-------------------------------CONTRAINDICATIONS-----------------------------­
`• Opioid non-tolerant patients. (4)
`
`• Management of acute or postoperative pain including headache/migraine and
`
`dental pain (4)
`• Intolerance or hypersensitivity to fentanyl, SUBSYS, or its components. (4)
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`• Clinically significant respiratory and CNS depression can occur. Monitor
`
`patients accordingly. (5.1)
`• Full and consumed SUBSYS units contain medicine that can be fatal to a
`child. Ensure proper storage and disposal. (5.3, 16.2)
`• Use with other CNS depressants and moderate or strong CYP450 3A4
`
`inhibitors may increase depressant effects including respiratory depression,
`
`hypotension, and profound sedation. Consider dosage adjustments if
`
`warranted. (5.4)
`
`• Titrate SUBSYS cautiously in patients with chronic obstructive pulmonary
`disease or preexisting medical conditions predisposing them to respiratory
`depression and in patients susceptible to intracranial effects of CO2
`
`
`retention. (5.6, 5.7)
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
`Most common adverse reactions during treatment (frequency ≥5%): vomiting,
`nausea, constipation, dyspnea, and somnolence. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Insys
`Therapeutics, Inc., at 1-855-978-2797 or FDA at 1-800-FDA-1088 or
`www.fda.gov/ medwatch.
`
`------------------------------DRUG INTERACTIONS------------------------------­
`• Boxed Warning and Warnings and Precautions (5.4, 7)
`
`
`-------------------USE IN SPECIFIC POPULATIONS-----------------------­
`• Safety and effectiveness in pediatric patients below 18 years of age have not
`
`been established. (8.4)
`• Administer SUBSYS with caution to patients with liver or kidney
`
`dysfunction. (8.6)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`
`
`Revised: 07/2013
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`SUBSYS safely and effectively. See full prescribing information for
`
`SUBSYS.
`SUBSYS®(fentanyl sublingual spray), CII
`
`
`Initial U.S. Approval: 1968
`
`
`
`
`
`
`
`
`WARNING: RISK OF RESPIRATORY DEPRESSION,
`
`
`MEDICATION ERRORS, ABUSE POTENTIAL
`
`See full prescribing information for complete boxed warning.
`
`
` Due to the risk of fatal respiratory depression, SUBSYS is
`contraindicated in opioid non-tolerant patients (1) and in
`management of acute or postoperative pain, including
`headache/migraines. (4)
`
` Keep out of reach of children. (5.3)
`
`
` Use with CYP3A4 inhibitors may cause fatal respiratory depression.
`(7)
`
`
` When prescribing, do not convert patients on a mcg per mcg basis
`
`from any other oral transmucosal fentanyl product to SUBSYS. ( 5.1)
`
`
`
` When dispensing, do not substitute with any other fentanyl products.
`(5.1)
`
` Contains fentanyl, a Schedule II controlled substance with abuse
`
`liability similar to other opioid analgesics. (9.1)
`
`
` SUBSYS is available only through a restricted program called the
`TIRF REMS Access program. Outpatients, healthcare professionals
`who prescribe to outpatients, pharmacies, and distributors are
`required to enroll in the program. (5.10)
`----------------------------INDICATIONS AND USAGE--------------------------­
`SUBSYS is an opioid agonist 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 must remain on around-the-clock opioids when taking
`
`SUBSYS. (1)
`Limitations of Use:
`SUBSYS may be dispensed only to patients enrolled in the TIRF REMS
`ACCESS program.
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`• Patients must require and use around-the-clock opioids when taking
`
`SUBSYS. (1)
`• Initial dose of SUBSYS: 100 mcg.
