Fentanyl Buccal Tablets are a potent opioid analgesic, intended for buccal mucosal administration. Fentanyl Buccal Tablets are formulated as a flat-faced, round, beveled-edge white to off-white tablet.
Fentanyl Buccal Tablets are designed to be placed and retained within the buccal cavity for a period sufficient to allow dissolution of the tablet and absorption of fentanyl across the oral mucosa.
Watson’s Fentanyl Buccal Tablets employ immediate-release drug delivery technology which releases the drug substance upon dissolution.
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, potassium bicarbonate, and magnesium stearate.
Fentanyl Buccal Tablets - Clinical Pharmacology
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.
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 Fentanyl Buccal Tablets should be individually titrated to achieve the desired effect. (See DOSAGE AND ADMINISTRATION.)
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).
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.
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.
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.
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.
(See BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE for additional information on hypoventilation.)
PHARMACOKINETICS
Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of Fentanyl Buccal Tablets increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range.
Absorption:
Following buccal administration of Fentanyl Buccal Tablets, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of Fentanyl Buccal Tablets 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 absorption from the gastrointestinal tract.
In a study that compared the absolute and relative bioavailability of Fentanyl Buccal Tablets and Actiq®‡ (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with Fentanyl Buccal Tablets) (Table 1).
Table 1. Pharmacokinetic Parameters* in Adult Subjects Receiving Fentanyl Buccal Tablets or Actiq®‡
Pharmacokinetic
Parameter (mean) |
Fentanyl Buccal Tablets
400 mcg |
Actiq®‡
400 mcg
(adjusted dose)*** |
| * Based on venous blood samples. |
| ** Data for Tmax presented as median (range). |
| *** Actiq®‡ data was dose adjusted (800 mcg to 400 mcg). |
Absolute
Bioavailability |
65% ± 20% |
47% ± 10.5% |
Fraction
Absorbed Transmucosally |
48% ± 31.8% |
22% ± 17.3% |
| Tmax (minute)** |
46.8 (20 to 240) |
90.8 (35 to 240) |
| Cmax (ng/mL) |
1.02 ± 0.42 |
0.63 ± 0.21 |
AUC0-tmax
(ng•hr/mL) |
0.40 ± 0.18 |
0.14 ± 0.05 |
AUC0-inf
(ng•hr/mL) |
6.48 ± 2.98 |
4.79 ± 1.96 |
Similarly, in another bioavailability study exposure following administration of Fentanyl Buccal Tablets was also greater (approximately 50%) compared to Actiq®‡.
Due to differences in drug delivery, measures of exposure (Cmax, AUC0-tmax, AUC0-inf) associated with a given dose of fentanyl were substantially greater with Fentanyl Buccal Tablets compared to Actiq®‡ (see Figure 1). Therefore, caution must be exercised when switching patients from one product to another. (See DOSAGE AND ADMINISTRATION.) Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 6 hours. The vertical line denotes the median Tmax for Fentanyl Buccal Tablets.
Systemic exposure to fentanyl following administration of Fentanyl Buccal Tablets 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.
Table 2. Pharmacokinetic Parameters* Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl Buccal Tablets in Healthy Subjects
| Pharmacokinetic Parameter (mean±SD) |
100 mcg |
200 mcg |
400 mcg |
800 mcg |
| * Based on venous sampling. |
| ** Data for Tmax presented as median (range) |
Cmax
(ng/mL) |
0.25 ± 0.14 |
0.40 ± 0.18 |
0.97 ± 0.53 |
1.59 ± 0.90 |
| Tmax, minute** (range) |
45.0
(25.0 to 181.0) |
40.0
(20.0 to 180.0) |
35.0
(20.0 to 180.0) |
40.0
(25.0 to 180.0) |
AUC0-inf
(ng•hr/mL) |
0.98 ± 0.37 |
2.11 ± 1.13 |
4.72 ± 1.95 |
9.05 ± 3.72 |
| AUC0-tmax (ng•hr/mL) |
0.09 ± 0.06 |
0.13 ± 0.09 |
0.34 ± 0.23 |
0.52 ± 0.38 |
| T1/2, hr** |
2.63
(1.47 to 13.57) |
4.43
(1.85 to 20.76) |
11.09
(4.63 to 20.59) |
11.70
(4.63 to 28.63) |
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 Fentanyl Buccal Tablets 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 tmax where range was used) are presented in Table 3.
