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Fentanyl Sublingual Tablets

DEA Controlled Substance Schedule C-II

TABLE OF CONTENTS

1. DESCRIPTION 8. ADVERSE REACTIONS
2. INDICATIONS AND USAGE 9. DRUG ABUSE AND DEPENDENCE
3. DOSAGE AND ADMINISTRATION 10. OVERDOSAGE
4. CONTRAINDICATIONS 11. DRUG INTERACTIONS
5. MECHANISM OF ACTION 12. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. WARNINGS AND PRECAUTIONS  

 


WARNINGS: POTENTIAL FOR ABUSE and IMPORTANCE OF PROPER PATIENT SELECTION

Fentanyl is an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Fentanyl can be abused in a manner similar to other opioid agonists, legal or illicit. Consider the potential for abuse when prescribing or dispensing fentanyl in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Serious adverse events, including deaths, in patients treated with other oral transmucosal fentanyl products have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of fentanyl sublingual tablets for any other fentanyl product may result in fatal overdose.

Fentanyl sublingual tablet is indicated only for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least 60 mg of oral morphine/daily, or at least 25 mcg transdermal fentanyl/hour, or at least 30 mg of oral oxycodone daily, or at least 8 mg oral hydromorphone daily, at least 25 mg oral oxymorphone daily or an equianalgesic dose of another opioid for a week or longer.

Fentanyl sublingual tablet is contraindicated in opioid non-tolerant patients and is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients treated with other fentanyl products.

When prescribing, do not convert patients on a mcg per mcg basis from another fentanyl product to fentanyl sublingual tablet. Patients beginning treatment with fentanyl sublingual tablet must begin with titration from the 100 mcg dose [See Dosage and Administration].

When dispensing, do not substitute an fentanyl sublingual tablet prescription for other fentanyl products. Differences exist in the pharmacokinetics of fentanyl sublingual tablet compared to other fentanyl products that could result in clinically important differences in the amount of fentanyl absorbed and could result in fatal overdose.

Special care must be used when dosing fentanyl sublingual tablet. If the breakthrough pain episode is not relieved patients must wait at least 2 hours before treating another episode of breakthrough pain with fentanyl sublingual tablet [See Dosage and Administration].

Fentanyl sublingual tablet is intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain.

Patients and their caregivers must be instructed that fentanyl sublingual tablet contains a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. All packs must be kept out of the reach of children [see Contraindications and How Supplied/Storage and Handling].

The concomitant use of fentanyl sublingual tablet with cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see Drug Interactions].

Because of the risk for misuse, abuse, addiction, and overdose, fentanyl sublingual tablet is available only through a restricted program, required by the Food and Drug Administration, called the ABSTRAL REMS (Risk Evaluation and Mitigation Strategy). Under the ABSTRAL REMS, healthcare professionals who prescribe to outpatients, outpatients, pharmacies and distributors must enroll in the program to prescribe, receive, dispense, and distribute fentanyl sublingual tablet, respectively. [see Warnings and Precautions]. Further information is available at www.abstralrems.com or by calling 1-888-227-8725.


 

1. DESCRIPTION

Fentanyl sublingual tablet is a solid formulation of fentanyl citrate, a potent opioid analgesic intended for oral sublingual administration.

Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1) and has the following structural formula:

C22H28N2O•C6H8O7 - M.W. 528.59

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.

Fentanyl sublingual tablet is available in six strengths, distinguishable by the shape of the tablet and by de-bossing on the tablet surface. All tablet strengths are expressed as the amount of fentanyl free base, e.g., the 100 mcg strength tablet contains 100 mcg of fentanyl free base.

Inactive Ingredients: Croscarmellose sodium, magnesium stearate, mannitol, and silicified microcrystalline cellulose.

2. INDICATIONS AND USAGE

Fentanyl sublingual tablets are indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, or at least 25 mcg of transdermal fentanyl/hour, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid medication daily for a week or longer. Patients must remain on around-the-clock opioids when taking fentanyl sublingual tablets.

