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
`
`
`
`
`SUBSYS may be dispensed by outpatient pharmacies only to outpatients enrolled
`
`
`in the program (5.7). For inpatient administration of SUBSYS, patient and
`
`
`prescriber enrollment are 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)
`
`
`
`
`WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION,
`
`ACCIDENTAL INGESTION; CYTOCHROME P450 3A4
`
`
`
`• Individualize dosing based on the severity of pain, patient response, prior
`
`
`INTERACTION; RISKS FROM CONCOMITANT USE WITH
`
`
`
`
`
`analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1)
`
`
`BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF
`
`
`
`• Discuss availability of naloxone with the patient and caregiver and assess each
`
`
`
`MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE;
`
`
`
`
`patient’s need for access to naloxone, both when initiating and renewing
`
`REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME
`
`
`
`treatment with SUBSYS. Consider prescribing naloxone based on the
`See full prescribing information for complete boxed warning.
`
`
`patient’s risk factors for overdose [2.2, 5.1, 5.4, 5.6].
`
`
`• Initiate treatment with 100 mcg except patients already using Actiq. (2.3)
`
`
`
`
`
`• Serious, life-threatening, and/or fatal respiratory depression has
`
`
`• Individually titrate to a tolerable dose that provides adequate analgesia using a
`
`occurred. Monitor closely, especially upon initiation or following a
`
`single SUBSYS dose per breakthrough cancer pain episode. (2.5)
`
`dose increase. Due to the risk of fatal respiratory depression, SUBSYS
`
`• No more than two doses can be taken per breakthrough pain episode. (25)
`
`
`is contraindicated in opioid non-tolerant patients (1) and in
`
`
`• Wait at least 4 hours before treating another episode of breakthrough pain
`
`
`
`management of acute or postoperative pain, including
`
`with SUBSYS. (2.5)
`
`headache/migraines. (5.1)
`
`
`• Limit consumption to four or fewer doses per day once successful dose is
`
`
`• Accidental ingestion of SUBSYS, especially by children, can result in a
`
`
`
`found. (2.5)
`
`fatal overdose of fentanyl. Keep out of reach of children. Ensure
`
`
`• When opioid therapy is no longer required, consider discontinuing SUBSYS
`
`
`proper storage and disposal. (5.2)
`
`
`along with a gradual downward titration of other opioids to minimize possible
`
`
` • Concomitant use with CYP3A4 inhibitors (or discontinuation of
`
`
`withdrawal effects. (2.6).
`
`CYP3A4 inducers) can result in a fatal overdose of fentanyl. (5.3, 7,
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`12.2)
`
`Sublingual spray in 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg dosage
`
` • Concomitant use of opioids with benzodiazepines or other central
`
`
`strengths. (3)
`
`nervous system (CNS) depressants, including alcohol, may result in
`
`
`
`profound sedation, respiratory depression, coma, and death. Reserve
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`concomitant prescribing for use in patients for whom alternative
`
`• Opioid non-tolerant patients. (4)
`
`
`treatment options are inadequate; limit dosages and durations to the
`• Management of acute or postoperative pain including headache/migraine and
`
`
`minimum required and follow patients for signs and symptoms of
`
`dental pain, or in emergency department. (4)
`
`respiratory depression and sedation. (5.4, 7)
`
`• Acute or severe bronchial asthma in an unmonitored setting or in absence of
`
`
`
`
`• When prescribing, do not convert patients on a mcg per mcg basis from
`
`
`
`
`
`resuscitative equipment. (4)
`
`
`any other oral transmucosal fentanyl product to SUBSYS. (2.3, 5.5)
`
`
`
`• Known or suspected gastrointestinal obstruction, including paralytic ileus. (4)
`
`
`
`• When dispensing, do not substitute with any other fentanyl products.
`
`
`• Known hypersensitivity to fentanyl, or components of SUBSYS. (4)
`
`
`
`(5.5)
`
`• SUBSYS exposes users to risks of addiction, abuse, and misuse, which
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`can lead to overdose and death. Assess patient’s risk before prescribing
`
`• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary
`
`
`
`and monitor regularly for these behaviors and conditions. (5.6)
`
`Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely,
`
`
`• SUBSYS is available only through a restricted program called the
`
`
`particularly during initiation and titration. (5.9)
`
`
`TIRF REMS. Pharmacies, outpatients, and healthcare professionals
`
`
`• Serotonin Syndrome: Potentially life-threatening condition could result from
`
`
`who prescribe to outpatients are required to enroll in the program.
`
`
`concomitant serotonergic drug administration. Discontinue SUBSYS if
`
`Patients must be opioid tolerant to receive a TIRF medicine (5.7)
`
`
`
`
`serotonin syndrome is suspected. (5.10)
`
`• Prolonged use of SUBSYS during pregnancy can result in neonatal
`
`
`
`• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of
`
`
`opioid withdrawal syndrome, which may be life-threatening if not
`
`
`corticosteroids, and wean patient off of the opioid. (5.11)
`
`recognized and treated. If prolonged opioid use is required in a
`
`
`• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use
`
`pregnant woman, advise the patient of the risk of neonatal opioid
`
`of SUBSYS in patients with circulatory shock. (5.12)
`
`
`withdrawal syndrome and ensure that appropriate treatment will be
`• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors,
`
`
`
`available. (5.8)
`
`Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory
`
`
` --------------------------- RECENT MAJOR CHANGES ------------------------­
`depression. Avoid use of SUBSYS in patients with impaired consciousness or
`
`coma. (5.13)
`
`
`
`
`
`
`
` 03/2021
` Boxed Warning
` Dosage and Administration (2.2)
`
`
`
`
` 03/2021
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
` Warnings and Precautions (5.1, 5.4, 5.6, 5.7)
`
`
`
` 03/2021
`
`Most common adverse reactions during treatment (incidence ≥ 5%): vomiting,
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`nausea, constipation, dyspnea, and somnolence. (6)
`
`
`
` SUBSYS is an opioid agonist indicated for the management of breakthrough pain
`To report SUSPECTED ADVERSE REACTIONS, contact West
`
`
`
`
`
`
` in cancer patients 18 years of age and older who are already receiving and who
`Therapeutic Development, LLC., at 1-844-452-9263 or FDA at 1-800-FDA­
` are tolerant to around-the-clock opioid therapy for their underlying persistent
`
`
`
`
`1088 or www.fda.gov/ medwatch.
`
`
` cancer pain. (1)
`
`------------------------------DRUG INTERACTIONS------------------------------­
`
` 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
`• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use
`
` per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral
`
`
`
`with SUBSYS because they may reduce analgesic effect of SUBSYS or
`
`
` oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg
`
`precipitate withdrawal symptoms. (7)
`
` oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an
`
`-------------------USE IN SPECIFIC POPULATIONS-----------------------­
`
` equianalgesic dose of another opioid daily for a week or longer. Patients must
`
`
`• Pregnancy: May cause fetal harm. (8.1)
`
`
`
`
`remain on around-the-clock opioids when taking SUBSYS.
`
`• Lactation: Not Recommended.
`
`
`Limitations of Use (1):
`
`
`• Renal and Hepatic Impairment: Administer SUBSYS with caution. (8.6)
`
`
`
`
`
`• Not for use in opioid non-tolerant patients.
`
`
`
`• Not for use in the management of acute or postoperative pain, including
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`headache/migraine, dental pain, or in the emergency room
`Revised 03/2021
`
`
`Guide.
`
`
`• As a part of the Transmucosal Immediate-Release Fentanyl (TIRF) REMS,
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`Page 1 of 53
`
`
`
`
`Reference ID: 4756533
`
`

