2.1 Initial Dose

Individually titrate OTFC to a dose that provides adequate analgesia and minimizes side effects. The initial dose of OTFC to treat episodes of breakthrough cancer pain is always 200 mcg. The OTFC unit should be consumed over 15 minutes. Patients should be prescribed an initial titration supply of six 200 mcg OTFC units, thus limiting the number of units in the home during titration. Patients should use up all units before increasing to a higher dose to prevent confusion and possible overdose.

2.2 Dose Titration

From this initial dose, closely follow patients and change the dosage level until the patient reaches a dose that provides adequate analgesia using a single OTFC dosage unit per breakthrough cancer pain episode. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should be removed from the patient’s mouth immediately, disposed of properly, and subsequent doses should be decreased. Patients should record their use of OTFC over several episodes of breakthrough cancer pain and review their experience with their physicians to determine if a dosage adjustment is warranted.

In cases where the breakthrough pain episode is not relieved 15 minutes after completion of the OTFC unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose of the same strength for that episode.  Thus, patients should take a maximum of two doses of OTFC for any breakthrough pain episode.

Patients must wait at least 4 hours before treating another episode of breakthrough pain with OTFC.  To reduce the risk of overdosing during titration, patients should have only one strength of OTFC available at any one time.

2.3 Maintenance Dosing

Once titrated to an effective dose, patients should generally use ONLY ONE OTFC unit of the appropriate strength per breakthrough pain episode.

On those occasions when the breakthrough pain episode is not relieved 15 minutes after completion of the OTFC unit, patient may take ONLY ONE additional dose using the same strength for that episode.

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with OTFC. Once a successful dose has been found (i.e., an average episode is treated with a single unit), patients should limit consumption to four or fewer units per day.

Dosage adjustment of OTFC may be required in some patients in order to continue to provide adequate relief of breakthrough pain.

Generally, the OTFC dose should be increased only when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes.

If the patient experiences greater than four breakthrough pain episodes per day, the dose of the maintenance (around-the-clock) opioid used for persistent pain should be re-evaluated.

2.4 Administration of OTFC

Open the blister package with scissors immediately prior to product use. The patient should place the OTFC unit in his or her mouth between the cheek and lower gum, occasionally moving the drug matrix from one side to the other using the handle. The OTFC unit should be sucked, not chewed. A unit dose of OTFC, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed [see Clinical Pharmacology (12.3)].

The OTFC unit should be consumed over a 15-minute period. Longer or shorter consumption times may produce less efficacy than reported in OTFC clinical trials. If signs of excessive opioid effects appear before the unit is consumed, remove the drug matrix from the patient’s mouth immediately and decrease future doses.

2.5 Discontinuation of OTFC

For patients requiring discontinuation of opioids, a gradual downward titration is recommended because it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal.

5.1 Important Information Regarding Prescribing and Dispensing

When prescribing, DO NOT convert a patient to OTFC from any other fentanyl product on a mcg per mcg basis as OTFC and other fentanyl products are not equivalent on a microgram per microgram basis.

OTFC is NOT a generic version of Fentora®. When dispensing, DO NOT substitute an OTFC prescription for a Fentora prescription under any circumstances. Fentora and OTFC are not equivalent. Substantial differences exist in the pharmacokinetic profile of OTFC compared to other fentanyl products including Fentora that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of OTFC for 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 OTFC should always be 200 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects [see Dosage And Administration (2.2)].

5.2 Respiratory Depression

As with all opioids, there is a risk of clinically significant respiratory depression in patients using OTFC. Accordingly, follow all patients for symptoms of respiratory depression. Respiratory depression may occur more readily when opioids are given in conjunction with other agents that depress respiration.

5.3 Patient/Caregiver Instructions

Patients and their caregivers must be instructed that OTFC contains a medicine in an amount which can be fatal to a child. Death has been reported in children who have accidentally ingested OTFC. Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible [see How Supplied/Storage And Handling (16.1, 16.2), and Patient Counseling Information (17.1) and the Medication Guide].

Physicians 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.

OTFC could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.