Table 3. Pharmacokinetic Parameters in Patients with Mucositis
| Patient status |
Cmax
(ng/mL) |
tmax
(min) |
AUC0-tmax
(ng•hr/mL) |
AUC0-8
(ng•hr/mL) |
| Mucositis |
1.25 ± 0.78 |
25.0 (15 to 45) |
0.21 ± 0.16 |
2.33 ± 0.93 |
| No mucositis |
1.24 ± 0.77 |
22.5 (10 to 121) |
0.25 ± 0.24 |
1.86 ± 0.86 |
Distribution:
Fentanyl is highly lipophilic. The plasma protein binding of fentanyl is 80 to 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.
Metabolism:
The metabolic pathways following buccal administration of Fentanyl Buccal Tablets 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. (See PRECAUTIONS: Drug Interactions for additional information.)
Elimination:
Disposition of fentanyl following buccal administration of Fentanyl Buccal Tablets 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 excretion is less important.
The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.
Special Populations:
The pharmacokinetics of Fentanyl Buccal Tablets has not been studied in Special Populations.
Race
The pharmacokinetic effects of race with the use of Fentanyl Buccal Tablets have not been systematically evaluated. In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in US subjects (mean Cmax and 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).
Age
The effect of age on the pharmacokinetics of Fentanyl Buccal Tablets has not been studied.
Gender
Systemic exposure was higher for women than men (mean Cmax and AUC values were approximately 28% and 22% higher, respectively). The observed differences between men and women were largely attributable to differences in weight.
Renal or Hepatic Impairment:
The effect of renal or hepatic impairment on the pharmacokinetics of Fentanyl Buccal Tablets 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 Fentanyl Buccal Tablets are titrated to clinical effect for all patients, special care should be taken in patients with severe hepatic or renal disease. (See PRECAUTIONS.)
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% to 420%) increase in fentanyl AUC0-inf. Coadministration of ritonavir in patients receiving Fentanyl Buccal Tablets has not been studied; however, an increase in fentanyl AUC is expected. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS.)
CLINICAL TRIALS
Breakthrough Pain:
The efficacy of Fentanyl Buccal Tablets was demonstrated in a double-blind, placebo-controlled, cross-over study in opioid tolerant patients with cancer and breakthrough pain. Patients considered opioid tolerant were those who were 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.
In this trial, patients were titrated in an open-label manner to a successful dose of Fentanyl Buccal Tablets. A successful dose was defined as the dose in which a patient obtained adequate analgesia with tolerable side effects. Patients who identified a successful dose were randomized to a sequence of 10 treatments with 7 being the successful dose of Fentanyl Buccal Tablets and 3 being placebo. Patients used one tablet (either Fentanyl Buccal Tablets or Placebo) per breakthrough pain episode.
Patients assessed pain intensity on a scale that rated the pain as 0=none to 10=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0 to 10) was measured at 15, 30, 45 and 60 minutes after the start of administration. The sum of differences in pain intensity scores at 15 and 30 minutes from baseline (SPID30) was the primary efficacy measure.
Sixty five percent of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 4. The median dose was 400 mcg.
Table 4. Successful Dose of Fentanyl Buccal Tablets Following Initial Titration
| Fentanyl Buccal Tablets Dose |
(N=80) n(%) |
| 100 mcg |
13 (16) |
| 200 mcg |
11 (14) |
| 400 mcg |
21 (26) |
| 600 mcg |
10 (13) |
| 800 mcg |
25 (31) |
The LS mean (SE) SPID30 for Fentanyl Buccal Tablets-treated episodes was 3.0 (0.12) while for placebo-treated episodes it was 1.8 (0.18) (p<0.0001).
Indications and Usage for Fentanyl Buccal Tablets
(See BOXED WARNING and CONTRAINDICATIONS.)
Fentanyl Buccal Tablets are indicated only for the management of breakthrough pain in patients with cancer 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 around-the-clock medicine consisting of at least 60 mg of oral morphine daily, 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 daily for a week or longer.
