FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION
`
`ERRORS, ABUSE POTENTIAL
`
`INDICATIONS AND USAGE
`1
`
`2 DOSAGE AND ADMINISTRATION
`
`Initial Dose
`2.1
`2.2 Dose Titration
`2.3 Maintenance Dosing
`2.4 Administration of SUBSYS
`
`2.5 Discontinuation of SUBSYS
`
`2.6 Oral Mucositis
`
`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.
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`Reference ID: 3140097
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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
`
`
`
`
`Pharmacology(12.3)]
`- When dispensing, do not substitute a SUBSYS prescription for other fentanyl products.
`
`
`
`Abuse Potential
`SUBSYS contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability
`
`similar to other opioid analgesics. SUBSYS can be abused in a manner similar to other opioid agonists, legal
`
`
`
`or illicit. This should be considered when prescribing or dispensing SUBSYS in situations where the
`physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.
`
`
`Because of the risk for misuse, abuse, addiction, and overdose, SUBSYS is available only through a restricted
`
`program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy
`
`
`(REMS). Under the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Access program, outpatients,
`
`healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. [See
`
`Warnings and Precautions (5.10)] Further information is available at www.TIRFREMSaccess.com or by calling 1­
`
`866-822-1483.
`
`Reference ID: 3140097
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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
`
`
`
`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.
`
`
`
`
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`e. Subsequent titration steps are 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg. See Table 1.
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`Reference ID: 3140097
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`

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` f. To reduce the risk of overdose during titration, patients should have only one strength of SUBSYS available at
`any time.
`
`
`Table 1. Titration Steps
`
`SUBSYS DOSE
`100 mcg
`200 mcg
`400 mcg
`600 mcg
`800 mcg
`
`1200 mcg
`
`1600 mcg
`
`
`SUBSYS Titration Process
`
`
`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
`
`
`
`
`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.
`
`
`
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`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.
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`Reference ID: 3140097
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`

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`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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`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.
`
`
`
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`
`
`5 WARNINGS AND PRECAUTIONS
`See Boxed Warning - WARNING RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS,
`
`
`ABUSE POTENTIAL
`
`
`5.1 Respiratory Depression
`
`
`Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in SUBSYS.
`
`
`Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or
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`
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`debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in
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`conjunction with other drugs that depress respiration.
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`Reference ID: 3140097
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`

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`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
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`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
`
`
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`
`
`
`
`
`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
`
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`children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from
`inadvertent exposure.
`
`
`SUBSYS could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.
`
`
`5.4 Additive CNS Depressant Effects
`
`The concomitant use of SUBSYS with other CNS depressants, including other opioids, sedatives or hypnotics,
`
`general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic
`
`
`beverages may produce increased depressant effects (e.g., respiratory depression, hypotension, and profound
`
`
`
`sedation). Concomitant use with strong and moderate inhibitors of CYP450 3A4 isoform (e.g., erythromycin,
`ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects
`
`[see Drug Interactions (7)].
`
`
`
`Patients on concomitant CNS depressants must be monitored for a change in opioid effects. Consideration should be
`given to adjusting the dose of SUBSYS if warranted.
`
`
`5.5 Effects on Ability to Drive and Use Machines
`
`
`
`Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous
`
`tasks (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.
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`Reference ID: 3140097
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`