5.4 Additive CNS Depressant Effects

The concomitant use of OTFC with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., respiratory depression, hypotension, and profound sedation). Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see Drug Interactions (7)].

Patients on concomitant CNS depressants must be monitored for a change in opioid effects. Consideration should be given to adjusting the dose of OTFC if warranted.

5.5 Effects on Ability to Drive and Use Machines

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). Warn patients taking OTFC of these dangers and counsel them accordingly.

5.6 Chronic Pulmonary Disease

Because potent opioids can cause respiratory depression, titrate OTFC with caution in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of OTFC may further decrease respiratory drive to the point of respiratory failure.

5.7 Head Injuries and Increased Intracranial Pressure

Administer OTFC 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.

5.8 Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use OTFC with caution in patients with bradyarrhythmias.

5.9 MAO Inhibitors

OTFC is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

6.1 Clinical Studies Experience

The safety of OTFC (oral transmucosal fentanyl citrate) has been evaluated in 257 opioid-tolerant chronic cancer pain patients. The duration of OTFC use varied during the open-label study. Some patients were followed for over 21 months. The average duration of therapy in the open-label study was 129 days.

The adverse reactions seen with OTFC are typical opioid side effects. Frequently, these adverse reactions will cease or decrease in intensity with continued use of OTFC, as the patient is titrated to the proper dose. Expect opioid side effects and manage them accordingly.

The most serious adverse reactions associated with all opioids including OTFC are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression.

Because the clinical trials of OTFC were designed to evaluate safety and efficacy in treating breakthrough cancer pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received OTFC for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of OTFC therapy, or cancer-related symptoms. Adverse reactions are included regardless of causality or severity.

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.

Three short-term clinical trials with similar titration schemes were conducted in 257 patients with malignancy and breakthrough cancer pain. Data are available for 254 of these patients. The goal of titration in these trials was to find the dose of OTFC that provided adequate analgesia with acceptable side effects (successful dose). Patients were titrated from a low dose to a successful dose in a manner similar to current titration dosing guidelines. Table 1 lists, by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during titration and are commonly associated with opioid administration or are of particular clinical interest. The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schemes used in these studies. Adverse reactions are listed in descending order of frequency within each body system.

* Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once

The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system.

Body as a Whole: Pain, fever, abdominal pain, chills, back pain, chest pain, infection

Cardiovascular: Migraine

Digestive: Diarrhea, dyspepsia, flatulence

Metabolic and Nutritional: Peripheral edema, dehydration

Nervous: Hypesthesia

Respiratory: Pharyngitis, cough increased

The following reactions occurred during titration with an overall frequency of less than 1% and are listed in descending order of frequency within each body system.

Body as a Whole: Flu syndrome, abscess, bone pain

Cardiovascular: Deep thrombophlebitis, hypertension, hypotension

Digestive: Anorexia, eructation, esophageal stenosis, fecal impaction, gum hemorrhage, mouth ulceration, oral moniliasis

Hemic and Lymphatic: Anemia, leukopenia

Metabolic and Nutritional: Edema, hypercalcemia, weight loss

Musculoskeletal: Myalgia, pathological fracture, myasthenia

Nervous: Abnormal dreams, urinary retention, agitation, amnesia, emotional lability, euphoria, incoordination, libido decreased, neuropathy, paresthesia, speech disorder

Respiratory: Hemoptysis, pleural effusion, rhinitis, asthma, hiccup, pneumonia, respiratory insufficiency, sputum increased

Skin and Appendages: Alopecia, exfoliative dermatitis

Special Senses: Taste perversion

Urogenital: Vaginal hemorrhage, dysuria, hematuria, urinary incontinence, urinary tract infection

A long-term extension study was conducted in 156 patients with malignancy and breakthrough cancer pain who were treated for an average of 129 days. Data are available for 152 of these patients. Table 2 lists by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during the long-term extension study and are commonly associated with opioid administration or are of particular clinical interest. Adverse reactions are listed in descending order of frequency within each body system.

The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system.