This product must not be used in opioid non-tolerant patients because life-threatening hypoventilation and death could occur at any dose in patients not on a chronic regimen of opioids. For this reason, Fentanyl Buccal Tablets are contraindicated in the management of acute or postoperative pain.
Fentanyl Buccal Tablets are intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.
Contraindications
Fentanyl Buccal Tablets are contraindicated in opioid non-tolerant patients. Fentanyl Buccal Tablets are contraindicated in the management of acute or postoperative pain including headache/migraine. Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.
Fentanyl Buccal Tablets are contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl.
Warnings
See BOXED WARNING
When prescribing, DO NOT convert a patient from Actiq®‡ to Fentanyl Buccal Tablets without following the instructions found in the prescribing information as Actiq®‡ and Fentanyl Buccal Tablets are not equivalent on a microgram per microgram basis. Fentanyl Buccal Tablets are NOT a generic version of Actiq®‡.
When dispensing, DO NOT substitute a Fentanyl Buccal Tablets prescription for an Actiq®‡ prescription under any circumstances. Fentanyl Buccal Tablets and Actiq®‡ are not equivalent. Substantial differences exist in the pharmacokinetic profile of Fentanyl Buccal Tablets compared to other fentanyl products including Actiq®‡ that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of the same dose of Fentanyl Buccal Tablets for the same dose of Actiq®‡ or any other fentanyl product may result in a fatal overdose.
There are no safe conversion directions available for patients on any other fentanyl products. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of Fentanyl Buccal Tablets should be 100 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects. (See DOSAGE AND ADMINISTRATION.)
Use with CNS Depressants
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.
Fentanyl Buccal Tablets are 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.
Pediatric Use: The safety and efficacy of Fentanyl Buccal Tablets have not been established in pediatric patients below the age of 18 years.
Patients and their caregivers must be instructed that Fentanyl Buccal Tablets contain 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. (See SAFETY AND HANDLING, PRECAUTIONS, and MEDICATION GUIDE for specific patient instructions.)
Drug Abuse, Addiction and Diversion of Opioids
Fentanyl Buccal Tablets contain 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. Fentanyl Buccal Tablets should be prescribed with caution to patients who have a higher risk of substance abuse, including patients with bipolar disorder and/or schizophrenia.
Patients with chronic pain may be at a higher risk for suicide.
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 nonmedical purposes, often in combination with other psychoactive substances. Since Fentanyl Buccal 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.
Fentanyl Buccal Tablets 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.
Physical Dependence and Withdrawal
The administration of Fentanyl Buccal Tablets 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.
Respiratory Depression
Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in Fentanyl Buccal Tablets. 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-tolerant patients, 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.
Precautions
General
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 Fentanyl Buccal Tablets should be warned of these dangers and should be counseled accordingly.
The use of concomitant CNS active drugs requires special patient care and observation. (See WARNINGS.)
Chronic Pulmonary Disease
Because potent opioids can cause respiratory depression, Fentanyl Buccal Tablets 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 Fentanyl Buccal Tablets may further decrease respiratory drive to the point of respiratory failure.
Head Injuries and Increased Intracranial Pressure
Fentanyl Buccal Tablets should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention 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.
Application Site Reactions
In clinical trials, 10% of all patients exposed to Fentanyl Buccal Tablets 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.
Cardiac Disease
Intravenous fentanyl may produce bradycardia. Therefore, Fentanyl Buccal Tablets should be used with caution in patients with bradyarrhythmias.
Hepatic or Renal Disease
Insufficient information exists to make recommendations regarding the use of Fentanyl Buccal Tablets 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.
Information for Patients and Caregivers
Patients and their caregivers must be instructed that children, especially small children, exposed to Fentanyl Buccal Tablets are at high risk of FATAL RESPIRATORY DEPRESSION. Patients and their caregivers must be instructed to keep Fentanyl Buccal Tablets out of the reach of children. (See SAFETY AND HANDLING, WARNINGS, and MEDICATION GUIDE for specific patient instructions.)
Patients and their caregivers must be provided a Medication Guide each time Fentanyl Buccal Tablets are dispensed because new information may be available.
Patients must be instructed not to take Fentanyl Buccal Tablets for acute pain, postoperative pain, pain from injuries, headache, migraine or any other short term pain, even if they have taken other opioid analgesics for these conditions.
