PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL - 800 mcg Tablet Blister Pack Carton

NDC 51862-638-28

FENTANYL Buccal Tablets CII

Equivalent to 800 mcg fentanyl base

28 Buccal Tablets (4 tablets x 7 cards)

Information for Pharmacist:

□

Counsel the patient about the use of this  

product including maximum dosing during
a single breakthrough pain episode

□

Instruct patients to read the enclosed  

fentanyl buccal tablets Medication Guide

□

Fentanyl buccal tablets must only be  

supplied through the TIRF REMS Access
restricted program. For more information
call 1-866-822-1483 or visit
www.TIRFREMSAccess.com.

WARNING: Keep out of the reach of children
PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY
DO NOT SUBSTITUTE FENTANYL BUCCAL TABLETS FOR OTHER FENTANYL PRODUCTS
Fentanyl buccal tablets can be harmful or fatal if given to someone for whom it was not prescribed

For Buccal or Sublingual Administration.
Do NOT Split, Crush, Suck, Chew, or Swallow Tablet.

Distributed by:
Mayne Pharma
Raleigh, NC 27609

mayne pharma

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RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

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DESCRIPTION SECTION

11 DESCRIPTION

Fentanyl buccal tablet is an opioid agonist, intended for buccal mucosal administration.

Fentanyl buccal tablet 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.

Fentanyl buccal tablet 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 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.

CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

12.2 Pharmacodynamics

Effects on the 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 a reduction in the responsiveness of the brain stem to both increases in carbon dioxide and to electrical stimulation.

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). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

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 in the small intestine is delayed 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 biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2)]. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Use of opioids for an extended period of time may influence the hypothalamic- pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

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 [see Dosage and Administration (2.1)].

The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.5)].

Concentration-Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.3, 2.4, 2.5)].

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. 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. 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 [see Warnings and Precautions (5), Overdosage (10)].

12.3 Pharmacokinetics

Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of fentanyl buccal tablet increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range.

Absorption

Following buccal administration of fentanyl buccal tablet, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of fentanyl buccal tablet 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 tablet and ACTIQ (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with fentanyl buccal tablet) (Table 5).

Table 5. Pharmacokinetic Parameters* in Adult Subjects Receiving Fentanyl Buccal Tablet or ACTIQ

Similarly, in another bioavailability study exposure following administration of fentanyl buccal tablet 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 tablet compared to ACTIQ (see Figure 1). Therefore, caution must be exercised when switching patients from one product to another [see Dosage and Administration (2.3), Warnings and Precautions (5.5)]. 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 tablet.

Figure 1. Mean Plasma Concentration Versus Time Profiles Following Single Doses of Fentanyl Buccal Tablet and ACTIQ in Healthy Subjects

ACTIQ data was dose adjusted (800 mcg to 400 mcg).

Mean pharmacokinetic parameters are presented in Table 6. Mean plasma concentration versus time profiles are presented in Figure 2.

Table 6. Pharmacokinetic Parameters* Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl Buccal Tablets in Healthy Subjects

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 tablet 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 7.

Table 7. Pharmacokinetic Parameters in Patients with Mucositis

Following sublingual tablet placement, systemic exposure (as measured by AUC and Cmax) of fentanyl is equivalent to systemic exposure following buccal tablet placement.

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.

Elimination

Metabolism

The metabolic pathways following buccal administration of fentanyl buccal tablet 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 Drug Interactions (7)].

Excretion

Disposition of fentanyl following buccal administration of fentanyl buccal tablet 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.

Sex

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.

Race

In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. 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 U.S. subjects (57.4 kg versus 73 kg).

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DOSAGE FORMS & STRENGTHS SECTION

Highlight: Buccal Tablets: 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg strengths as fentanyl base. (3)

3 DOSAGE FORMS AND STRENGTHS

Fentanyl buccal tablets are flat-faced, round, beveled-edge in shape; are white in color; and are available in 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg strengths as fentanyl base. Each tablet strength is marked with a unique identifier [see How Supplied/Storage and Handling (16)].

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CONTRAINDICATIONS SECTION

Highlight: * Opioid non-tolerant patients. (4)

• Management of acute or postoperative pain, including headache/migraine and dental pain. (4)
• Significant respiratory depression. (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 fentanyl buccal tablet. (4)

4 CONTRAINDICATIONS

Fentanyl Buccal Tablet 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 fentanyl buccal tablet (e.g., anaphylaxis, hypersensitivity) [see Adverse Reactions (6.2)].

