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: LIFE-THREATENING RESPIRATORY DEPRESSION,
`ACCIDENTAL INGESTION; CYTOCHROME P450 3A4
`INTERACTION; RISKS FROM CONCOMITANT USE WITH
`BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF
`MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE;
`REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME
`See full prescribing information for complete boxed warning.
`
`• Serious, life-threatening, and/or fatal respiratory depression has
`occurred. Monitor closely, especially upon initiation or following a
`dose increase. 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. (5.1)
`• Accidental ingestion of SUBSYS, especially by children, can result in a
`fatal overdose of fentanyl. Keep out of reach of children. Ensure
`proper storage and disposal. (5.2)
`• Concomitant use with CYP3A4 inhibitors (or discontinuation of
`CYP3A4 inducers) can result in a fatal overdose of fentanyl. (5.3, 7,
`12.2)
`• Concomitant use of opioids with benzodiazepines or other central
`nervous system (CNS) depressants, including alcohol, may result in
`profound sedation, respiratory depression, coma, and death. Reserve
`concomitant prescribing for use in patients for whom alternative
`treatment options are inadequate; limit dosages and durations to the
`minimum required and follow patients for signs and symptoms of
`respiratory depression and sedation. (5.4, 7)
`• When prescribing, do not convert patients on a mcg per mcg basis from
`any other oral transmucosal fentanyl product to SUBSYS. (2.2, 5.5)
`• When dispensing, do not substitute with any other fentanyl products.
`(5.5)
`• SUBSYS exposes users to risks of addiction, abuse, and misuse, which
`can lead to overdose and death. Assess patient’s risk before prescribing
`and monitor regularly for these behaviors and conditions. (5.6)
`• 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. (5.7)
`• Prolonged use of SUBSYS during pregnancy can result in neonatal
`opioid withdrawal syndrome, which may be life-threatening if not
`recognized and treated. If prolonged opioid use is required in a
`pregnant woman, advise the patient of the risk of neonatal opioid
`withdrawal syndrome and ensure that appropriate treatment will be
`available. (5.8)
`
`
`--------------------------- RECENT MAJOR CHANGES -------------------------
`Warnings and Precautions (5.1)
`
`
`
`10/2019
`
`----------------------------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 around-the-clock opioid therapy for their underlying
`persistent cancer pain. (1)
`Patients considered opioid tolerant are those who are taking, for one week or
`longer, around-the-clock medicine consisting of at least 60 mg of oral
`morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30
`mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day,
`at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per
`day, or an equianalgesic dose of another opioid daily for a week or longer.
`Patients must remain on around-the-clock opioids when taking SUBSYS.
`
`Limitations of Use (1):
`• Not for use in opioid non-tolerant patients.
`• Not for use in the management of acute or postoperative pain, including
`headache/migraine, dental pain, or in the emergency room.
`• As a 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 (5.7)]. For
`inpatient
`Page 1 of 37
`
`Reference ID: 4501156
`
`administration of SUBSYS (e.g., hospitals, hospices, and long-term care
`facilities that prescribe for inpatient use), patient and prescriber enrollment
`is not required.
`
`
`
`-------------------DOSAGE AND ADMINISTRATION------------------
`• Patients must require and use around-the-clock opioids when taking
`SUBSYS. (1)
`• Use the lowest effective dose for the shortest duration consistent with
`individual patient treatment goals (2.1)
`• Individualize dosing based on the severity of pain, patient response, prior
`analgesic experience, and risk factors for addiction, abuse, and misuse.
`(2.1)
`• Initiate treatment with 100 mcg except patients already using Actiq. (2.2)
`• Individually titrate to a tolerable dose that provides adequate analgesia
`using a single SUBSYS dose per breakthrough cancer pain episode. (2.4)
`• No more than two doses can be taken per breakthrough pain episode. (2.4)
`• Wait at least 4 hours before treating another episode of breakthrough pain
`with SUBSYS. (2.4)
`• Limit consumption to four or fewer doses per day once successful dose is
`found. (2.4)
`• When opioid therapy is no longer required, consider discontinuing
`SUBSYS along with a gradual downward titration of other opioids to
`minimize possible withdrawal effects. (2.5).
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Sublingual spray in 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg dosage
`strengths. (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`• Opioid non-tolerant patients. (4)
`• Management of acute or postoperative pain including headache/migraine
`and dental pain, or in emergency department. (4)
`• Acute or severe bronchial asthma in an unmonitored setting or in absence
`of resuscitative equipment. (4)
`• Known or suspected gastrointestinal obstruction, including paralytic ileus.
`(4)
`• Known hypersensitivity to fentanyl, or components of SUBSYS. (4)
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`• Life-Threatening Respiratory Depression in Patients with Chronic
`Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients:
`Monitor closely, particularly during initiation and titration. (5.9)Serotonin
`Syndrome: Potentially life-threatening condition could result from
`concomitant serotonergic drug administration. Discontinue SUBSYS if
`serotonin syndrome is suspected. (5.10)
`• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of
`corticosteroids, and wean patient off of the opioid. (5.11)
`• Severe Hypotension: Monitor during dosage initiation and titration. Avoid
`use of SUBSYS in patients with circulatory shock. (5.12)
`• Risks of Use in Patients with Increased Intracranial Pressure, Brain
`Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and
`respiratory depression. Avoid use of SUBSYS in patients with impaired
`consciousness or coma. (5.13)
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reactions during treatment (incidence ≥ 5%): vomiting,
`nausea, constipation, dyspnea, and somnolence. (6)
`
`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-------------------------------
`• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid
`use with SUBSYS because they may reduce analgesic effect of SUBSYS
`or precipitate withdrawal symptoms. (7)
`
`-------------------USE IN SPECIFIC POPULATIONS------------------------
`• Pregnancy: May cause fetal harm. (8.1)
`• Lactation: Not Recommended.
`• Renal and Hepatic Impairment: Administer SUBSYS with caution. (8.6)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 10/2019
`
`