`• Individually titrate to a tolerable dose that provides adequate analgesia using
`a single SUBSYS dose 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 SUBSYS. (2.3)
`• Limit consumption to four or fewer doses per day once successful dose is
`found. (2.3)
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`• Sublingual spray in 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg dosage
`strengths. (3)
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`
`Page 1 of 22
`
`
`
`Reference ID: 3350257
`
`

`

`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION
`
`ERRORS, ABUSE POTENTIAL
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`Initial Dose
`
`2.1
`2.2 Dose Titration
`
`2.3 Maintenance Dosing
`
`2.4 Administration of SUBSYS
`
`2.5 Disposal of SUBSYS
`
`2.6 Oral Mucositis
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
` Respiratory Depression
`
`5.1
`
` Important Information Regarding Prescribing and Dispensing
`
`5.2
`
`5.3 Patient/Caregiver Instructions
`
`5.4 Additive CNS Depressant Effects
`
`5.5 Effects on Ability to Drive and Use Machines
`
`5.6 Chronic Pulmonary Disease
`
`
`5.7 Head Injuries and Increased Intracranial Pressure
`
`
`5.8 Cardiac Disease
`
`5.9 MAO Inhibitors
`5.10 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation
`
`
`and Mitigation Strategy (REMS) ACCESS Program
`
`
`
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`
`
`
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.2 Labor and Delivery
`
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Patients with Renal or Hepatic Impairment
`
`
`8.7 Gender
`
`
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`
`9.2 Abuse and Addiction
`
`9.3 Dependence
`
`10 OVERDOSAGE
`10.1 Clinical Presentation
`
`10.2 Immediate Management
`
`10.3 Treatment of Overdosage (Accidental Ingestion) in the Opioid
`
`NON-Tolerant Person
`
`
`
`10.4 Treatment of Overdose in Opioid-Tolerant Patients
`
`
`
`10.5 General Considerations for Overdose
`
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 Storage and Handling
`
`
`
`16.2 Disposal of SUBSYS
`
`
`16.3 How Supplied
`
`
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Patient/Caregiver Instructions
`
`
`17.2 SUBSYS Child Safety Kit
`
`
`17.3 Disposal of Used SUBSYS Unit Dose Systems
`
`
`17.4 Disposal of Unopened SUBSYS Unit Dose Systems When No
`
`Longer Needed
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`Page 2 of 22
`
`
`
`Reference ID: 3350257
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: RISK OF RESPIRATORY DEPRESSION,
`
`
`
`MEDICATION ERRORS, ABUSE POTENTIAL
`
`
`
`Respiratory Depression
`Fatal respiratory depression has occurred in patients treated with transmucosal immediate-release fentanyl
`
`products such as SUBSYS, including following use in opioid non-tolerant patients and improper dosing. The
`
`
`substitution of SUBSYS for any other fentanyl product may result in fatal overdose.
`
`
`Due to the risk of respiratory depression, SUBSYS is contraindicated in the management of acute or
`
`
`postoperative pain including headache/migraine and in opioid non-tolerant patients.
`
`
`Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl
`
`
`products. SUBSYS must be kept out of reach of children. [see Patient Counseling Information (17.3) and How
`Supplied/Storage and Handling (16.1)]
`
`
`
`
`The concomitant use of SUBSYS with CYP3A4 inhibitors may result in an increase in fentanyl plasma
`
`concentrations, and may cause potentially fatal respiratory depression [see Drug Interactions (7)].
`
`
`
`Medication Errors
`Substantial differences exist in the pharmacokinetic profile of SUBSYS compared to other fentanyl products
`that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal
`overdose.
`
`- When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to
`
`
`
`SUBSYS. [see Dosage and Administration (2.1),Warnings and Precautions (5.2,) and Clinical Pharmacology
`
`
`(12.3)]
`
`- When dispensing, do not substitute a SUBSYS prescription for other fentanyl products.
`
`
`Abuse Potential
`
`SUBSYS contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability
`
`
`
`
`similar to other opioid analgesics. SUBSYS can be abused in a manner similar to other opioid agonists, legal or
`illicit. This should be considered when prescribing or dispensing SUBSYS in situations where the physician or
`
`pharmacist is concerned about an increased risk of misuse, abuse or diversion.
`
`
`Because of the risk for misuse, abuse, addiction, and overdose, SUBSYS is available only through a restricted
`
`
`program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy
`(REMS). Under the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Access program, outpatients,
`
`healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. [See
`
`
`Warnings and Precautions (5.10)] Further information is available at www.TIRFREMSaccess.com or by calling 1­
`866-822-1483.