BOXED WARNING SECTION

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF FENTANYL BUCCAL

TABLET

See full prescribing information for complete boxed warning.

*Fentanyl buccal tablet exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. (5.1) *Serious, life-threatening, or fatal respiratory depression has occurred in patients treated with fentanyl buccal tablet, including following use in opioid non-tolerant patients and improper dosing. Regularly evaluate patients, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of fentanyl buccal tablet are essential. The substitution of fentanyl buccal tablet for any other fentanyl product may result in fatal overdose. Due to the risk of fatal respiratory depression, fentanyl buccal tablet is contraindicated in opioid non-tolerant patients and in management of acute or postoperative pain, including headache/migraines. (1,4,5.2) *Accidental ingestion of fentanyl buccal tablet, especially by children, can result in a fatal overdose of fentanyl. Keep out of reach of children. Ensure proper storage and disposal. (2.8,5.3) *Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (5.4,7) *If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.8) *Fentanyl buccal tablet is available only through a restricted program called the TIRF REMS. Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Patients must be opioid tolerant to receive a TIRF medicine (5.7) *When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl product to fentanyl buccal tablet. (5.5) *When dispensing, do not substitute with any other fentanyl products. (5.5) *Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of fentanyl. (5.6,7,12.3)

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Pregnancy: May cause fetal harm. (8.1)

• Lactation: Not recommended. (8.2)
• Renal and Hepatic Impairment: Administer fentanyl buccal tablet with caution. (8.6)

8 USE IN SPECIFIC POPULATIONS

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 fentanyl buccal tablet 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 fentanyl buccal tablet 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 antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Fentanyl buccal tablet is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including fentanyl buccal tablet, 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) was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6-17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is equivalent to 1.4-times the exposure of a single human dose of 800 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 7.5-times the exposure of a single human dose of 800 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 (0.4 times the 800 mcg dose of fentanyl buccal tablet on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of fentanyl buccal tablet based on a mg/m2 basis). No evidence of teratogenicity was reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 6 times the human dose of 800 mcg fentanyl buccal tablet per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are approximately 5 times higher than the mean Cmax observed following administration of 800 mcg dose of fentanyl buccal tablet 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 approximately equal the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.

8.2 Lactation

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with fentanyl buccal tablet.

Clinical Considerations

Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and efficacy of fentanyl buccal tablet have not been established in pediatric patients below the age of 18 years.

8.5 Geriatric Use

Of the 304 patients with cancer in clinical studies of fentanyl buccal tablets, 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 fentanyl buccal tablet in elderly patients to provide adequate efficacy while minimizing risk.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of fentanyl buccal tablet slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.11)].

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

8.6 Patients with Renal or Hepatic Impairment

Insufficient information exists to make recommendations regarding the use of fentanyl buccal tablet in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

8.7 Sex

Both male and female opioid-tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions.

8.8 Race

The pharmacokinetic effects of race with the use of fentanyl buccal tablet have not been systematically evaluated. In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. subjects.

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DRUG ABUSE AND DEPENDENCE SECTION

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Fentanyl buccal tablet contains fentanyl, a Schedule II controlled substance.

9.2 Abuse

Fentanyl buccal tablet contains fentanyl, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of fentanyl buccal tablet increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of fentanyl buccal tablet with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of fentanyl buccal tablet abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use fentanyl buccal tablet in combination with other abused drugs.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Fentanyl buccal tablet, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Fentanyl Buccal Tablet

Abuse of fentanyl buccal tablet poses a risk of overdose and death. The risk is increased with concurrent use of fentanyl buccal tablet with alcohol and/or other CNS depressants.

Fentanyl buccal tablet is approved for oral transmucosal use only.

9.3 Dependence

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

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ADVERSE REACTIONS SECTION

Highlight: Most common (frequency ≥10%): nausea, dizziness, vomiting, fatigue, anemia, constipation, edema peripheral, asthenia, dehydration, and headache. (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 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)]

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 fentanyl buccal tablets 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 clinical trials of fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets therapy or cancer-related symptoms.