`

`_______________________________________________________________________________________________________________________________________
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: LIFE-THREATENTING RESPIRATORY DEPRESSION;
`ACCIDENTAL EXPOSURE, CYTOCHROME P450 3A4
`INTERACTION; RISKS FROM CONCOMITANT USE WITH
`BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF
`MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE;
`REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME
`
` 1
`
`
`
`5.17 Cardiac Disease
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Patients with Renal or Hepatic Impairment
`8.7 Sex
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`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
`17 PATIENT COUNSELING INFORMATION
`
`
`INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Dosage and Administration Instructions
`2.2 Initial Dose
`2.3 Dosage Modifications in Patients with Oral Mucositis
`2.4 Titration and Maintenance of Therapy
`2.5 Discontinuation of SUBSYS
`2.6 Disposal of SUBSYS
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Life-Threatening Respiratory Depression
`5.2 Increased risk of overdose in children due to accidental ingestion
`5.3 Risks of Concomitant Use or Discontinuation of Cytochrome P450
`3A4 Inhibitors and Inducers
`5.4 Risks from Concomitant Use with Benzodiazepines or other CNS
`Depressants
`5.5 Risk of Medication Errors
`5.6 Addiction, Abuse, and Misuse
`5.7 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation
`and Mitigation Strategy (REMS) ACCESS Program
`5.8 Neonatal Opioid Withdrawal Syndrome
`5.9 Life-Threatening Respiratory Depression in Patients with Chronic
`Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
`5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
`5.11 Adrenal Insufficiency
`5.12 Severe Hypotension
`5.13 Risks of Use in Patients with Increased Intracranial Pressure, Brain
`Tumors, Head Injury, or Impaired Consciousness
`5.14 Risks of Use in Patients with Gastrointestinal Conditions
`5.15 Increased Risk of Seizures in Patients with Seizure Disorders
`5.16 Risks of Driving and Operating Machinery
`_______________________________________________________________________________________________________________________________________
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`Page 2 of 37
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`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL
`INGESTION; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT
`USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF
`MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS and NEONATAL
`OPIOID WITHDRAWAL SYNDROME
`
`
`Life-Threatening Respiratory Depression
`Serious, life-threatening, and/or fatal respiratory depression has occurred in patients treated
`with SUBSYS, including following use in opioid non-tolerant patients and improper dosing.
`Monitor for respiratory depression, especially during initiation of SUBSYS or following a dose
`increase. The substitution of SUBSYS for any other fentanyl product may result in fatal
`overdose [see Warnings and Precautions (5.1)]
`
`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.
`[see Contraindications (4)]
`
`Accidental INGESTION
`Accidental ingestion of even one dose of SUBSYS especially by children, can result in a fatal
`overdose of fentanyl [see Warnings and Precautions (5.2 )].
`
`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 Warnings and
`Precautions (5.2); How Supplied/Storage and Handling (16)].
`
`Cytochrome P450 3A4 Interaction
`The concomitant use of SUBSYS with all cytochrome P450 3A4 inhibitors may result in an
`increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions
`and may cause potentially fatal respiratory depression. In addition, discontinuation of a
`concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma
`concentration. Monitor patients receiving SUBSYS and any CYP3A4 inhibitor or inducer [see
`Warnings and Precautions (5.3), Drug Interactions (7), Clinical Pharmacology (12.3)].
`
`Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
`Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)
`depressants, including alcohol, may result in profound sedation, respiratory depression,
`coma, and death [see Warnings and Precautions (5.4), Drug Interactions (7)].
`• Reserve concomitant prescribing of SUBSYS and benzodiazepines or other CNS
` depressants for use in patients for whom alternative treatment options are inadequate.
`• Limit dosages and durations to the minimum required.
`• Follow patients for signs and symptoms of respiratory depression and sedation.
`
`
`
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`