`
`
`1 INDICATIONS AND USAGE
`
`SUBSYS is indicated for the management of breakthrough pain in adult cancer patients 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 SUBSYS.
`
`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, SUBSYS is contraindicated in
`
`
`the management of acute or postoperative pain.
`
`
`
`
`
`SUBSYS 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.
`
`
`
`Page 3 of 22
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`

`

`
`
`Limitations of Use:
`
`
`
`As part of the Transmucosal Immediate-Release Fentanyl (TIRF) REMS ACCESS Program, SUBSYS may be dispensed
`
`only to outpatients enrolled in the program. [see Warnings and Precautions (5.10)]. For inpatient administration (e.g.
`
`
`
`
`hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of SUBSYS, patient enrollment is not
`
`
`required.
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`Healthcare professionals who prescribe SUBSYS on an outpatient basis must enroll in the TIRF REMS ACCESS
`
`program and comply with the requirements of the REMS to ensure safe use of SUBSYS. [see Warnings and Precautions
`(5.10)]
`
`
`
`
`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.
`
`
`
`2.1 Initial Dose
`
`
`SUBSYS is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other
`
`
`
`fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than
`
`
`
`Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.)
`
`
`Patients on Actiq
`
`
`
`
`The initial dose of SUBSYS is always 100 mcg with the only exception of patients already using Actiq.
`
`
`
`
`a. For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patients on
`
`
`Actiq table below (Table 1). Patients must be instructed to stop the use of Actiq and dispose of any remaining units.
`
`
`Table 1. Initial Dosing Recommendations for Patients on ACTIQ
`
`
`
`Current ACTIQ
`Dose
`
`(mcg)
`
`200
`
`400
`
`600
`
`800
`1200
`1600
`
`Initial SUBSYS Dose
`(mcg)
`
`
`
`100 mcg spray
`
`100 mcg spray
`
`200 mcg spray
`
`200 mcg spray
`
`400 mcg spray
`
`400 mcg spray
`
`
`b. For patients converting from Actiq doses 400 mcg and below, titration should be initiated with 100 mcg SUBSYS and
`
`
`
`
`
`
`should proceed using multiples of this strength.
`
`
`c. For patients converting from Actiq doses of 600 and 800 mcg, titration should be initiated with 200 mcg SUBSYS
`
`
`and should proceed using multiples of this strength.
`
`
`
`d. For patients converting from Actiq doses of 1200 and 1600 mcg, titration should be initiated with 400 mcg SUBSYS
`
`
`and should proceed using multiples of this strength.
`
`
`All Other Patients
`Individually titrate SUBSYS to a dose that provides adequate analgesia and minimizes side effects. The initial dose of
`
`SUBSYS to treat episodes of breakthrough cancer pain is always 100 mcg. When prescribing, do not switch patients
`
`on a mcg per mcg basis from any other oral transmucosal fentanyl product to SUBSYS as SUBSYS is not
`
`equivalent on a mcg per mcg basis with any other fentanyl product [see Warnings and Precautions (5.2) and Clinical
`
`
`
`
`Pharmacology (12.3)].
`
`
`
`
`
`Prescribe an initial titration supply of 100 mcg SUBSYS units, which limits the number of units in the home during
`
`titration.
`
`
`Page 4 of 22
`
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`Reference ID: 3350257
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`

`

`
`
`
`
`
`Avoid prescribing a higher dose until patients have used up all units to prevent confusion and possible overdose.
`
`
`
`2.2 Dose Titration
`
`
`
`a. From the 100 mcg initial dose, closely follow patients and change the dosage level until the patient reaches a dose
`that provides adequate analgesia using a single SUBSYS dose per breakthrough cancer pain episode with tolerable
`
`
`side effects. Patients should record their use of SUBSYS over several episodes of breakthrough cancer pain and
`
`
`review their experience with their physicians to determine if a dosage adjustment is warranted.
`
`b. For each breakthrough pain episode treated, if pain is not relieved after 30 minutes, patients may take ONLY ONE
`
`
`
`
`
`
`
`additional dose of the same strength for that episode. Thus patients should take a maximum of two doses of
`
`
`SUBSYS for any breakthrough pain episode.
`
`
`
`c. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with SUBSYS.