Fentanyl sublingual tablet is contraindicated for patients who are not already tolerant to opioids because life-threatening respiratory depression and death could result at any dose in patients not on a chronic regimen of opioids. For this reason, fentanyl sublingual tablet is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room.

Fentanyl sublingual tablet is intended to be prescribed only by healthcare professionals who are knowledgeable of, and skilled in, the use of Schedule II opioids to treat cancer pain.

Limitations of Use:

As a part of the TIRF REMS Access program, fentanyl sublingual tablets may be dispensed only to outpatients enrolled in the program [see Warnings and Precautions]. For inpatient administration of fentanyl sublingual tablets (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.

3. 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. Healthcare professionals who prescribe fentanyl sublingual tablet for outpatient use, must enroll in the ABSTRAL REMS program [See Warnings and Precautions].

3.1 Dose Titration

The objective of dose titration is to identify an effective and tolerable maintenance dose for ongoing management of breakthrough cancer pain episodes. The effective and tolerable dose of fentanyl sublingual tablet will be determined by dose titration in individual patients.

Carefully supervise patients until a dose that provides adequate analgesia with tolerable side effects is reached for breakthrough pain control.

Starting Dose: Individually titrate fentanyl sublingual tablet to a dose that provides adequate analgesia with tolerable side effects. Begin titration of all patients with an initial dose of fentanyl sublingual tablet of 100 mcg. Due to differences in the pharmacokinetic properties and individual variability, even patients switching from other fentanyl containing products to fentanyl sublingual tablet must start with the 100 mcg dose. Fentanyl sublingual tablet is not equivalent on a mcg per mcg basis with all other fentanyl products, therefore, do not switch patients on a mcg per mcg basis from any other fentanyl product. Fentanyl sublingual tablet is NOT a generic version of any other fentanyl product.

Start all patients with a single 100 mcg tablet.

• If adequate analgesia is obtained within 30 minutes of administration of the 100 mcg tablet, continue to treat subsequent episodes of breakthrough pain with this dose.

• If adequate analgesia is not obtained after fentanyl sublingual tablet, the patient may use a second fentanyl sublingual tablet dose (after 30 minutes) as directed by their health care provider. No more than two doses of fentanyl sublingual tablets may be used to treat an episode of breakthrough pain.

• Patients must wait at least 2 hours before treating another episode of breakthrough pain with fentanyl sublingual tablet.

Titration Steps: If adequate analgesia was not obtained with the first 100 mcg dose, continue dose escalation in a stepwise manner over consecutive breakthrough episodes until adequate analgesia with tolerable side effects is achieved. Increase the dose by 100 mcg multiples up to 400 mcg as needed. If adequate analgesia is not obtained with a 400 mcg dose, the next titration step is 600 mcg. If adequate analgesia is not obtained with a 600 mcg dose, the next titration step is 800 mcg. During titration, patients can be instructed to use multiples of 100 mcg tablets and/or 200 mcg tablets for any single dose. Instruct patients not to use more than 4 tablets at one time. If adequate analgesia is not obtained 30 minutes after the use of fentanyl sublingual tablet, the patient may repeat the same dose of fentanyl sublingual tablet. No more than two doses of fentanyl sublingual tablet may be used to treat an episode of breakthrough pain. Rescue medication as directed by the health care provider can be used if adequate analgesia is not achieved after use of fentanyl sublingual tablet.

The efficacy and safety of doses higher than 800 mcg have not been evaluated in clinical studies in patients.

In order to minimize the risk of fentanyl sublingual tablet-related adverse reactions and to identify the appropriate dose, it is imperative that patients be supervised closely by health professionals during the titration process.

3.2 Maintenance Therapy

Once an appropriate dose for pain management has been established, instruct patients to use only one fentanyl sublingual tablet of the appropriate strength per dose. Maintain patients on this dose.

