Data from FDA - Curated by EPG Health - Last updated 19 December 2016

Indication(s)

1. INDICATIONS AND USAGE Oral Transmucosal Fentanyl Citrate (OTFC) is indicated only for the management of breakthrough cancer pain in patients 16 and older with malignancies who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer.

Patients must remain on around-the-clock opioids when taking OTFC.

This product must not be used in opioid non-tolerant patients because life-threatening respiratory depression and death could occur at any dose in patients not on a chronic regimen of opioids.

For this reason, OTFC is contraindicated in the management of acute or postoperative pain.

OTFC is intended to be used only in the care of cancer patients and only by oncologists and pain specialists who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.

OTFC is an opioid analgesic indicated only for the management of breakthrough cancer pain in patients 16 and older with malignancies who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

Patients must remain on around-the-clock opioids when taking OTFC. (1)

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Advisory information

contraindications

4. CONTRAINDICATIONS OTFC is contraindicated in opioid non-tolerant patients.

OTFC is contraindicated in the management of acute or postoperative pain including headache/migraine.

Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.

Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid daily for a week or longer.

OTFC is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl.

Anaphylaxis and hypersensitivity have been reported in association with the use of OTFC. Opioid non-tolerant patients.

(4) Management of acute or postoperative pain including headache/migraines.

(4) Intolerance or hypersensitivity to fentanyl, OTFC, or its components.

(4)

Adverse reactions

6. ADVERSE REACTIONS Most common adverse reactions during titration phase (frequency?5 %): nausea, dizziness, somnolence, vomiting, asthenia, and headache.

(6.1) Most common adverse reactions during treatment (frequency?5 %): dyspnea, constipation, anxiety, confusion, depression, rash, and insomnia.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Cephalon, Inc., at 1-800-896-5855 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 can not 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.

Table 1.

Percent of Patients with Specific Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Titration (Events in 1 % or More of Patients) Dose Group Percentage of Patients Reporting Event 200-600 mcg 800-1400 mcg 1600 mcg >1600 mcg Any Dose * (n=230) (n=138) (n=54) (n=41) (n=254) * Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once Body As A Whole Asthenia 6 4 0 7 9 Headache 3 4 6 5 6 Accidental Injury 1 1 4 0 2 Digestive Nausea 14 15 11 22 23 Vomiting 7 6 6 15 12 Constipation 1 4 2 0 4 Nervous Dizziness 10 16 6 15 17 Somnolence 9 9 11 20 17 Confusion 1 6 2 0 4 Anxiety 3 0 2 0 3 Abnormal Gait 0 1 4 0 2 Dry Mouth 1 1 2 0 2 Nervousness 1 1 0 0 2 Vasodilatation 2 0 2 0 2

Hallucinations 0 1 2 2 1 Insomnia 0 1 2 0 1 Thinking Abnormal 0 1 2 0 1 Vertigo 1 0 0 0 1 Respiratory Dyspnea 2 3 6 5 4 Skin Pruritus 1 0 0 5 2 Rash 1 1 0 2 2 Sweating 1 1 2 2 2 Special Senses Abnormal Vision 1 0 2 0 2 The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1 % or greater and are listed in descending order of frequency within each body system.

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

Table 2.

Percent of Patients with Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Long Term Treatment (Events in 1 % or More of Patients) Dose Group Percentage of Patients Reporting Event 200-600 mcg 800-1400 mcg 1600 mcg >1600 mcg Any Dose * (n=98) (n=83) (n=53) (n=27) (n=152) Body As A Whole Asthenia 25 30 17 15 38 Headache 12 17 13 4 20 Accidental Injury 4 6 4 7 9 Hypertonia 2 2 2 0 3 Digestive Nausea 31 36 25 26 45 Vomiting 21 28 15 7 31 Constipation 14 11 13 4 20 Intestinal Obstruction 0 2 4 0 3 Cardiovascular Hypertension 1 1 0 0 1 Nervous Dizziness 12 10 9 0 16 Anxiety 9 8 8 7 15 Somnolence 8 13 8 7 15 Confusion 2 5 13 7 10 Depression 9 4 2 7 9 Insomnia 5 1 8 4 7 Abnormal

Gait 5 1 0 0 4 Dry Mouth 3 1 2 4 4 Nervousness 2 2 0 4 3 Stupor 4 1 0 0 3 Vasodilatation 1 1 4 0 3 Thinking Abnormal 2 1 0 0 2 Abnormal Dreams 1 1 0 0 1 Convulsion 0 1 2 0 1 Myoclonus 0 0 4 0 1 Tremor 0 1 2 0 1 Vertigo 0 0 4 0 1 Respiratory Dyspnea 15 16 8 7 22 Skin Rash 3 5 8 4 8 Sweating 3 2 2 0 4 Pruritus 2 0 2 0 2 Special Senses Abnormal Vision 2 2 0 0 3 Urogenital Urinary Retention 1 2 0 0 2 The following reactions not reflected in Table 2 occurred with an overall frequency of 1 % or greater in the long-term extension study and are listed in descending order of frequency within each body system.

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

Usage information

Dosing and administration

2. DOSAGE AND ADMINISTRATION As with all opioids, the safety of patients using such products is dependent on health care professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.

Initial dose of OTFC: 200 mcg. Prescribe an initial supply of six 200 mcg OTFC units.

(2.1) Individually titrate to a tolerable dose that provides adequate analgesia using single OTFC dosage unit per breakthrough cancer pain episode.

(2) No more than two doses can be taken per breakthrough pain episode.

(2.2) Wait at least 4 hours before treating another episode of breakthrough pain with OTFC. (2.3) Limit consumption to four or fewer units per day once successful dose is found.

(2.3) 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.

Use in special populations

8. USE IN SPECIFIC POPULATIONS Safety and efficacy below age 16 years have not been established.

(8.4) Administer OTFC with caution to patients with liver or kidney dysfunction.

(8.6) 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.

Pregnancy and lactation
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.

Interactions

7. DRUG INTERACTIONS Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when OTFC is given concurrently with agents that affect CYP3A4 activity.

The concomitant use of OTFC with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug effects including fatal respiratory depression.

Patients receiving OTFC concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time.

Dosage increase should be done conservatively.

Grapefruit and grapefruit juice decrease CYP3A4 activity, increasing blood concentrations of fentanyl, thus should be avoided.

Drugs that induce cytochrome P450 3A4 activity may have the opposite effects.

Concomitant use of OTFC with an MAO inhibitor, or within 14 days of discontinuation, is not recommended [see Warnings And Precautions (5.9)].

Monitor patients who begin or end therapy with potent inhibitors of CYP450 3A4 for signs of opioid toxicity.

(5.4, 7)

More information

Category Value
Authorisation number NDA020747
Orphan designation No
Product NDC 52959-566,52959-549,52959-548
Date Last Revised 06-09-2011
Type HUMAN PRESCRIPTION DRUG
RXCUI 310293
Marketing authorisation holder H.J. Harkins Company, Inc.
Warnings WARNING: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE Reports of serious adverse events, including deaths in patients treated with OTFC have been reported. Deaths occurred as a resul