Body as a Whole: Pain, fever, back pain, abdominal pain, chest pain, flu syndrome, chills, infection, abdomen enlarged, bone pain, ascites, sepsis, neck pain, viral infection, fungal infection, cachexia, cellulitis, malaise, pelvic pain

Cardiovascular: Deep thrombophlebitis, migraine, palpitation, vascular disorder

Digestive: Diarrhea, anorexia, dyspepsia, dysphagia, oral moniliasis, mouth ulceration, rectal disorder, stomatitis, flatulence, gastrointestinal hemorrhage, gingivitis, jaundice, periodontal abscess, eructation, glossitis, rectal hemorrhage

Hemic and Lymphatic: Anemia, leukopenia, thrombocytopenia, ecchymosis, lymphadenopathy, lymphedema, pancytopenia

Metabolic and Nutritional: Peripheral edema, edema, dehydration, weight loss, hyperglycemia, hypokalemia, hypercalcemia, hypomagnesemia

Musculoskeletal: Myalgia, pathological fracture, joint disorder, leg cramps, arthralgia, bone disorder

Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech disorder

Respiratory: Cough increased, pharyngitis, pneumonia, rhinitis, sinusitis, bronchitis, epistaxis, asthma, hemoptysis, sputum increased

Skin and Appendages: Skin ulcer, alopecia

Special Senses: Tinnitus, conjunctivitis, ear disorder, taste perversion

Urogenital: Urinary tract infection, urinary incontinence, breast pain, dysuria, hematuria, scrotal edema, hydronephrosis, kidney failure, urinary urgency, urination impaired, breast neoplasm, vaginal hemorrhage, vaginitis

The following reactions occurred with a frequency of less than 1% in the long-term extension study and are listed in descending order of frequency within each body system.

Body as a Whole: Allergic reaction, cyst, face edema, flank pain, granuloma, bacterial infection, injection site pain, mucous membrane disorder, neck rigidity

Cardiovascular: Angina pectoris, hemorrhage, hypotension, peripheral vascular disorder, postural hypotension, tachycardia

Digestive: Cheilitis, esophagitis, fecal incontinence, gastroenteritis, gastrointestinal disorder, gum hemorrhage, hemorrhage of colon, hepatorenal syndrome, liver tenderness, tooth caries, tooth disorder

Hemic and Lymphatic: Bleeding time increased

Metabolic and Nutritional: Acidosis, generalized edema, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, thirst

Musculoskeletal: Arthritis, muscle atrophy, myopathy, synovitis, tendon disorder

Nervous: Acute brain syndrome, agitation, cerebral ischemia, facial paralysis, foot drop, hallucinations, hemiplegia, miosis, subdural hematoma

Respiratory: Hiccup, hyperventilation, lung disorder, pneumothorax, respiratory failure, voice alteration

Skin and Appendages: Herpes zoster, maculopapular rash, skin discoloration, urticaria, vesiculobullous rash

Special Senses: Ear pain, eye hemorrhage, lacrimation disorder, partial permanent deafness, partial transitory deafness

Urogenital: Kidney pain, nocturia, oliguria, polyuria, pyelonephritis

6.2 Post-Marketing Experience

Adverse reactions are reported voluntarily from a population of uncertain size, and, therefore, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors:  (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to OTFC.

The following adverse reactions have been identified during postapproval use of OTFC (which contains approximately 2 grams of sugar per unit):

Digestive: Dental decay of varying severity including dental caries, tooth loss, and gum line erosion.

General Disorders and Administration Site Conditions: Application site reactions including irritation, pain, and ulcer.

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. OTFC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.

Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome.

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.

Fentanyl is embryocidal in rats as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for OTFC.

Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21, of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic (the high dose was approximately 3-times the human dose of 1600 mcg per pain episode on a mg/m2 basis). Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but was not teratogenic.

8.2 Labor and Delivery

Fentanyl readily passes across the placenta to the fetus; therefore do not use OTFC during labor and delivery.

8.3 Nursing Mothers

Fentanyl is excreted in human milk; therefore, do not use OTFC in nursing women because of the possibility of sedation and/or respiratory depression in their infants. Symptoms of opioid withdrawal may occur in infants at the cessation of nursing by women using OTFC.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients below 16 years of age have not been established.