Table 2 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 2. Adverse Events Which Occurred During Titration at a Frequency of ≥ 5%

Table 3 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.

Table 3. Adverse Events Which Occurred During Long-Term Treatment at a Frequency of ≥ 5%

In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of fentanyl buccal tablets. There was no evidence of excess toxicity in this subset of patients.

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.

The duration of exposure to fentanyl buccal tablets varied greatly, and included open-label and double-blind studies. The frequencies listed below represent the ≥1% of patients (and not listed in Tables 2 and 3 above) from three clinical trials (titration and post-titration periods combined) who experienced that event while receiving fentanyl buccal tablets. Events are classified by system organ class.

Adverse Events (≥1%)

Blood and Lymphatic System Disorders: Thrombocytopenia, Leukopenia

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: 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: Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain

Hepatobiliary Disorders: Jaundice

Infections and Infestations: 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 Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count

Metabolism and Nutrition Disorders: Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake

Musculoskeletal and Connective Tissue Disorders: Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain

Nervous System Disorders: Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy

Psychiatric Disorders: Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness

Renal and Urinary Disorders: Renal Failure

Respiratory, Thoracic, and Mediastinal Disorders: 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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders:

- Serotonin syndrome: Cases of serotonin syndrome, a potentially life- threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

- Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.9)].

Endocrine Disorders:

- Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

- Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Immune System Disorders:

- Anaphylaxis: Anaphylaxis has been reported with ingredients contained in fentanyl buccal tablet.

General Disorders and Administration Site Conditions:

- Drug withdrawal syndrome

Metabolic and Nutritional Disorders:

- Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

The efficacy of fentanyl buccal tablet 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 daily, at least 25 mcg/hour of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer.

In this trial, patients were titrated in an open-label manner to a successful dose of fentanyl buccal tablet. 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 tablet and 3 being placebo. Patients used one tablet of study drug (either fentanyl buccal tablet 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 (0-10) was then 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 (65%) of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 8. The median dose was 400 mcg.

Table 8. Successful Dose of Fentanyl Buccal Tablet Following Initial Titration

The LS mean (SE) SPID30 for fentanyl buccal tablet-treated episodes was 3.0 (0.12) while for placebo-treated episodes it was 1.8 (0.18).

PID=pain intensity difference; SEM=standard error of the mean

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Fentanyl was evaluated for carcinogenic potential in a 104-week rat study and in a 6-month Tg.AC transgenic mouse study. In rats, doses up to 50 mcg/kg in males and 100 mcg/kg in females were administered subcutaneously and no treatment-related neoplasms were observed (doses are equivalent to 2.3- and 3.4-times the exposure of a single human dose of 800 mcg per pain episode, respectively, based on an AUC comparison). In a 26-week transgenic mice model (Tg.AC), at topical doses up to 50 mcg/dose/day, no increase in the occurrence of treatment-related neoplasms was observed.

Mutagenesis

Fentanyl citrate was not mutagenic in the Ames reverse mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay. Fentanyl citrate was not clastogenic in the in vivo mouse micronucleus assay.

Impairment of Fertility

In a fertility study, female rats were administered fentanyl subcutaneously for 14 days prior to mating with untreated males at doses up to 300 mcg/kg and no effects on female fertility were observed. The systemic exposure at the dose of 300 mcg/kg was approximately 8.6 times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison. Males were administered fentanyl subcutaneously for 28 days prior to mating with untreated females at doses up to 300 mcg/kg. At 300 mcg/kg, adverse effects on sperm parameters, which affected fertility, were observed. These effects included decreased percent mobile sperm, decreased sperm concentrations as well as an increase in the percent abnormal sperm. The dose in males at which no effects on fertility were observed was 100 mcg/kg, which is approximately 5.7- times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.

Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for fentanyl buccal tablet.

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Storage and Disposal of Unused and Used Fentanyl Buccal Tablets [see Medication Guide / Instructions for Use].

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store fentanyl buccal tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving fentanyl buccal tablets unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)].