`

`Risk of 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 [see Dosage and Administration (2.1), Warnings and
`Precautions (5.5)].
`• When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl
`products to SUBSYS.
`• When dispensing, do not substitute a SUBSYS prescription for other fentanyl products.
`
`Addiction, Abuse, and Misuse
`SUBSYS exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
`which can lead to overdose and death. Assess each patient’s risk prior to prescribing SUBSYS,
`and monitor all patients regularly for the development of these behaviors and conditions [see
`Warnings and Precautions (5.6)].
`
`Risk Evaluation and Mitigation Strategy (REMS) Access Program
`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 (5.7)]. Further information is available at www.TIRFREMSaccess.com or by calling
`1-866-822-1483.
`
`Neonatal Opioid Withdrawal Syndrome
`Prolonged use of SUBSYS during pregnancy can result in neonatal opioid withdrawal
`syndrome, which may be life-threatening if not recognized and treated, and requires
`management according to protocols developed by neonatology experts. If opioid use is required
`for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid
`withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings
`and Precautions (5.8)].
`
`
`INDICATIONS AND USAGE
`1.
`SUBSYS is 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 around-the-clock opioid therapy for their
`underlying persistent cancer pain.
`Patients considered opioid tolerant are those who are taking for one week or longer, around-the-clock
`medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl
`per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, or at
`least 25 mg oral oxymorphone per day, or at least 60 mg oral hydrocodone per day, or an equianalgesic
`dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids
`when taking SUBSYS.
`
`
`
`
`
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`
`

`

`•
`
`•
`
`Limitations of Use:
`• Not for use in opioid non-tolerant patients.
`• Not for use in the management of acute or postoperative pain, including headache/migraine, dental
`pain, or in the emergency room [see Contraindications (4)].
`• 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 (5.7)]. 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
`2.1
`Important Dosage and Administration Instructions
`• 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 (5.7)]
`• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment
`goals [see Warnings and Precautions (5)].
`It is important to minimize the number of strengths available to patients at any time to prevent
`confusion and possible overdose.
`Initiate the dosing regimen for each patient individually, taking into account the patient's severity of
`pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and
`misuse [see Warnings and Precautions (5.6)].
`• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of
`initiating therapy and following dosage increases with SUBSYS and adjust the dosage accordingly
`[see Warnings and Precautions (5.1)].
`Instruct patients and caregivers to take steps to store SUBSYS securely and to properly dispose of
`unused SUBSYS as soon as no longer needed [see Warnings and Precautions (5.2, 5.6), Patient
`Counseling Information (17)].
`• Other TIRF formulations and SUBSYS are not equivalent. DO NOT substitute a SUBSYS
`prescription for any other TIRF formulation under any circumstances. Do not convert patients on a
`mcg per mcg basis from any other fentanyl product to SUBSYS [see Warnings and Precautions
`(5.5)]
`• 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.) [see Warnings and Precautions (5.5)].
`• SUBSYS is NOT a generic version of any other oral transmucosal fentanyl product [see Warnings
`and Precautions (5.5)].
`2.2
`Initial Dosage
`Initiate treatment with SUBSYS for all patients (including those switching from another fentanyl
`product) using ONE 100 mcg spray sublingually.
`
`•
`
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`

`

`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.
`Conversion from Actiq to SUBSYS
`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.
`
`
`Dosage Modifications in Patients with Oral Mucositis
`2.3
`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)]
`
`2.4 Titration and Maintenance of Therapy
`Individually titrate SUBSYS to a dose that provides adequate analgesia and minimizes adverse reactions.
`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
`
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`

`

`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 2.
`f. To reduce the risk of overdose during titration, patients should have only one strength of
`SUBSYS available at any time.
`Table 2.
`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
`
`
`
`
`
`
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`

`
`SUBSYS Titration Process
`
`
`
`
`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.
`
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`