`

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`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
`
`
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`available only through a restricted program under a REMS called the TIRF REMS ACCESS program. Under the
`
`TIRF REMS ACCESS program, outpatients, prescribers who prescribe to outpatients, pharmacies, and distributors
`
`must enroll in the program. For inpatient administration (e.g. hospitals, hospices, and long-term care facilities that
`
`prescribe for inpatient use) of SUBSYS, patient and prescriber enrollment is not required.
`
`
`
`
`
`Required components of the TIRF REMS ACCESS program are:
`
` Healthcare professionals who prescribe SUBSYS must review the prescriber educational materials for the
`
`
`TIRF REMS ACCESS program, enroll in the program, and agree to comply with the REMS requirements.
`
` To receive SUBSYS, patients must understand the risks and benefits and sign a Patient-Prescriber
`Agreement.
`
` Pharmacies that dispense SUBSYS must enroll in the program and agree to comply with the REMS
`requirements.
`
`
` Wholesalers and distributors that distribute SUBSYS must enroll in the program and distribute only to
`authorized pharmacies.
`
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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.
`
`
`
`
`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.
`
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`
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`The safety of SUBSYS has been evaluated in a total of 359 opioid-tolerant patients with breakthrough cancer pain.
`
`
`The duration of SUBSYS use varied during the open-label study. Safety data from a long-term extension study
`
`
`showed that the average duration of therapy in the open-label study was 66 days. The maximum duration of therapy
`
`
`was 149 days. The dose range studied in these trials ranged from 100 mcg per dose to 1600 mcg per dose.
`
`The most commonly observed adverse reactions seen with SUBSYS are typical opioid side effects such as nausea,
`vomiting, somnolence, and constipation. Expect opioid side effects and manage them accordingly.
`
`
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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.
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`Reference ID: 3140097
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`

`

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` 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
`
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`persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing
`each adverse effect among patients who received SUBSYS for breakthrough cancer pain along with a concomitant
`
`opioid for persistent cancer pain.
`
`
`
`
`
`Table 2 lists adverse reactions with an overall frequency of 5% or greater that occurred during titration in the clinical
`trials. Adverse reactions are listed in descending order of frequency within each system organ class.
`
`
`Table 2. Percent of Patients with Specific Adverse Events During Titration in the Clinical Trials (Events in
`5% or More of Patients)
`
`
`System Organ Class
`
`Titration
`n=359 (%)
`
`
`
`47 (13.1%)
`
`37 (10.3%)
`
`18 (5.0%)
`
`
`34 (9.5%)
`
`26 (7.2%)
`
`
`
`
`Gastrointestinal Disorders
`Nausea
`Vomiting
`Constipation
`Nervous System Disorders
`Somnolence
`Dizziness
`A patient was counted only once within each category.
`
`
`The following adverse reactions occurred during titration in the clinical trials with an overall frequency of 1% or
`
`
`greater and are listed in descending order of frequency within each system organ class.
`
`
`Cardiac Disorders: Tachycardia
`Gastrointestinal Disorders: Diarrhea, stomatitis, dry mouth
`
`
`General Disorders and Administration Site Conditions: Application site irritation, pyrexia, edema peripheral,
`
`
`
`
`fatigue, asthenia
`Metabolism and Nutrition Disorders: Decreased appetite
`
`Nervous System Disorders: Lethargy, sedation, tremor, headache
`Psychiatric Disorders: Depression, confusional state, hallucination, insomnia
`
`
`Respiratory, Thoracic and Mediastinal Disorders: Dyspnea
`Skin and Subcutaneous Tissue Disorders: Pruritus
`
`The following reactions occurred during titration in the clinical trials with an overall frequency of less than 1% and
`
`
`
`
`are listed in descending order of frequency within each system organ class.
`
`
`
`Eye Disorders: Vision blurred, dry eye
`
`Gastrointestinal Disorders: Abdominal pain
`
`
`Infections and Infestations: Oral candidiasis, cellulitis
`Injury, Poisoning and Procedural Complications: Fall
`
`
`Metabolism and Nutrition Disorders: Dehydration, anorexia
`
`Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, joint swelling
`
`
`Psychiatric Disorders: Anxiety, agitation
`
`Renal and Urinary Disorders: Urinary retention
`
`
`Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, dysphonia,
`
`pharyngolaryngeal pain
`
`Skin and Subcutaneous Tissue Disorders: Hyperhidrosis
`Vascular Disorders: Hot flush
`
`
`Table 3 lists adverse reactions with an overall frequency of 5% or greater for the total safety database subsequent to
`
`
`
`
`titration during the clinical trials.
`
`Table 3. Adverse Reactions Subsequent to Titration in 5% or More of Patients
`
`
`Reference ID: 3140097
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`

