absolute and relative bioavailability of FENTORA and Actiq (oral transmucosal fentanyl citrate [OTFC]), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with FENTORA) (Table 1). Similarly, in another bioavailability study exposure following administration of FENTORA was also greater (approximately 50%) compared to Actiq (OTFC). Due to differences in drug delivery, measures of exposure (C, AUC, AUC) associated with a given dose of fentanyl were substantially greater with FENTORA compared to Actiq (OTFC) (see Figure 1). Therefore, caution must be exercised when switching patients from one product to another. Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 6 hours. The vertical line denotes the median Tfor FENTORA. Systemic exposure to fentanyl following administration of FENTORA increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range. Mean pharmacokinetic parameters are presented in Table 2. Mean plasma concentration versus time profiles are presented in Figure 2. Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not appear to affect early systemic exposure to fentanyl. The effect of mucositis (Grade 1) on the pharmacokinetic profile of FENTORA was studied in a group of patients with (N = 8) and without mucositis (N = 8) who were otherwise matched. A single 200 mcg tablet was administered, followed by sampling at appropriate intervals. Mean summary statistics (standard deviation in parentheses, expected twhere range was used) are presented in Table 3.<br/>Distribution:: Fentanyl is highly lipophilic. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The mean oral volume of distribution at steady state (Vss/F) was 25.4 L/kg.<br/>Metabolism:: The metabolic pathways following buccal administration of FENTORA have not been characterized in clinical studies. The progressive decline of fentanyl plasma concentrations results from the uptake of fentanyl in the tissues and biotransformation in the liver. Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. In animal studies, norfentanyl was not found to be pharmacologically active.<br/>Elimination:: Disposition of fentanyl following buccal administration of FENTORA has not been characterized in a mass balance study. Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretionis less important. The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.<br/>Special Populations:: The pharmacokinetics of FENTORA has not been studied in Special Populations.<br/>Race:: The pharmacokinetic effects of race with the use of FENTORA have not been systematically evaluated. In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in US subjects (mean Cand AUC values were approximately 50% and 20% higher, respectively). The observed differences were largely attributed to the lower mean weight of the Japanese subjects compared to US subjects (57.4 kg versus 73 kg).<br/>Age:: The effect of age on the pharmacokinetics of FENTORA has not been studied.<br/>Gender:: Systemic exposure was higher for women than men (mean Cand AUC values were approximately 28% and 22% higher, respectively). The observed differences between men and women were largely attributable to differences in weight.<br/>Renal or Hepatic Impairment:: The effect of renal or hepatic impairment on the pharmacokinetics of FENTORA has not been studied. Although fentanyl kinetics are known to be altered as a result of hepatic and renal disease due to alterations in metabolic clearance and plasma protein binding, the duration of effect for the initial dose of fentanyl is largely determined by the rate of distribution of the drug. Diminished metabolic clearance may, therefore, become significant, primarily with repeated dosing or at very high single doses. For these reasons, while it is recommended that FENTORA is titrated to clinical effect for all patients, special care should be taken in patients with severe hepatic or renal disease.<br/>Drug Interactions:: The interaction between ritonavir and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg tid on Day 1 and 300 mg tid on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%-420%) increase in fentanyl AUC. Coadministration of ritonavir in patients receiving FENTORA has not been studied; however, an increase in fentanyl AUC is expected.
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Because life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients, FENTORA is contraindicated in the management of acute or postoperative pain. This product must not be used in opioid non-tolerant patients. FENTORA is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl.
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Each carton contains 7 blister cards with 4 white tablets in each card. The blisters are child-resistant, encased in peelable foil, and provide protection from moisture. Each tablet is debossed on one side with, and the other side of each dosage strength is uniquely identified by the debossing on the tablet as described in the table below. The dosage strength of each tablet is marked on the tablet, the blister package and the carton. See blister package and carton for product information. Rx only. DEA order form required. A Schedule CII narcotic. Manufactured for:Cephalon, Inc.Frazer, PA 19355 By:CIMA LABS, INC.10000 Valley View RoadEden Prairie, MN 55344 andCephalon, Inc.4745 Wiley Post WaySalt Lake City, UT 84116 U. S. Patent Nos. 6,200,604 and 6,974,590Printed in USA Label code 074000107.02April 2007 ��2006, 2007 Cephalon, Inc. All rights reserved.
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FENTORA contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. FENTORA can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing FENTORA in situations where the physician or pharmacist is concerned about an increased riskof misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. FENTORA is indicated only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least 60 mg of oral morphine/day, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer. Because life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients, FENTORA is contraindicated in the management of acute or postoperative pain. This product is not indicated for use in opioid non-tolerant patients. Patients and their caregivers must be instructed that FENTORA contains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep all tablets out of the reach of children. (See Information for Patients and Caregivers for disposal instructions.) Due to the higher bioavailability of fentanyl in FENTORA, when converting patients from other oral fentanyl products, including oral transmucosal fentanyl citrate (OTFC and Actiq), to FENTORA, do not substitute FENTORA on a mcg per mcg basis. Adjust doses as appropriate. FENTORA is 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. The concomitant use of FENTORA with strong and moderate cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression.