`
`
`
`
`
`
`d.
`If there is a need to titrate to a 200 mcg dose, prescribe 200 mcg SUBSYS units.
`
`
`
`
`
`e. Subsequent titration steps are 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg. See Table 1.
`
`
`
`
`
`f. To reduce the risk of overdose during titration, patients should have only one strength of SUBSYS available at any
`time.
`
`
`Using
`
`1 × 100 mcg unit
`
`1 × 200 mcg unit
`
`1 × 400 mcg unit
`
`1 × 600 mcg unit
`
`1 × 800 mcg unit
`2 × 600 mcg unit
`2 × 800 mcg unit
`
`
`Table 1. Titration Steps
`
`SUBSYS DOSE
`
`100 mcg
`200 mcg
`400 mcg
`600 mcg
`800 mcg
`
`1200 mcg
`
`1600 mcg
`
`
`SUBSYS Titration Process
`
`
`Page 5 of 22
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`

`

`
`
`
`
`
`
`
`
`
`
`2.3 Maintenance Dosing
`
`Once titrated to a dose that provides adequate pain relief and tolerable side effects, patients should generally use ONLY
`
`ONE SUBSYS dose of the appropriate strength per breakthrough pain episode.
`
`
`
`
`On those occasions when the breakthrough pain episode is not relieved within 30 minutes after administration of the
`SUBSYS dose, the 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 SUBSYS. Once a
`
`
`successful dose has been found, patients should limit consumption to four or fewer doses per day.
`
` Dosage adjustment of SUBSYS may be required in some patients in order to continue to provide adequate relief of
`breakthrough pain.
`
` If signs of excessive opioid effects appear following administration of a single SUBSYS dose, subsequent doses should
`be decreased.
`
` Generally, only increase the SUBSYS dose 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. In addition, if pain worsens, re-evaluate the patient for
`
`
`
`
`
`
` changes in the underlying pain condition.
`
`
`
`
` 2.4 Administration of SUBSYS
` The blister package should be opened with scissors immediately prior to product use. The patient should carefully spray
`
` the contents of the unit into his or her mouth underneath the tongue.
`
`
`
`
`
`2.5 Disposal of SUBSYS
`
`Patients and caregivers must be advised to dispose of used unit dose systems immediately after use and any unneeded
`
`
`
`
`
`unit dose systems remaining from a prescription as soon as they are no longer needed. 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 (17.3)].
`
`
`A disposal bottle is provided with every carton dispensed. This container is to be used by patients or their caregivers to
`
`
`
`
`dispose of the contents of any unneeded unit dose systems when they are no longer needed. Instructions for usage of the
`
`
`
`
`
`
`
`disposal bottle are included in the Medication Guide and Instructions for Use.
`
`
`
`2.6 Oral Mucositis
`
`
`In cancer patients with mucositis, exposure to SUBSYS was greater than in patients without mucositis. For patients with
`
`
`Grade 1 mucositis, the increased maximum serum concentration and overall exposure requires closer monitoring for
`
`respiratory depression and central nervous system depression, particularly during initiation of therapy with SUBSYS.
`For patients with Grade 2 mucositis or higher, avoid use of SUBSYS unless the benefits outweigh the potential risk of
`
`
`
`respiratory depression from increased exposure. [see Clinical Pharmacology (12.3)]
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`SUBSYS is a sublingual spray available in 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg strengths [see How
`
`
`Supplied (16.3) and Storage and Handling (16.1)].
`
`
`4 CONTRAINDICATIONS
`SUBSYS is contraindicated:
`
`
`in opioid non-tolerant patients.
`
`
`
`
`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.
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`Page 6 of 22
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`

`

`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`See Boxed Warning - WARNING RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE
`
`POTENTIAL
`
`
`5.1 Respiratory Depression
`
`
`Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in SUBSYS.
`
`
`
`Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated
`
`
`
`
`patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction
`
`
`with other drugs that depress respiration.
`
`
`
`Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often
`
`
`
`
`
`
`associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide
`
`retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes
`
`overdoses involving drugs with sedative properties and opioids especially dangerous.
`
`5.2 Important Information Regarding Prescribing and Dispensing
`
`SUBSYS is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from
`
`other fentanyl products.