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused fentanyl buccal tablets should be disposed of by removing fentanyl buccal tablets from the blister cards and flushing the unused medication down the toilet (if a drug take-back option is not readily available). Do not flush the fentanyl buccal tablet blister packages or cartons down the toilet. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Disposal of Unopened Fentanyl Buccal Tablet Blister Packages When No Longer Needed:

• Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of fentanyl buccal tablet are provided in the Fentanyl Buccal Tablet Medication Guide. Instruct patients to read this information in its entirety and provide 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, instruct them to call the Teva Pharmaceuticals toll-free number (1-888-483-8279) or seek assistance from their local DEA office.

Addiction, Abuse, and Misuse

Inform patients that the use of fentanyl buccal tablet, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share fentanyl buccal tablet with others and to take steps to protect fentanyl buccal tablet from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting fentanyl buccal tablet or when the dosage is increased, and that it can occur even at recommended dosages.

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 [see Warnings and Precautions (5.2)].

Accidental Ingestion

• 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 [see Warnings and Precautions (5.3)].
• Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].
• Instruct patients to take steps to store fentanyl buccal tablet securely and to dispose of unused fentanyl buccal tablet [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.7)].
• Instruct patients and caregivers to keep both used and unused fentanyl buccal tablet out of the reach of children [see Warnings and Precautions (5.3)].

Interactions with Benzodiazepines and Other CNS Depressants (including Alcohol)

Inform patients that potentially fatal additive effects may occur if fentanyl buccal tablet is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with fentanyl buccal tablet. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone's effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose
• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

Transmucosal Immediate-Release Fentanyl (TIRF) REMS

Fentanyl buccal tablet is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS [see Warnings and Precautions (5.7)]. Inform the patient of the following notable requirements:

• Outpatients must be enrolled in the REMS program
• Patients must be opioid-tolerant to receive fentanyl buccal tablet.

Fentanyl buccal tablet is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.

Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require fentanyl buccal tablet while hospitalized [see Warnings and Precautions (5.7)].

Hyperalgesia and Allodynia

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life- threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.10), Drug Interactions (7)].

MAOI Interaction

Inform patients to avoid taking fentanyl buccal tablet while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking fentanyl buccal tablet [see Warnings and Precautions (5.10), Drug Interactions (7)].

Important Administration Instructions [see Dosage and Administration (2)]

• Instruct patients not to take fentanyl buccal tablet 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.
• Instruct patients on the meaning of opioid tolerance and that fentanyl buccal tablet is 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.
• Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take fentanyl buccal tablet.
• Instruct patients 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).
• Instruct patients that, if the breakthrough pain episode is not relieved after 30 minutes, they may take ONLY ONE ADDITIONAL DOSE OF FENTANYL BUCCAL TABLET USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take a maximum of two doses of fentanyl buccal tablet for any breakthrough pain episode.
• Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablet.
• Instruct patients NOT to share fentanyl buccal tablet and that sharing fentanyl buccal tablet with anyone else could result in the other individual's death due to overdose.
• Make patients aware that fentanyl buccal tablet contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
• Instruct patients not to open the blister until ready to use fentanyl buccal tablet and not to store the tablet in a temporary container such as a pill box, once it has been removed from the blister package.
• Instruct patients that fentanyl buccal tablet is not to be swallowed whole; this will reduce the effectiveness of the medication. The tablet is to be placed between the cheek and gum above a molar tooth or under the tongue and allowed to dissolve. After 30 minutes if remnants of the tablet still remain, patients may swallow it with a glass of water.
• Caution patients to talk to their healthcare provider if breakthrough pain is not alleviated or worsens after taking fentanyl buccal tablet.
• Instruct patients to use fentanyl buccal tablet exactly as prescribed by their healthcare provider and not to take fentanyl buccal tablet more often than prescribed.
• Provide patients and their caregivers with a Medication Guide each time fentanyl buccal tablet is dispensed because new information may be available.

Driving or Operating Heavy Machinery

Inform patients that fentanyl buccal tablet may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.17)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non- specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.12)].

Hypotension

Inform patients that fentanyl buccal tablet may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.13)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in fentanyl buccal tablet. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform patients that use of fentanyl buccal tablet for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that fentanyl buccal tablet can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].

Lactation

Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

SPL MEDGUIDE SECTION

Dispense with Medication Guide available at: products.maynepharma.com

How should I store fentanyl buccal tablets?