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General: The extent of fentanyl absorption with different formulations of transmucosal delivery systems can be substantially different; therefore, the same dose of fentanyl in two different formulations should not be viewed as equivalent. Therefore, caution must be exercised when switching patients from one product to another. For patients not previously using oral transmucosal fentanyl citrate, the initial dose of FENTORA should be 100 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects. Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Patients taking FENTORA should be warned of these dangers and should be counseled accordingly. The use of concomitant CNS active drugs requires special patient care and observation.<br/>Chronic Pulmonary Disease: Because potent opioids can cause respiratory depression, FENTORA should be titrated with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of FENTORA may further decrease respiratory drive to the point of respiratory failure.<br/>Head Injuries and Increased Intracranial Pressure: FENTORA should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of COretention such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.<br/>Application Site Reactions: In clinical trials, 10% of all patients exposed to FENTORA reported application site reactions. These reactions ranged from paresthesia to ulceration and bleeding. Application site reactions occurring in���1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients.<br/>Cardiac Disease: Intravenous fentanyl may produce bradycardia. Therefore, FENTORA should be used with caution in patients with bradyarrhythmias.<br/>Hepatic or Renal Disease: Insufficient information exists to make recommendations regarding the use of FENTORA 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.<br/>Information for Patients and Caregivers:<br/>Disposal of Unopened FENTORA Blister Packages When No Longer Needed: Patients and members of their household must be advised to dispose of any unopened blister packages remaining from a prescription as soon as they are no longer needed. To dispose of unused FENTORA, remove FENTORA tablets from blister packages and flush down the toilet. Do not flush the FENTORA blister packages or cartons down the toilet. Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of FENTORA are provided in the FENTORA Medication Guide. Patients should be encouraged to read this information in its entirety and be given an opportunity to have their questions answered. In the event that a caregiver requires additional assistance in disposing of excess unusable tablets that remain in the home after a patient has expired, they should be instructed to call the Cephalon toll-free number (1-800-896-5855) or seek assistance from their local DEA office.<br/>Laboratory Tests: The effects of FENTORA on laboratory tests have not been evaluated.<br/>Drug Interactions: See WARNINGS. Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when FENTORA is given concurrently with agents that affect CYP3A4 activity. The concomitant use of FENTORA with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazadone) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug effects including fatal respiratory depression. Patients receiving FENTORA concomitantly with moderate or strong CYP 3A4 inhibitors should be carefully monitored foran extended period of time. Dosage increase should be done conservatively. Grapefruit and grapefruit juice decrease CYP3A4 activity, increasing blood concentrations, thus should be avoided. Drugs that induce cytochrome P450 3A4 activity may have the opposite effects. Concomitant use of FENTORA with an MAO inhibitor, or within 14 days of discontinuation, is not recommended.<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fentanyl. Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. tymphimurium or E. coli, or the mouse lymphoma mutagenesis assay. Fentanyl citrate was not clastogenic in the in vivo mouse micronucleus assay. Fentanyl impairs fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for FENTORA.<br/>Pregnancy - Category C: There are no adequate and well-controlled studies in pregnant women. FENTORA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Fentanyl is embryocidal as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for FENTORA. Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21, of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic (the high dose was approximately 3-times the human dose of 1600 mcg per pain episode on a mg/mbasis). Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but was not teratogenic.<br/>Labor and Delivery: Fentanyl readily passes across the placenta to the fetus; therefore FENTORA is not recommended for analgesia during labor and delivery.<br/>Nursing Mothers: Fentanyl is excreted in human milk; therefore FENTORA should not be used in nursing women because of the possibility of sedation and/or respiratory depression in their infants. Symptoms of opioid withdrawal may occur in infants at the cessation of nursing by women using FENTORA.<br/>Pediatric Use: See WARNINGS.<br/>Geriatric Use: Of the 304 patients with cancer in clinical studies of FENTORA, 69 (23%) were 65 years of age and older. Patients over the age of 65 years tended to titrate to slightly lower doses than younger patients. Patients over the age of 65 years reported a slightly higher frequency for some adverse events specifically vomiting, constipation, and abdominal pain. Therefore, caution should be exercised in individually titrating FENTORA in elderly patients to provide adequate efficacy while minimizing risk.