`
`
`When dispensing, DO NOT substitute a SUBSYS prescription for any other fentanyl product. Substantial
`
`
`differences exist in the pharmacokinetic profile of SUBSYS compared to other fentanyl products that result in clinically
`important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution
`
`
`
`
`
`
`
`of the same dose of SUBSYS for the same dose of any other fentanyl product may result in a fatal overdose.
`
`There are no conversion directions available for patients on any other fentanyl products. (Note: This includes
`oral, transdermal, or parenteral formulations of fentanyl.) All patients should be titrated from the 100 mcg dose.
`
`
`Titrate each patient individually to provide adequate analgesia while minimizing side effects. [See Dosage and
`Administration (2.1) and Clinical Pharmacology (12.3)]
`
`
`
`5.3 Patient/Caregiver Instructions
`Patients and their caregivers must be instructed that SUBSYS contains a medicine in an amount which can be
`fatal to a child. Death has been reported in children who have accidentally ingested transmucosal immediate-
`release fentanyl products. Patients and their caregivers must be instructed to keep both used and unused dosage units
`
`
`
`
`
`
`
`
`
`out of the reach of children. All used units should be disposed of immediately after use as they represent a special risk to
`
`children. [see How Supplied/Storage and Handling (16.1, 16.2), Patient Counseling Information (17.1), and 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.
`
`
`SUBSYS 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 SUBSYS 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 strong and moderate inhibitors of CYP450 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 SUBSYS 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
`
`
`
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`(e.g., driving a car or operating machinery). Warn patients taking SUBSYS of these dangers and counsel them
`accordingly.
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`5.6 Chronic Pulmonary Disease
`
`Because potent opioids can cause respiratory depression, titrate SUBSYS 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 SUBSYS may further decrease respiratory drive to the point of respiratory
`
`
`failure.
`
`
`5.7 Head Injuries and Increased Intracranial Pressure
`
`Administer SUBSYS 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 SUBSYS with caution in patients with bradyarrhythmias.
`
`
`5.9 MAO Inhibitors
`
`SUBSYS 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.
`
`5.10 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS)
`
`ACCESS Program
`Because of the risk of misuse, abuse, addiction and overdose [see Drug Abuse and Dependence (9)], SUBSYS is
`
`
`
`
`available only through a restricted program under a REMS called the TIRF REMS ACCESS program. Under the TIRF
`
`
`REMS ACCESS program, outpatients, prescribers 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 SUBSYS, patient and prescriber enrollment is not required.
`
`
`
`
`Required components of the TIRF REMS ACCESS program are:
`
` Healthcare professionals who prescribe SUBSYS must review the prescriber educational materials for the TIRF
`REMS ACCESS program, enroll in the program, and agree to comply with the REMS requirements.
`
` To receive SUBSYS, patients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
`
` Pharmacies that dispense SUBSYS must enroll in the program and agree to comply with the REMS
`requirements.
`
`
` Wholesalers and distributors that distribute SUBSYS 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.
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Studies Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
`
`trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
`
`
`
`observed in practice.
`
`The safety of SUBSYS has been evaluated in a total of 359 opioid-tolerant patients with breakthrough cancer pain. The
`
`
`
`duration of SUBSYS use varied during the open-label study. Safety data from a long-term extension study showed that
`
`the average duration of therapy in the open-label study was 66 days. The maximum duration of therapy was 149 days.
`
`The dose range studied in these trials ranged from 100 mcg per dose to 1600 mcg per dose.
`
`
`The most commonly observed adverse reactions seen with SUBSYS are typical opioid side effects such as nausea,
`vomiting, somnolence, and constipation. Expect opioid side effects and manage them accordingly.
`
`The most serious adverse reactions associated with all opioids including SUBSYS are respiratory depression (potentially
`
`leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms
`
`
`
`
`of respiratory depression.
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`The most common adverse reaction leading to discontinuation of SUBSYS was nausea. There were also adverse
`
`
`reactions of abdominal distension, anorexia, confusional state, disorientation, somnolence, and constipation.
`
`
`The clinical trials of SUBSYS 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 SUBSYS for breakthrough cancer pain along with a concomitant opioid for
`
`persistent cancer pain.