`
`Discontinuation of SUBSYS
`2.5
`For patients no longer requiring opioid therapy, consider discontinuing SUBSYS 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, SUBSYS therapy can usually be discontinued immediately. [see Drug Abuse and Dependence
`(9.3)].
`
`Disposal of SUBSYS
`2.6
`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)].
`Charcoal-lined disposal pouches are provided with every carton dispensed. A charcoal-lined disposal
`pouch 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 charcoal-lined disposal pouch are
`included in the Medication Guide and Instructions for Use.
`
`3. DOSAGE FORMS AND STRENGTHS
`SUBSYS is a sublingual spray available in 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg,
`and 1600 mcg strengths. SUBSYS is supplied as spray units consisting of a white actuator attached to a
`light purple vial holder [see How Supplied/Storage and Handling (16)]. 100 mcg, 200 mcg, 400 mcg,
`600 mcg, and 800 mcg doses are delivered as a single unit (spray). To administer 1200 mcg and 1600
`mcg doses, two units (sprays) must be used.
`Each dosage strength is differentiated by the color of the blister package, and carton as described below
`in Table 3. The strength of the spray unit is indicated on the actuator.
`Table 3.
`Subsys Strengths
`Dosage
`Using
`Strength
`(fentanyl base)
`100 mcg
`200 mcg
`400 mcg
`600 mcg
`800 mcg
`1200 mcg
`1600 mcg
`
`Blue
`1 × 100 mcg unit packaged in a single blister
`Green
`1 × 200 mcg unit packaged in a single blister
`1 × 400 mcg unit packaged in a single blister Magenta (Pink)
`1 × 600 mcg unit packaged in a single blister
`Purple
`1 × 800 mcg unit packaged in a single blister
`Orange
`2 × 600 mcg units packaged in a single blister
`Brown
`2 × 800 mcg units packaged in a single blister
`Red
`
`Carton/Blister
`Package Color
`
`
`
`
`
`
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`

`

`4. CONTRAINDICATIONS
`SUBSYS is contraindicated in:
`• Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at
`any dose in opioid non-tolerant patients [see Indications and Usage (1); Warnings and
`Precautions (5.1)].
`• Acute or postoperative pain including headache/migraine and dental pain, or in the emergency
`department [see Indications and Usage (1)].
`• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative
`equipment [see Warnings and Precautions (5.9)].
`• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and
`Precautions (5.14)].
`• Known hypersensitivity (e.g., anaphylaxis) to fentanyl or components of SUBSYS [see
`Adverse Reactions (6.2)].
`
`
`5. WARNINGS AND PRECAUTIONS
`5.1
`Life-Threatening Respiratory Depression
`Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even
`when used as recommended. Respiratory depression, if not immediately recognized and treated, may
`lead to respiratory arrest and death. Management of respiratory depression may include close
`observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status
`[see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can
`exacerbate the sedating effects of opioids.
`While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of
`SUBSYS, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor
`patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy
`with and following dosage increases of SUBSYS.
`To reduce the risk of respiratory depression, proper dosing and titration of SUBSYS are essential [see
`Dosage and Administration (2.4)]. Overestimating the SUBSYS dosage can result in a fatal overdose
`with the first dose. The substitution of SUBSYS for any other fentanyl product may result in fatal
`overdose [see Warnings and Precautions (5.5)].
`SUBSYS could be fatal to individuals for whom it is not prescribed and for those who are not opioid-
`tolerant.
`Accidental ingestion or exposure to even one dose of SUBSYS, especially in children, can result in
`respiratory depression and death due to an overdose of fentanyl.
`Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related
`hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present
`with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and
`Administration (2.4)].
`5.2
`Increased Risk of Overdose in Children Due to Accidental Ingestion
`Death has been reported in children who have accidentally ingested transmucosal immediate–release
`fentanyl products.
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`Patients and their caregivers must be informed that SUBSYS contains a medicine in an amount which
`can be fatal to a child. 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.
`Patients and their caregivers must be instructed to keep both used and unused dosage units out of the
`reach of children. While all units should be disposed of immediately after use, partially consumed units
`represent a special risk to children. In the event that a unit is not completely consumed it must be
`properly disposed as soon as possible [see Patient Counseling Information (17)].
`Detailed instructions for the proper storage, administration, disposal, and important instructions for
`managing an overdose of SUBSYS are provided in the SUBSYS Medication Guide. Encourage patients
`to read this information in its entirety and give them an opportunity to have their questions answered.
`5.3
`Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and
`Inducers
`Concomitant use of SUBSYS with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g.,
`erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may
`increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause
`potentially fatal respiratory depression [see Warnings and Precautions (5.9)], particularly when an
`inhibitor is added after a stable dose of SUBSYS is achieved. Similarly, discontinuation of a CYP3A4
`inducer, such as rifampin, carbamazepine, and phenytoin, in SUBSYS-treated patients may increase
`fentanyl plasma concentrations and prolong opioid adverse reactions. When using SUBSYS with
`CYP3A4 inhibitors or discontinuing CYP3A4 inducers in SUBSYS-treated patients, monitor patients
`closely at frequent intervals and consider dosage reduction of SUBSYS until stable drug effects are
`achieved [see Drug Interactions (7)].
`Concomitant use of SUBSYS with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could
`decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal
`syndrome in a patient who had developed physical dependence to fentanyl. When using SUBSYS with
`CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and
`consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid
`withdrawal occur [see Drug Interactions (7)].
`5.4
`Risks from Concomi