In a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with OTFC. The study was too small to allow conclusions on safety and efficacy in this patient population. Twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received OTFC at doses ranging from 200 mcg to 600 mcg. The mean (CV%; range) dose-normalized (to 200 mcg) Cmax and AUC0-8 values were 0.87 ng/mL (51%; 0.42-1.30) and 4.54 ng×h/mL (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (N = 3) and 0.68 ng/mL (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages >11 to <16 y (N = 9).

8.5 Geriatric Use

Of the 257 patients in clinical studies of OTFC in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. Those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. No difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in OTFC clinical trials.

Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. Therefore, exercise caution when individually titrating OTFC in elderly patients to provide adequate efficacy while minimizing risk.

8.6 Patients with Renal or Hepatic Impairment

Insufficient information exists to make recommendations regarding the use of OTFC 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 Gender

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

9.1 Controlled Substance

Fentanyl is a Schedule II controlled substance that can produce drug dependence of the morphine type. OTFC may be subject to misuse, abuse and addiction.

9.2 Abuse and Addiction

Manage the handling of OTFC to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law [see How Supplied/Storage And Handling (16.1, 16.2)]. 

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, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. "Drug-seeking" behavior is very common in addicts and drug abusers.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Since OTFC 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.

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.

9.3 Dependence

Guide the administration of OTFC by the response of the patient. Physical dependence, per se, is not ordinarily a concern when one is treating a patient with chronic cancer 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.

10.1 Clinical Presentation

The manifestations of OTFC overdosage are expected to be similar in nature to intravenous fentanyl and other opioids, and are an extension of its pharmacological actions with the most serious significant effect being respiratory depression [see Clinical Pharmacology (12.2)].

10.2 Immediate Management

Immediate management of opioid overdose includes removal of the OTFC unit, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, and assessment of level of consciousness, ventilatory and circulatory status.

10.3 Treatment of Overdosage (Accidental Ingestion) in the Opioid NON-Tolerant Person

Provide ventilatory support, obtain intravenous access, and employ naloxone or other opioid antagonists as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist’s action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the package insert of the individual opioid antagonist for details about such use.

10.4 Treatment of Overdose in Opioid-Tolerant Patients

Provide ventilatory support and obtain intravenous access as clinically indicated. Judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.

10.5 General Considerations for Overdose

Management of severe OTFC overdose includes: securing a patent airway, assisting or controlling ventilation, establishing intravenous access, and GI decontamination by lavage and/or activated charcoal, once the patient's airway is secure. In the presence of respiratory depression or apnea, assist or control ventilation, and administer oxygen as indicated.

Although muscle rigidity interfering with respiration has not been seen following the use of OTFC, this is possible with fentanyl and other opioids. If it occurs, manage it by using assisted or controlled ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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.

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 OTFC should be individually titrated to achieve the desired effect [see Dosage And Administration (2.2)].

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).

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.

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.

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.

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 OTFC. 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 - Warning: Importance Of Proper Patient Selection, Dosing, and Potential for Abuse, Contraindications (4), Warnings And Precautions (5.2), Adverse Reactions (6), and Overdosage (10)].

12.3 Pharmacokinetics

The absorption pharmacokinetics of fentanyl from the oral transmucosal dosage form is a combination of an initial rapid absorption from the buccal mucosa and a more prolonged absorption of swallowed fentanyl from the GI tract. Both the blood fentanyl profile and the bioavailability of fentanyl will vary depending on the fraction of the dose that is absorbed through the oral mucosa and the fraction swallowed.

Absolute bioavailability, as determined by area under the concentration-time curve, of 15 mcg/kg in 12 adult males was 50% compared to intravenous fentanyl.

Normally, approximately 25% of the total dose of OTFC is rapidly absorbed from the buccal mucosa and becomes systemically available. The remaining 75% of the total dose is swallowed with the saliva and then is slowly absorbed from the GI tract. About 1/3 of this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. Thus, the generally observed 50% bioavailability of OTFC is divided equally between rapid transmucosal and slower GI absorption. Therefore, a unit dose of OTFC, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed.