`
`
`
`
`
`Table 2 lists adverse reactions with an overall frequency of 5% or greater that occurred during titration in the clinical
`trials. Adverse reactions are listed in descending order of frequency within each system organ class.
`
`
`
`Table 2. Percent of Patients with Specific Adverse Events During Titration in the Clinical Trials (Events in 5% or
`
`More of Patients)
`
`System Organ Class
`
`Titration
`n=359 (%)
`
`
`47 (13.1%)
`
`
`
`37 (10.3%)
`
`
`
`18 (5.0%)
`
`34 (9.5%)
`
`
`26 (7.2%)
`
`
`
`
`Gastrointestinal Disorders
`
`Nausea
`Vomiting
`Constipation
`Nervous System Disorders
`
`Somnolence
`Dizziness
`A patient was counted only once within each category.
`
`
`The following adverse reactions occurred during titration in the clinical trials with an overall frequency of 1% or greater
`
`
`
`and are listed in descending order of frequency within each system organ class.
`
`
`Cardiac Disorders: Tachycardia
`Gastrointestinal Disorders: Diarrhea, stomatitis, dry mouth
`
`General Disorders and Administration Site Conditions: Application site irritation, pyrexia, edema peripheral,
`
`
`
`
`fatigue, asthenia
`Metabolism and Nutrition Disorders: Decreased appetite
`
`Nervous System Disorders: Lethargy, sedation, tremor, headache
`
`Psychiatric Disorders: Depression, confusional state, hallucination, insomnia
`
`
`Respiratory, Thoracic and Mediastinal Disorders: Dyspnea
`
`Skin and Subcutaneous Tissue Disorders: Pruritus
`
`The following reactions occurred during titration in the clinical trials with an overall frequency of less than 1% and are
`
`
`
`listed in descending order of frequency within each system organ class.
`
`Eye Disorders: Vision blurred, dry eye
`
`Gastrointestinal Disorders: Abdominal pain
`
`
`Infections and Infestations: Oral candidiasis, cellulitis
`Injury, Poisoning and Procedural Complications: Fall
`
`
`Metabolism and Nutrition Disorders: Dehydration, anorexia
`
`Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, joint swelling
`
`
`Psychiatric Disorders: Anxiety, agitation
`Renal and Urinary Disorders: Urinary retention
`
`Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, dysphonia,
`
`pharyngolaryngeal pain
`
`Skin and Subcutaneous Tissue Disorders: Hyperhidrosis
`Vascular Disorders: Hot flush
`
`Table 3 lists adverse reactions with an overall frequency of 5% or greater for the total safety database subsequent to
`
`
`
`
`titration during the clinical trials.
`
`
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`Table 3. Adverse Reactions Subsequent to Titration in 5% or More of Patients
`
`
`
`
`Dosing
`
`n=269
`
`
`
`43 (16.0%)
`
`
`28 (10.4%)
`
`
`28 (10.4%)
`
`
`26 (9.7%)
`
`
`
`28 (10.4%)
`
`
`16 (5.9%)
`
`System Organ Class
`Gastrointestinal Disorders
`
`Vomiting
`Nausea
`
`Constipation
`General Disorders and Administration Site
`
`Conditions
`Asthenia
`
`
`
`Respiratory, Thoracic and Mediastinal Disorders
`Dyspnea
`
`Psychiatric Disorders
`
`Anxiety
`
`A patient was counted only once within each category.
`
`
`
`
`
`
`
`
`
`
`The following adverse reactions occurred during the dosing period of the clinical trial with an overall frequency of 1% or
`greater and are listed in descending order of frequency within each system organ class.
`Blood and Lymphatic System Disorders: Anemia, neutropenia, lymphadenopathy, thrombocytopenia, leukopenia
`
`
`Cardiac Disorders: Tachycardia, sinus tachycardia
`Gastrointestinal Disorders: Diarrhea, stomatitis, abdominal pain, abdominal distension, gastritis, dysphagia,
`
`
`dyspepsia, gastroesophageal reflux disease, ascites, hematemesis
`
`
`General Disorders and Administration Site Conditions: Edema periphe