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
`
`
`
`
`
`
`
`
`
`
`
`
` Page 1 of 26
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`
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`Reference ID: 3066874
`
`-------------------------------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.
`
`
`
`
`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)
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`Revised: 1/2012
`
` Insys Exhibit 2009
`CFAD v. Insys
`IPR2015-01799
`
`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: IMPORTANCE OF PROPER PATIENT SELECTION,
`
`DOSING, AND POTENTIAL FOR ABUSE
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`Initial Dose
`2.1
`
`
`2.2 Dose Titration
`
`2.3 Maintenance Dosing
`2.4 Administration of SUBSYS
`2.5 Discontinuation of SUBSYS
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Important Information Regarding Prescribing and Dispensing
`5.2 Respiratory Depression
`
`
`
`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 26
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`

`
`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
`Pharmacolog y(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 (5.11)] Further information is available at
`
`www.TIRFREMSaccess.com or by calling 1-866-822-1483.
`
`
`
`
`
` Page 3 of 26
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`Reference ID: 3066874
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`

`
`
`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.
`
`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
`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.
`
`
`
`
`Avoid prescribing a higher dose until patients have used up all units to prevent
`confusion and possible overdose.
`
`
`2.2 Dose Titration
`
`
`Page 4 of 26
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`Reference ID: 3066874
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`

`
` 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.
`
`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.
`
`d.
`
`
`
`Table 1. Titration Steps
`
`SUBSYS DOSE
`100 mcg
`200 mcg
`400 mcg
`600 mcg
`800 mcg
`1200 mcg
`1600 mcg
`
`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
`
`
`
`
`
`
`
`SUBSYS Titration Process
`
`Page 5 of 26
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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
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`

`
`
`
`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.
`
`
`
`
`
`
`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
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`Page 7 of 26
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`

`
`
`
`
`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)].
`
`
`Page 8 of 26
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`Reference ID: 3066874
`
`

`
`
`
`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 (e.g., driving a car or operating
`
`
`machinery). Warn patients taking SUBSYS of these dangers and counsel them
`accordingly.
`
`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:
`
`
`
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` Healthcare professionals who prescribe SUBSYS must review the
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`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.
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` Pharmacies that dispense SUBSYS must enroll in the program and
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`agree to comply with the REMS requirements.
` Wholesalers and distributors that distribute SUBSYS must enroll in the
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`program and distribute only to authorized pharmacies.
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`Page 9 of 26
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`Reference ID: 3066874
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`Further information, including a list of qualified pharmacies/distributors, is
`available at www.TIRFREMSaccess.com or by calling 1-866-822-1483.
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`
`
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`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
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`
`
`patients with breakthrough cancer pain. The duration of SUBSYS use varied
`during the open-label study. Safety data from a long-term extension study
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`
`
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`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
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`
`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.
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`
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`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.
`
`
`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%)
`
`
`
`
`
`Gastrointestinal Disorders
`Nausea
`Vomiting
`Constipation
`Nervous System Disorders
`Somnolence
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`Reference ID: 3066874
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`26 (7.2%)
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`Dizziness
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`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.
`
`
`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%)
`
`
`
`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.
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`26 (9.7%)
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`
`28 (10.4%)
`
`16 (5.9%)
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`

`
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`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 peripheral,
`
`fatigue, pyrexia, chest pain, drug withdrawal syndrome, chills, irritability,
`
`malaise, application site irritation
`Infections and Infestations: Oral candidiasis, pneumonia, urinary tract
`
`infection, oral herpes, gastroenteritis, laryngitis
`
`
`
`Injury, Poisoning and Procedural Complications: Contusion
`Investigations: Weight decreased, aspartate aminotransferase increased, blood
`
`alkaline phosphatase increased, blood glucose increased, blood lactate increased
`
`Metabolism and Nutrition Disorders: Anorexia, dehydration, hypokalemia,
`
`decreased appetite, hyponatremia, hypocalcemia, hypoalbuminemia, cachexia
`
`Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia,
`muscular weakness
`Nervous System Disorders: Hypoesthesia, lethargy, sedation, tremor,
`
`somnolence, headache, dizziness
`Psychiatric Disorders: Depression, restlessness, agitation, confusional state,
`
`
`insomnia, hallucination, disorientation,
`
`Renal and Urinary Disorders: hypertension, hypotension
`Respiratory, Thoracic and Mediastinal Disorders: Cough, increased
`
`bronchial secretion, wheezing, pharyngolaryngeal pain, hypoxia, dyspnea
`exertional
`Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus
`
`
`In a single-dose mucositis study, a group of patients with Grade 1 or 2 oral
`mucositis (n=9) and without oral mucositis (n=9) were included in a clinical trial
`
`designed to support the safety of SUBSYS. Two of the nine subjects with
`
`
`mucositis (one with Grade 1 and one