Dose proportionality among four of the available strengths of OTFC (200, 400, 800, and 1600 mcg) has been demonstrated in a balanced crossover design in adult subjects (n=11). Mean serum fentanyl levels following these four doses of OTFC are shown in Figure 1. The curves for each dose level are similar in shape with increasing dose levels producing increasing serum fentanyl levels. Cmax and AUC0→∞ increased in a dose-dependent manner that is approximately proportional to the OTFC administered.

Figure 1. Mean Serum Fentanyl Concentration (ng/mL) in Adult Subjects Comparing 4 Doses of OTFC

The pharmacokinetic parameters of the four strengths of OTFC tested in the dose-proportionality study are shown in Table 3. The mean Cmax ranged from 0.39 - 2.51 ng/mL. The median time of maximum plasma concentration (Tmax) across these four doses of OTFC varied from 20 - 40 minutes (range of 20 - 480 minutes) as measured after the start of administration.

Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. 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 free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.

Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies [see Drug Interactions (7)].

Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the 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 was 0.5 L/hr/kg (range 0.3 - 0.7 L/hr/kg). The terminal elimination half-life after OTFC administration is about 7 hours.

13.1 Carcinogenesis, Mutagenesis, 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. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay.

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 OTFC.

16.1 Storage and Handling

OTFC (oral transmucosal fentanyl citrate) is supplied in individually sealed child-resistant blister packages. The amount of fentanyl contained in OTFC can be fatal to a child. Patients and their caregivers must be instructed to keep OTFC out of the reach of children [see Boxed Warning - Warning: Importance Of Proper Patient Selection, Dosing, and Potential For Abuse, Warnings And Precautions (5), and Patient Counseling Information (17.1)].

Store at 20-25ºC (68-77ºF) with excursions permitted between 15° and 30°C (59° to 86°F) until ready to use. (See USP Controlled Room Temperature.) Protect OTFC from freezing and moisture. Do not use if the blister package has been opened.

16.2 Disposal of OTFC

Patients must be advised to dispose of any units remaining from a prescription as soon as they are no longer needed. While all units should be disposed of immediately after use, partially consumed units represent a special risk because they are no longer protected by the child resistant blister package, yet may contain enough medicine to be fatal to a child [see Patient Counseling Information (17.5)].

A temporary storage bottle is provided as part of the OTFC Child Safety Kit [see Patient Counseling Information (17.4)]. This container is to be used by patients or their caregivers in the event that a partially consumed unit cannot be disposed of promptly. Instructions for usage of this container are included in the Medication Guide.

Patients and members of their household must be advised to dispose of any units remaining from a prescription as soon as they are no longer needed. Instructions are included in Patient Counseling Information (17.6) and in the Medication Guide. If additional assistance is required, call Cephalon, Inc., at 1-800-896-5855.

16.3 How Supplied

OTFC is supplied in six dosage strengths. Each unit is individually wrapped in a child-resistant, protective blister package. These blister packages are packed 30 per shelf carton for use when patients have been titrated to the appropriate dose.

Each dosage unit has a white to off-white color. Each individual solid drug matrix is marked with "FENTANYL" and the strength of the unit ("200" ,"400", "600", "800" ,"1200", or "1600"). The dosage strength is also marked on the handle tag, the blister package and the carton. See blister package and carton for product information.

Note: Colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.