*Always keep fentanyl buccal tablets in a safe place away from children and from anyone for whom it has not been prescribed. Protect fentanyl buccal tablets from theft. *Store fentanyl buccal tablets at room temperature, 59°F to 86°F (15°C to 30°C) until ready to use. Do not freeze fentanyl buccal tablets. *Keep fentanyl buccal tablets in the original blister unit. Do not remove fentanyl buccal tablets from its blister packaging for storage in a temporary container, such as a pill box. *Keep fentanyl buccal tablets dry.

How should I dispose of unused fentanyl buccal tablets when they are no longer needed?

*Dispose of any unused fentanyl buccal tablets remaining from a prescription as soon as they are no longer needed. *Remove the tablets from blister packages and flush them down the toilet. *Do not flush the fentanyl buccal tablets packaging (card, blister units, or cartons) down the toilet. *If you need help with disposal of fentanyl buccal tablets, call Teva Pharmaceuticals at 1-888-483-8279 or call your local Drug Enforcement Agency (DEA) office.

General information about fentanyl buccal tablet

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use fentanyl buccal tablet only for the purpose for which it was prescribed. Do not give fentanyl buccal tablet to other people, even if they have the same symptoms you have. Fentanyl buccal tablet can harm other people and even cause death. Sharing fentanyl buccal tablet is against the law.

This Medication Guide summarizes the most important information about fentanyl buccal tablet. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about fentanyl buccal tablet that is written for health professionals.

For more information about the TIRF REMS Access program, go to www.TIRFREMSAccess.com or call 1-866-822-1483.

What are the ingredients in fentanyl buccal tablet?

Active Ingredient: fentanyl citrate

Inactive Ingredients: mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Fentanyl buccal tablets are supplied in individually sealed, child-resistant blister packages. 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. In addition, the dosage strength is indicated on the blister package and the carton. See blister package and carton for product information.

Note: Carton/blister package colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F to 86°F) until ready to use. (See USP Controlled Room Temperature.)

Protect fentanyl buccal tablet from freezing and moisture. Do not use if the blister package has been tampered with.

Store fentanyl buccal tablet securely and dispose of properly.

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INSTRUCTIONS FOR USE SECTION

Patient Instructions for Use

Before you use fentanyl buccal tablet, it is important that you read the Medication Guide and these Instructions for Use. Be sure that you read, understand, and follow these Instructions for Use so that you use fentanyl buccal tablet the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use fentanyl buccal tablet.

When you get an episode of breakthrough cancer pain, use the dose of fentanyl buccal tablet prescribed by your healthcare provider as follows:

Fentanyl buccal tablets come packaged as a blister card containing 4 blister units. Each blister unit contains 1 fentanyl buccal tablet. Do not open a blister until ready to use. Separate one of the blister units from the blister card by tearing apart at the perforations. Bend the blister unit along the line where indicated. The product strength of your fentanyl buccal tablets will be printed in the boxed area shown as
**(SeeFigure 1****).

Figure 1

Peel back foil on blister unit to expose tablet (See**Figure 2***).**

Figure 2

Do not push the tablet through the foil on the blister unit because this could damage the tablet. When removed from the blister unit, fentanyl buccal tablet must be used right away. Use fentanyl buccal tablet whole. Do not crush, split, suck, or chew fentanyl buccal tablet, or swallow the tablet whole. You will get less relief for your breakthrough cancer pain. You can place a fentanyl buccal tablet: in your mouth above a rear molar tooth between the upper cheek and gum (See**Figure 3). Switch (alternate) sides of your mouth for each dose.

Figure 3

OR,

on the floor of your mouth, under your tongue (See**Figures 4a***,4b,4c,4d).** *When placing the tablet under your tongue, first lift your tongue (4b), then place the tablet under your tongue (4c), and lower your tongue over the tablet (4d).

*Leave the tablet in place until it dissolves. A fentanyl buccal tablet generally takes between 14 to 25 minutes to dissolve. *After 30 minutes, if there is any fentanyl buccal tablet left in your mouth, you may drink a glass of water to help you swallow the left over medicine. *If you cannot use fentanyl buccal tablet in this manner, tell your healthcare provider. Your healthcare provider will tell you what to do.

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SPL UNCLASSIFIED SECTION

Dispense with Medication Guide available at: products.maynepharma.com

Distributed By:
Mayne Pharma Raleigh, NC 27609

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