If adequate analgesia is not obtained after use of fentanyl sublingual tablet, the patient may use a second fentanyl sublingual tablet dose (after 30 minutes) as directed by their health care provider. No more than two doses of fentanyl sublingual tablets may be used to treat an episode of breakthrough pain.

Patients must wait at least 2 hours before treating another episode of breakthrough pain with fentanyl sublingual tablets.

3.3 Dose Re-Adjustment

If the response (analgesia or adverse reactions) to the titrated fentanyl sublingual tablet dose markedly changes, an adjustment of dose may be necessary to ensure that an appropriate dose is maintained.

If more than four episodes of breakthrough pain are experienced per day, re-evaluate the dose of the long-acting opioid used for persistent underlying cancer pain. If the long-acting opioid or dose of long-acting opioid is changed, re-evaluate and re-titrate the fentanyl sublingual tablet dose as necessary to ensure the patient is on an appropriate dose.

Limit the use of fentanyl sublingual tablet to treat four or fewer episodes of breakthrough pain per day.

It is imperative that any dose re-titration is monitored carefully by a healthcare professional.

3.4 Administration of Fentanyl Sublingual Tablet

Place fentanyl sublingual tablets on the floor of the mouth directly under the tongue immediately after removal from the blister unit. Do not chew, suck, or swallow fentanyl sublingual tablets. Allow fentanyl sublingual tablets to completely dissolve in the sublingual cavity. Advise patients not to eat or drink anything until the tablet is completely dissolved.

In patients who have a dry mouth, water may be used to moisten the buccal mucosa before taking fentanyl sublingual tablets.

3.5 Discontinuation of Therapy

For patients no longer requiring opioid therapy, consider discontinuing fentanyl sublingual tablets along with a gradual downward titration of other opioids to minimize possible withdrawal effects.

In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, fentanyl sublingual tablet therapy can usually be discontinued immediately.

4. CONTRAINDICATIONS

Fentanyl sublingual tablet is contraindicated in the management of pain in opioid non-tolerant patients, because life-threatening hypoventilation could occur at any dose in patients not already taking around-the-clock opioid therapy. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, or at least 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for a week or longer.

Fentanyl sublingual tablet is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room.

Fentanyl sublingual tablet 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 other oral transmucosal fentanyl products.

5. 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women.

Use fentanyl sublingual tablet 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.

6.2 Labor and Delivery

Fentanyl readily crosses the placenta. Therefore do not use fentanyl sublingual tablet during labor and delivery (including caesarean section) since it may cause respiratory depression in the fetus or in the newborn infant.

6.3 Nursing Mothers

Fentanyl is excreted in human milk; therefore, do not use fentanyl sublingual tablet in women who are nursing 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 fentanyl sublingual tablet.

6.4 Pediatric Use

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

6.5 Geriatric Use

Of the 270 opioid tolerant patients with breakthrough cancer pain in the Phase 3 clinical studies of fentanyl sublingual tablets, 58 (21%) were 65 years of age and older. There was no difference in the median titrated dose in patients aged 65 years and older compared to those <65 years. No clinically meaningful difference was noted in the safety profile of the group 65 years of age and older as compared to younger patients in fentanyl sublingual tablet clinical trials.

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

6.6 Patients with Renal and Hepatic Impairment

Insufficient information exists to make recommendations regarding the use of fentanyl sublingual tablets in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and the inactive metabolite is mostly eliminated in urine. If the drug is used in these patients, use the drug with caution because of the reduced hepatic metabolism and renal excretion capacity in such patients.

6.7 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 efficacy or in observed adverse reactions.

7. WARNINGS AND PRECAUTIONS

See Boxed Warning - WARNINGS: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE

7.1 Fentanyl Sublingual Tablets and Other Fentanyl Products

Fentanyl sublingual tablet is NOT equivalent to all other fentanyl products used to treat breakthrough pain on a mcg per mcg basis. There are differences in the pharmacokinetics of fentanyl sublingual tablet relative to other fentanyl products which could potentially result in clinically important differences in the amount of fentanyl absorbed and could result in a fatal overdose.