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Clinical Presentation: The manifestations of FENTORA overdosage are expected to be similar in nature to intravenous fentanyl and other opioids, and are an extension of its pharmacological actions with the most serious significant effect being hypoventilation.<br/>General: Immediate management of opioid overdose includes removal of the FENTORA tablet, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, and assessment of level of consciousness, as well as ventilatory and circulatory status.<br/>Treatment of Overdosage in the Opioid Non-Tolerant Person: Ventilatory support should be provided, intravenous access obtained, and naloxone or other opioid antagonists should be employed as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist's action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the package insert of the individual opioid antagonist for details about such use.<br/>Treatment of Overdose in Opioid-Tolerant Patients: Ventilatory support should be provided and intravenous access obtained as clinically indicated. Judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.<br/>General Considerations for Overdose: Management of severe FENTORA overdose includes: securing a patent airway, assisting or controlling ventilation, establishing intravenous access, and GI decontamination by lavage and/or activated charcoal, once the patient's airway is secure. In the presence of hypoventilation or apnea, ventilation should be assisted or controlled and oxygen administered as indicated. Patients with overdose should be carefully observed and appropriately managed until their clinical condition is well controlled. Although muscle rigidity interfering with respiration has not been seen following the use of FENTORA, this is possible with fentanyl and other opioids. If it occurs, it should be managed by the use of assisted or controlled ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.
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fentanyl citrate
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FENTORA (Tablet)
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Pre-Marketing Clinical Trial Experience: The safety of FENTORA has been evaluated in 304 opioid tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months. The most commonly observed adverse events seen with FENTORA are typical of opioid side effects. Opioid side effects should be expected and managed accordingly. The clinical trials of FENTORA were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received FENTORA for breakthrough pain along with a concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of FENTORA therapy or cancer-related symptoms. Table 5 lists, by maximum dose received, adverse events with an overall frequency of 5% or greater within the total population that occurred during titration. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies. Table 6 lists, by successful dose, adverse events with an overall frequency of���5% within the total population that occurred after a successful dose had been determined. In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of FENTORA. There was no evidence of excess toxicity in this subset of patients. The duration of exposure to FENTORA varied greatly, and included open-label and double-blind studies. The frequencies listed below represent the���1% of patients from three clinical trials (titration and post-titration periods combined) who experienced that event while receiving FENTORA. Events are classified by system organ class. Adverse Events (���1%) Blood and Lymphatic System Disorders: Anemia, Neutropenia, Thrombocytopenia, Leukopenia Cardiac Disorders: Tachycardia Gastrointestinal Disorders: Nausea, Vomiting, Constipation, Abdominal Pain, Diarrhea, Stomatitis, Dry Mouth, Dyspepsia, Upper Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain, Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia, Mouth Ulceration General Disorders and Administration Site Conditions: Fatigue, Edema Peripheral, Asthenia, Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain Hepatobiliary Disorders: Jaundice Infections and Infestations: Pneumonia, Oral Candidiasis, Urinary Tract Infection, Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection, Influenza, Tooth Abscess Injury, Poisoning and Procedural Complications: Fall, Spinal Compression Fracture Investigations: Decreased Weight, Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count Metabolism and Nutrition Disorders: Dehydration, Anorexia, Hypokalemia, Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake Musculoskeletal and Connective Tissue Disorders: Arthralgia, Back Pain, Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain Nervous System Disorders: Dizziness, Headache, Somnolence, Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy Psychiatric Disorders: Confusional State, Depression, Insomnia, Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness Renal and Urinary Disorders: Renal Failure Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Cough, Pharyngolaryngeal Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds, Wheezing Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis, Cold Sweat Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein Thrombosis
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| dailymed-instance:warning |
See BOXED WARNING The concomitant use of other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors), and alcoholic beverages may produce increased depressant effects. Hypoventilation, hypotension, and profound sedation may occur. FENTORA is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.<br/>Pediatric Use:: The safety and efficacy of FENTORA have not been established in pediatric patients below the age of 18 years. Patients and their caregivers must be instructed that FENTORAcontains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep tablets out of the reach of children.<br/>Drug Abuse, Addiction and Diversion of Opioids:: FENTORA contains fentanyl, a mu-opioid agonist and a Schedule II controlled substance with high potential for abuse similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Fentanyl can be abused and is subject to misuse, and criminal diversion. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. ���Drug-seeking���behavior is very common in addicts and drug abusers. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since FENTORA tablets may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of patients, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. FENTORA should be handled appropriately to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.<br/>Physical Dependence and Withdrawal:: The administration of FENTORA should be guided by the response of the patient. Physical dependence, per se, is not ordinarily a concern when one is treating a patient with cancer and chronic pain, and fear of tolerance and physical dependence should not deter using doses that adequately relieve the pain. Opioid analgesics may cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia.<br/>Respiratory Depression:: Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in FENTORA. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerantpatients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the���sighing���pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.
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| dailymed-instance:indicatio... |
FENTORA is indicated only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least 60 mg of oral morphine/day, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer. This product must not be used in opioid non-tolerant patients because life-threatening hypoventilation could occur at any dose in patients not on a chronic regimen of opiates. For this reason, FENTORA is contraindicated in the management of acute or postoperative pain. FENTORA is 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.
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FENTORA
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