Patients must be instructed on the meaning of opioid tolerance and that Fentanyl Buccal Tablets are only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication, and who need additional opioid treatment of breakthrough pain episodes.
Patients must be instructed that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take Fentanyl Buccal Tablets.
Patients should be instructed that the titration phase is the only period in which they may take more than ONE tablet to achieve a desired dose (e.g., two 100 mcg tablets for a 200 mcg dose).
Patients must be instructed that, if the breakthrough pain episode is not relieved after 30 minutes, they may take ONLY ONE ADDITIONAL DOSE OF Fentanyl Buccal Tablets USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take a maximum of two doses of Fentanyl Buccal Tablets for any breakthrough pain episode.
Patients must be instructed that they MUST wait at least 4 hours before treating another episode of breakthrough pain with Fentanyl Buccal Tablets.
Patients must be instructed NOT to share Fentanyl Buccal Tablets and that sharing Fentanyl Buccal Tablets with anyone else could result in the other individual’s death due to overdose.
Patients must be aware that Fentanyl Buccal Tablets contain fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
Patients must be instructed that the active ingredient in Fentanyl Buccal Tablets, fentanyl, is a drug that some people abuse. Fentanyl Buccal Tablets should be taken only by the patient they were prescribed for, and they should be protected from theft or misuse in the work or home environment.
Patients should be instructed that Fentanyl Buccal Tablets are not to be swallowed whole; this will reduce the effectiveness of the medication. Tablets are to be placed between the cheek and gum above a molar tooth and allowed to dissolve. After 30 minutes if remnants of the tablet still remain, patients may swallow it with a glass of water.
Patients must be cautioned to talk to their doctor if breakthrough pain is not alleviated or worsens after taking Fentanyl Buccal Tablets.
Patients must be instructed to use Fentanyl Buccal Tablets exactly as prescribed by their doctor and not to take Fentanyl Buccal Tablets more often than prescribed.
Patients must be cautioned that Fentanyl Buccal Tablets can affect a person’s ability to perform activities that require a high level of attention (such as driving or using heavy machinery). Patients taking Fentanyl Buccal Tablets should be warned of these dangers and counseled accordingly.
Patients must be warned to not combine Fentanyl Buccal Tablets with alcohol, sleep aids, or tranquilizers except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.
Female patients must be informed that if they become pregnant or plan to become pregnant during treatment with Fentanyl Buccal Tablets, they should ask their doctor about the effects that Fentanyl Buccal Tablets (or any medicine) may have on them and their unborn children.
Patients and caregivers must be advised that if they have been receiving treatment with Fentanyl Buccal Tablets and the medicine is no longer needed they should flush any remaining product down the toilet, and if they then need further assistance, contact Watson at 1-866-510-7780.
Disposal of Unopened Fentanyl Buccal Tablets 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 Fentanyl Buccal Tablets, remove Fentanyl Buccal Tablets from blister packages and flush down the toilet. Do not flush the Fentanyl Buccal Tablets blister packages or cartons down the toilet. (See SAFETY AND HANDLING.)
Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of Fentanyl Buccal Tablets are provided in the Fentanyl Buccal Tablets 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 Watson toll-free number (1-866-510-7780) or seek assistance from their local DEA office.
Laboratory Tests
The effects of Fentanyl Buccal Tablets on laboratory tests have not been evaluated.
Drug Interactions
See WARNINGS.
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when Fentanyl Buccal Tablets are given concurrently with agents that affect CYP3A4 activity. The concomitant use of Fentanyl Buccal Tablets 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 Fentanyl Buccal Tablets concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done conservatively. (See PHARMACOKINETICS, Drug Interactions and DOSAGE AND ADMINISTRATION.)
Grapefruit and grapefruit juice decrease CYP3A4 activity, increasing blood concentrations of fentanyl, thus should be avoided.
Drugs that induce cytochrome P450 3A4 activity may have the opposite effects.
Concomitant use of Fentanyl Buccal Tablets with an MAO inhibitor, or within 14 days of discontinuation, is not recommended.
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 Fentanyl Buccal Tablets.
Pregnancy-Category C
There are no adequate