When prescribing fentanyl sublingual tablet to a patient, DO NOT convert from other fentanyl products. Directions for safely converting patients to fentanyl sublingual tablet from other fentanyl products are not currently available. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl). Therefore, for opioid-tolerant patients starting treatment for breakthrough pain, the initial dose of fentanyl sublingual tablet is 100 mcg. Individually titrate each patient's dose to provide adequate analgesia while minimizing side effects. [See Dosage and Administration]

When dispensing fentanyl sublingual tablet to a patient, DO NOT substitute it for any other fentanyl product prescription.

7.2 Hypoventilation (Respiratory Depression)

Serious or fatal respiratory depression can occur even at recommended doses in patients using fentanyl sublingual tablet. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses, including fentanyl sublingual tablet, in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the "sighing" pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

7.3 Patient/Caregiver Instructions

Patients and their caregivers must be instructed that fentanyl sublingual tablet contains a medicine in an amount which can be fatal to a child. Even though fentanyl sublingual tablet is provided in child-resistant packaging, patients and their caregivers must be instructed to keep tablets out of the reach of children. [see How Supplied/Storage and Handling].

Taking fentanyl sublingual tablet could be fatal in individuals for whom it is not prescribed and for those who are not opioid-tolerant.

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.

7.4 Additive CNS Depressant Effects

The concomitant use of fentanyl sublingual tablet 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., hypoventilation, 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].

Patients on concomitant CNS depressants must be monitored for a change in opioid effects and the dose of fentanyl sublingual tablet adjusted, if warranted.

7.5 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 fentanyl sublingual tablet of these dangers and counsel them accordingly.

7.6 Chronic Pulmonary Disease

Because potent opioids can cause hypoventilation, titrate fentanyl sublingual tablet with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to hypoventilation. In such patients, even normal therapeutic doses of fentanyl sublingual tablet may further decrease respiratory drive to the point of respiratory failure.

7.7 Head Injuries and Increased Intracranial Pressure

Administer fentanyl sublingual tablet 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; use only if clinically warranted.

7.8 Cardiac Disease

Intravenous administration of fentanyl may produce bradycardia. Therefore, use fentanyl sublingual tablet with caution in patients with bradyarrhythmias.

7.9 MAO Inhibitors

Fentanyl sublingual tablet is not recommended for use in patients who have received MAO inhibitors within the past 14 days. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

7.10 Transmucosal immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program

Because of the risk for misuse, abuse, addiction, and overdose [see Drug Abuse and Dependence], fentanyl sublingual tablet is available only through a restricted program called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of fentanyl sublingual tablets, patient and prescriber enrollment is not required.

Required components of the TIRF REMS Access program are:

• Healthcare professionals who prescribe fentanyl sublingual tablets must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.

• To receive fentanyl sublingual tablets, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.

• Pharmacies that dispense fentanyl sublingual tablets must enroll in the program and agree to comply with the REMS requirements.

• Wholesalers and distributors that distribute fentanyl sublingual tablets must enroll in the program and distribute only to authorized pharmacies.

Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

8. ADVERSE REACTIONS

8.1 Clinical Studies Experience

The safety of fentanyl sublingual tablets has been evaluated in 311 opioid-tolerant cancer patients with breakthrough pain. Two hundred and seventy (270) of these patients were treated in multiple-dose studies. The duration of therapy for patients in multiple-dose studies ranged from 1-405 days with an average duration of 131 days and with 44 patients treated for at least 12 months.

The most commonly observed adverse reactions with fentanyl sublingual tablets include typical opioid adverse reactions, such as nausea, constipation, somnolence and headache. Expect opioid side effects and manage them accordingly.

The clinical trials of fentanyl sublingual 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 reaction data presented in Table 1 reflect the actual percentage of patients experiencing reactions among patients who received fentanyl sublingual tablets for breakthrough pain along with concomitant opioid use for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of fentanyl sublingual tablet therapy or cancer-related symptoms.