17.1 Patient/Caregiver Instructions

1. Patients and their caregivers must be instructed that children exposed to OTFC are at high risk of FATAL RESPIRATORY DEPRESSION. Patients and their caregivers must be instructed to keep OTFC out of the reach of children [See How Supplied/Storage And Handling (16.1), Warnings And Precautions (5.2 and 5.3) and Medication Guide for specific patient instructions.]
2. Provide patients and their caregivers with a Medication Guide each time OTFC is dispensed because new information may be available
3. Instruct patients and their caregivers to keep both used and unused dosage units out of the reach of children. Partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible [see How Supplied/Storage And Handling (16.1), Warnings And Precautions (5.3), and Patient Counseling Information (17.5)]
4. Instruct patients not to take OTFC 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
5. Instruct patients on the meaning of opioid tolerance and that OTFC 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
6. Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take OTFC
7. Instruct patients that, if the breakthrough pain episode is not relieved 15 minutes after finishing the OTFC unit, they may take ONLY ONE ADDITIONAL UNIT OF OTFC USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take no more than two units of OTFC for any breakthrough pain episode.
8. Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with OTFC
9. Instruct patients NOT to share OTFC and that sharing OTFC with anyone else could result in the other individual's death due to overdose
10. Make patients aware that OTFC contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone
11. Instruct patients that the active ingredient in OTFC, fentanyl, is a drug that some people abuse. OTFC should be taken only by the patient it was prescribed for, and it should be protected from theft or misuse in the work or home environment
12. Caution patients to talk to their doctor if breakthrough pain is not alleviated or worsens after taking OTFC
13. Instruct patients to use OTFC exactly as prescribed by their doctor and not to take OTFC more often than prescribed
14. Caution patients that OTFC can affect a person's ability to perform activities that require a high level of attention (such as driving or using heavy machinery). Warn patients taking OTFC of these dangers and counsel them accordingly
15. Warn patients to not combine OTFC 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
16. Inform female patients that if they become pregnant or plan to become pregnant during treatment with OTFC, they should ask their doctor about the effects that OTFC (or any medicine) may have on them and their unborn children

17.2 Dental Care

Because each OTFC unit contains approximately 2 grams of sugar (hydrated dextrates), frequent consumption may increase the risk of dental decay.  The occurrence of dry mouth associated with the use of opioid medications (such as fentanyl) may add to this risk.

Post-marketing reports of dental decay have been received in patients taking OTFC [see Adverse Reactions (6.2)]. In some of these patients, dental decay occurred despite reported routine oral hygiene. As dental decay in cancer patients may be multi-factorial, patients using OTFC should consult their dentist to ensure appropriate oral hygiene.

17.3 Diabetic Patients

Advise diabetic patients that OTFC contains approximately 2 grams of sugar per unit.

17.4 OTFC Child Safety Kit

Provide patients and their caregivers with an OTFC Child Safety Kit, which contains educational materials and safe interim storage containers to help patients store OTFC and other medicines out of the reach of children. To obtain a supply of Child Safety Kits, health care professionals can call Cephalon, Inc., at 1-800-896-5855.

17.5 Disposal of Used OTFC Units

Patients must be instructed to dispose of completely used and partially used OTFC units.

1. After consumption of the unit is complete and the matrix is totally dissolved, throw away the handle in a trash container that is out of the reach of children.
2. If any of the drug matrix remains on the handle, place the handle under hot running tap water until all of the drug matrix is dissolved, and then dispose of the handle in a place that is out of the reach of children.
3. Dispose of handles in the child-resistant container (as described in steps 1 and 2) at least once a day.

If the patient does not entirely consume the unit and the remaining drug cannot be immediately dissolved under hot running water, the patient or caregiver must temporarily store the OTFC unit in the specially provided child-resistant container out of the reach of children until proper disposal is possible.

17.6 Disposal of Unopened OTFC Units When No Longer Needed

Patients and members of their household must be advised to dispose of any unopened units remaining from a prescription as soon as they are no longer needed.

To dispose of the unused OTFC units:

1. Remove the OTFC unit from its blister package using scissors, and hold the OTFC by its handle over the toilet bowl.
2. Using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet.
3. Dispose of the handle in a place that is out of the reach of children.
4. Repeat steps 1, 2, and 3 for each OTFC unit. Flush the toilet twice after 5 units have been cut and deposited into the toilet.

Do not flush the entire OTFC units, OTFC handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it [see How Supplied/Storage And Handling (16.1)].

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of OTFC are provided in the OTFC Medication Guide. Encourage patients to read this information in its entirety and giv then an opportunity to have their questions answered.

In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Cephalon, Inc., (1-800-896-5855) or seek assistance from their local DEA office.

Relabeling of "Additional barcode label" by:
Physicians Total Care, Inc.
Tulsa, OK       74146