`

`
`
`
`
`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
`
`
`
`
`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
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Important Dosage and Administration Instructions
`
`
`
`
`2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid
`
`
`Overdose
`
`
`
`2.3 Initial Dose
`
`
`
`2.4 Dosage Modifications in Patients with Oral Mucositis
`
`
`
`2.5 Titration and Maintenance of Therapy
`
`
`
`2.6 Discontinuation of SUBSYS
`
`
`
`2.7 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)
`
`
`
`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 53
`
`
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`
`Reference ID: 4756533
`
`

`

`
`
` 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.
`
`
`
`
`Page 3 of 53
`
`
`
`
`Reference ID: 4756533
`
`

`

`
`
`
`
` 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)
`
`
`Because of the risk for accidental exposure, 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, pharmacies, outpatients, and healthcare professionals who
`
`
`prescribe to outpatients must enroll in the program. Inpatient pharmacies must develop policies
`and procedures to verify opioid tolerance in inpatients who require SUBSYS while hospitalized
`[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.
`
`
`Page 4 of 53
`
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`Reference ID: 4756533
`
`

`

`
`
` 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, SUBSYS may be
`
`
`
`
`
`
`
` dispensed by outpatient pharmacies only to outpatients enrolled in the program. [see Warnings and
` Precautions (5.7)]. For inpatient administration of SUBSYS, patient and prescriber enrollment are
`
`
`
`
` not required.
` 2. DOSAGE AND ADMINISTRATION
`
`
`
` 2.1
`
` Important Dosage and Administration Instructions
` • Healthcare professionals who prescribe SUBSYS for outpatients must enroll in the TIRF REMS 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)].
`
`
`
`
`•
`
`
`•
`
`
`•
`
`Page 5 of 53
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`Reference ID: 4756533
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`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
`
` Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and
`
` caregiver and assess the potential need for access to naloxone, both when initiating and renewing
`
`
`
` treatment with SUBSYS [see Warnings and Precautions (5.1), Patient Counseling Information (17)].
`
` Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual
`
`
`
` state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from
`
`
` a pharmacist, or as part of a community-based program).
` Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use
`
` of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk
`
` factors for overdose should not prevent the proper management of pain in any given patient [see
`
`
` Warnings and Precautions (5.1, 5.4, 5.6)].
`
` Consider prescribing naloxone if the patient has household members (including children) or other close
` contacts at risk for accidental ingestion or overdose.
`
`
`
`
` Initial Dosage
`2.3
`
`
`Initiate treatment with SUBSYS for all patients (including those switching from another fentanyl
`product) using ONE 100 mcg spray sublingually.
`
`
`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.
`
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`
`
` 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
`2.4
`
`
`
`
`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)]
`
`
`
`Titration and Maintenance of Therapy
`2.5
`
`
`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
`
`
`
`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
` 2.6
`
`
`
`
`
` 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
`2.7
`
`
`
`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.
`
`
` Dosage
`
`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
`
`
`
`
`
`Page 9 of 53
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`Reference ID: 4756533
`
`Subsys Strengths
`
`
` Using
`
`
`
`
` Carton/Blister
`
` Package Color
`
`

`

`
` 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 o