Table 1 lists adverse reactions with an overall frequency of 5% or greater within the total population that occurred during titration by maximum dose received. The ability to assign fentanyl sublingual tablets a dose-response relationship to these adverse reactions is limited by the titration schemes used in these studies.

Table 1: Adverse Reactions Which Occurred During Titration at a Frequency of ≥ 5%

Table 2 lists, by successful dose, adverse reactions with an overall frequency of ≥ 5% within the total population that occurred after a successful dose had been determined.

Table 2: Adverse Reactions Which Occurred During Maintenance Therapy at a Frequency of ≥ 5%

The frequencies listed below represent adverse reactions that occurred in ≥ 1% of patients from two clinical trials who experienced that reaction while receiving fentanyl sublingual tablets. Reactions are classified by system organ class.

Cardiac disorders: bradycardia, tachycardia.

Eye disorders: vision blurred.

Gastrointestinal disorders: abdominal pain, abdominal pain upper, aphthous stomatitis, constipation, dry mouth, dyspepsia, gingival ulceration, impaired gastric emptying, lip ulceration, mouth ulceration, nausea, stomach discomfort, stomatitis, tongue disorder, vomiting.

General disorders and administration site conditions: asthenia, drug withdrawal syndrome, fatigue, malaise.

Immune system disorders: drug hypersensitivity.

Injury, poisoning and procedural complications: accidental overdose.

Metabolism and nutrition disorders: anorexia, decreased appetite.

Nervous system disorders: amnesia, disturbance in attention, dizziness, dysgeusia, headache, hypoesthesia, lethargy, parosmia, somnolence, tremor.

Psychiatric disorders: affect lability, anxiety, confusional state, depression, disorientation, dysphoria, euphoric mood, insomnia, mental status changes, paranoia, sleep disorder.

Reproductive system and breast disorders: erectile dysfunction.

Respiratory, thoracic and mediastinal disorder: dyspnea, oropharyngeal pain, throat tightness.

Skin and subcutaneous disorders: hyperhidrosis, night sweats, pruritus, rash, skin lesion.

Vascular disorders: hypotension.

9. DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Fentanyl is a Schedule II substance. Schedule II opioid substances such as fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have a high potential for abuse and addiction. Fentanyl sublingual tablet is also subject to misuse and criminal diversion.

9.2 Abuse and Addiction

Manage the handling of fentanyl sublingual tablets to minimize the risk of misuse, including the restriction of access and accounting procedures as appropriate to the clinical setting and as required by law [see How Supplied/Storage and Handling].

Concerns about abuse, addiction, and diversion must 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. Be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since fentanyl sublingual tablets may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

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

Contact your 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

Physical dependence is not ordinarily a concern in the treatment of patients with chronic cancer pain, and fear of tolerance and physical dependence must not deter using opiate doses that adequately relieve the pain.

Opioid analgesics may cause physical dependence that can result 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. OVERDOSAGE

10.1 Clinical Presentation

The manifestations of fentanyl sublingual tablet overdosage are expected to be similar in nature to intravenous fentanyl and other opioids, and are an extension of its pharmacological actions with the most serious significant effect being hypoventilation.

10.2 Immediate Management

Immediate management of opioid overdose includes removal of the fentanyl sublingual tablet, 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 administer 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.

10.4 Treatment of Overdosage 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 at the risk of precipitating an acute withdrawal syndrome.

10.5 General Considerations for Overdose

Management of severe fentanyl overdose includes: securing a patent airway, assisting or controlling ventilation and establishing intravenous access. In the presence of hypoventilation or apnea, assist or control ventilation, and administer oxygen as indicated.

Carefully observe and appropriately manage patients with overdose until their clinical condition is well controlled.

Although muscle rigidity interfering with respiration has not been seen following the use of fentanyl sublingual tablets, 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.