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`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.
`
`
`
`Dosing
`
`
`n=269
`
`
`43 (16.0%)
`
`28 (10.4%)
`
`28 (10.4%)
`
`
`
`26 (9.7%)
`
`
`28 (10.4%)
`
`16 (5.9%)
`
`
`
`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 with Grade 2) reported a burning sensation in the oral mucosa
`
`after treatment. Both of these events were considered mild and probably related to treatment. There was no change
`
`
`in grade of mucositis after treatment for any subject.
`
`7 DRUG INTERACTIONS
`
`
`Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore
`
`
`
`potential interactions may occur when SUBSYS is given concurrently with agents that affect CYP3A4 activity.
`
`The concomitant use of SUBSYS with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole,
`
`troleandomycin, clarithromycin, nelfinavir, and nefazodone) or moderate CYP3A4 inhibitors (e.g., amprenavir,
`
`
`
`
`aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil) may result in increased fentanyl
`
`Reference ID: 3140097
`
`
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`
`
`
`

`

` plasma concentrations, potentially causing serious adverse drug effects including fatal respiratory depression.
`
`
`Patients receiving SUBSYS concomitantly with moderate or strong CYP3A4 inhibitors should be carefully
`
`
`monitored for an extended period of time. Dosage increase should be done conservatively.
`
`
`The concomitant use of SUBSYS with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz,
`glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin,
`
`
`St. John's wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the
`efficacy of SUBSYS. Patients receiving SUBSYS who stop therapy with, or decrease the dose of, CYP3A4 inducers
`
`
`
`should be monitored for signs of increased SUBSYS activity and the dose of SUBSYS should be adjusted
`accordingly.
`
`
`
`Concomitant use of SUBSYS with an MAO inhibitor, or within 14 days of discontinuation, is not recommended
`[see Warnings and Precautions (5.9)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`Pregnancy Category C
`
`
`There are no adequate and well-controlled studies in pregnant women.
`
`
`
`SUBSYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No
`
`
`
`
`
`epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy
`
`
`have been reported.
`
`
`
`Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory
`
`
`depression, behavioral changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome.
`
`
`
`
`
`In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or
`
`
`
`
`neurological depression were no more frequent than would be expected in infants of untreated mothers.
`
`
`
`
`
`
`Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous
`
`fentanyl.
`
`
`
`
`
`
`Fentanyl is embryocidal in rats as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg
`
`
`
`
`intravenously or 160 mcg/kg subcutaneously. Conversion to human equivalent doses indicates this is within the
`
`
`
`
`range of the human recommended dosing for SUBSYS.
`
`
`
`
`Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that
`
`
`
`
`
`
`
`administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21, of their 21 day gestation,
`
`
`via implanted microosmotic minipumps was not teratogenic (the high dose was approximately 3-times the human
`
`dose of 1600 mcg per pain episode on a mg/m2 basis). Intravenous administration of fentanyl (10 or 30 mcg/kg) to
`
`
`
`
`
`
`
`pregnant female rats from gestation day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean
`
`delivery time in the 30 mcg/kg/day group, but was not teratogenic.
`
`
`8.2 Labor and Delivery
`
`Fentanyl readily passes across the placenta to the fetus; therefore do not use SUBSYS during labor and delivery
`since it may cause respiratory depression in the fetus or in the newborn infant.
`
`8.3 Nursing Mothers
`
`
`
`Fentanyl is excreted in human milk; therefore, do not use SUBSYS in nursing women because of the possibility of
`
`sedation and/or respiratory depression in their infants. Symptoms of opioid withdrawal may occur in infants at the
`
`cessation of nursing by women using SUBSYS.
`
`
`8.4 Pediatric Use
`Safety and efficacy in pediatric patients below the age of 18 years have not been established.
`
`8.5 Geriatric Use
`
`Reference ID: 3140097
`
`

`

`
`
`Of the 359 patients in clinical studies of SUBSYS in breakthrough cancer pain, 27% were 60 years of age and older,
`
`
`17% were 65 years of age and older, and 3% were 75 years of age and older. No difference was noted in the safety
`
`
`
`
`profile of the group over 65 years of age as compared to younger patients in SUBSYS clinical trials.
`
`
`
`Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously,
`
`
`
`compared with the younger population. Therefore, monitor patients for respiratory depression and C