11. DRUG INTERACTIONS

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

The concomitant use of fentanyl sublingual tablet with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl sublingual tablet who begin therapy with, or increase the dose of, CYP3A4 inhibitors need to be carefully monitored for signs of opioid toxicity over an extended period of time. Increase dosage conservatively.

The concomitant use of fentanyl sublingual tablet with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of fentanyl sublingual tablet. Patients receiving fentanyl sublingual tablet who stop therapy with, or decrease the dose of, CYP3A4 inducers need to be monitored for signs of increased fentanyl sublingual tablet activity and the dose of fentanyl sublingual tablet must be adjusted accordingly.

12. PHARMACOKINETICS

Absorption

Fentanyl is a highly lipophilic drug. Orally administered fentanyl undergoes pronounced hepatic and intestinal first pass effects. Absorption of fentanyl from fentanyl sublingual tablets is mainly through the oral mucosa.

The bioavailability of fentanyl sublingual tablets has been calculated to be 54%.

Dose proportionality across the 100 mcg to 800 mcg fentanyl sublingual tablet dose range has been demonstrated (Table 3). Mean plasma fentanyl levels following single doses of fentanyl sublingual tablet are shown in Figure 1. The median time to maximum plasma concentration (Tmax) across these four doses of fentanyl sublingual tablets varied from 30 to 60 minutes (range of 15 - 240 minutes).

Figure 1: Mean (+/-SD) Plasma Fentanyl Concentration versus Time after Administration of Single Doses of 100 mcg, 200 mcg, 400 mcg and 800 mcg Fentanyl Sublingual Tablets to Healthy Subjects

Pharmacokinetic parameters are presented in Table 3.

Table 3. Mean (CV%) Fentanyl Pharmacokinetic Parameters after Single-Dose Administration of 100, 200, 400 and 800 mcg Doses of Fentanyl Sublingual Tablets to Healthy Subjects (n=12 per Dose Level)

In another study, dose proportionality between 800 mcg and 1600 mcg in Cmax and AUC has also been demonstrated.

Pharmacokinetic studies have shown that multiple tablets are bioequivalent to single tablets of the equivalent dose.

Distribution

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.

Metabolism

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].

Elimination

Fentanyl is 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).

13. HOW SUPPLIED/STORAGE AND HANDLING

13.1 How Available:

a) Brand name: ABSTRAL, by ProStrakan, Inc.

b) Generic drugs: None.

13.2 How Supplied:

ABSTRAL is supplied in six dosage strengths. Tablets are supplied in child-resistant, protective blister cards with peelable foil. Each blister card contains 4 tablets, in pack sizes of 12 (100 mcg, 200 mcg, 300 mcg and 400 mcg strengths) or 32 (all strengths) tablets.

Each tablet is white in color, with the strength distinguishable by the shape of the dosage unit and by de-bossing on the tablet surface:

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

13.3 Storage:

ABSTRAL is supplied in individually sealed child-resistant blister packages contained in a cardboard outer carton, in pack sizes of 12 (100 mcg, 200 mcg, 300 mcg and 400 mcg strengths) or 32 (all strengths) tablets. The packaging is color-coded for each ABSTRAL tablet strength. The amount of fentanyl contained in ABSTRAL can be fatal to a child, individual for whom it is not prescribed or non-opioid tolerant adult. Patients and their caregivers must be instructed to keep ABSTRAL out of the reach of children [see Boxed Warning -Warnings: Potential For Abuse and Importance Of Proper Patient Selection and, Warnings And Precautions].

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture.

13.4 Disposal of ABSTRAL:

Patients and their household members must be advised to dispose of any tablets remaining from a prescription as soon as they are no longer needed. Instructions are included in Patient Counseling Information and in the Medication Guide.

To dispose of any unused ABSTRAL tablets, remove them from the blister cards and flush down the toilet. Do not dispose of the ABSTRAL blister cards or cartons down the toilet.

If additional assistance is required, call ProStrakan, Inc. at 1-888-227-8725.

Rx only

Rev 12/11