July 23, 2016
Recommended Topic Related To:


"The U.S. Food and Drug Administration today approved Yondelis (trabectedin), a chemotherapy, for the treatment of specific soft tissue sarcomas (STS) – liposarcoma and leiomyosarcoma – that cannot be removed by surgery (unresect"...





Included as part of the PRECAUTIONS section.



Respiratory Depression

Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in SUBSYS. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

Important Information Regarding Prescribing And Dispensing

SUBSYS is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products.

When dispensing, DO NOT substitute a SUBSYS prescription for any other fentanyl product. Substantial differences exist in the pharmacokinetic profile of SUBSYS compared to other fentanyl products that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of the same dose of SUBSYS for the same dose of any other fentanyl product may result in a fatal overdose.

There are no conversion directions available for patients on any other fentanyl products. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) All patients should be titrated from the 100 mcg dose. Titrate each patient individually to provide adequate analgesia while minimizing side effects. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]

Patient/Caregiver Instructions

Patients and their caregivers must be instructed that SUBSYS contains a medicine in an amount which can be fatal to a child. Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. All used units should be disposed of immediately after use as they represent a special risk to children. [see HOW SUPPLIED/Storage and Handling, PATIENT INFORMATION, and Medication Guide].

Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.

SUBSYS could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.

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].

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.

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.

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.

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.

Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use SUBSYS with caution in patients with bradyarrhythmias.

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.

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], SUBSYS is available only through a restricted program under a REMS called the TIRF REMS ACCESS program. Under the TIRF REMS ACCESS program, outpatients, prescribers who prescribe to outpatients, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g. hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of SUBSYS, patient and prescriber enrollment is not required.

Required components of the TIRF REMS ACCESS program are:

  • Healthcare professionals who prescribe SUBSYS must review the prescriber educational materials for the TIRF REMS ACCESS program, enroll in the program, and agree to comply with the REMS requirements.
  • To receive SUBSYS, patients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
  • Pharmacies that dispense SUBSYS must enroll in the program and agree to comply with the REMS requirements.
  • Wholesalers and distributors that distribute SUBSYS must enroll in the program and distribute only to authorized pharmacies.

Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSaccess.com or by calling 1-866-822-1483.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Patient/Caregiver Instructions

Before initiating treatment with SUBSYS, explain the statements below to patients and/or caregivers. Instruct patients to read the Medication Guide each time SUBSYS is dispensed because new information may be available.

  • Outpatients must be enrolled in the TIRF REMS Access program before they can receive SUBSYS.
  • Allow patients the opportunity to ask questions and discuss any concerns regarding SUBSYS or the TIRF REMS Access program.
  • As a component of the TIRF REMS Access program, prescribers must review the contents of the SUBSYS Medication Guide with every patient before initiating treatment with SUBSYS.
  • Advise the patient that SUBSYS is available only from pharmacies that are enrolled in the TIRF REMS Access program, and provide them with the telephone number and website for information on how to obtain the drug.
  • Advise the patient that only enrolled healthcare providers may prescribe SUBSYS.
  • Patient must sign the Patient-Prescriber Agreement to acknowledge that they understand the risks of SUBSYS.
  • Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the TIRF REMS Access program.
  1. Patients and their caregivers must be instructed that children exposed to SUBSYS are at high risk OF FATAL RESPIRATORY DEPRESSION. Patients and their caregivers must be instructed to keep SUBSYS out of the reach of children [See HOW SUPPLIED/Storage and Handling, WARNINGS AND PRECAUTIONS and Medication Guide for specific patient instructions.]
  2. Provide patients and their caregivers with a Medication Guide each time SUBSYS is dispensed because new information may be available.
  3. Instruct patients and their caregivers to keep both used and unused dosage units out of the reach of children. Consumed units must be properly disposed of as soon as possible [see HOW SUPPLIED/Storage and Handling, WARNINGS AND PRECAUTIONS, and PATIENT INFORMATION].
  4. Instruct patients not to take SUBSYS for acute pain, postoperative pain, pain from injuries, headache, migraine or any other short-term pain, even if they have taken other opioid analgesics for these conditions.
  5. Instruct patients on the meaning of opioid tolerance and that SUBSYS is only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication, and who need additional opioid treatment of breakthrough pain episodes.
  6. Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take SUBSYS.
  7. Instruct patients that, if the breakthrough pain episode is not relieved 30 minutes after administration, they may take ONLY ONE ADDITIONAL DOSE OF SUBSYS USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take no more than two doses of SUBSYS for any breakthrough pain episode.
  8. Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with SUBSYS.
  9. Instruct patients NOT to share SUBSYS and that sharing SUBSYS with anyone else could result in the other individual's death due to overdose.
  10. Make patients aware that SUBSYS contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
  11. Instruct patients that the active ingredient in SUBSYS, fentanyl, is a drug that some people abuse. SUBSYS should be taken only by the patient it was prescribed for, and it should be protected from theft or misuse in the work or home environment.
  12. Caution patients to talk to their doctor if breakthrough pain is not alleviated or worsens after taking SUBSYS.
  13. Instruct patients to use SUBSYS exactly as prescribed by their doctor and not to take SUBSYS more often than prescribed.
  14. Caution patients that SUBSYS can affect a person's ability to perform activities that require a high level of attention (such as driving or using heavy machinery). Warn patients taking SUBSYS of these dangers and counsel them accordingly.
  15. Warn patients to not combine SUBSYS with alcohol, sleep aids, or tranquilizers except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.
  16. Inform female patients that if they become pregnant or plan to become pregnant during treatment with SUBSYS, they should ask their doctor about the effects that SUBSYS (or any medicine) may have on them and their unborn children.
SUBSYS Child Safety Kit

Provide patients and their caregivers with a SUBSYS Child Safety Kit. The kit consists of a portable carrying case, a lock for the bag and contains a package of cabinet and drawer child safety latches for securing the storage space at home to help patients store SUBSYS and other medicines out of the reach of children. To obtain a supply of Child Safety Kits, health care professionals can call Insys Therapeutics, Inc., at 1-877-978-2797.

Disposal Of Used SUBSYS Unit Dose Systems

Patients must be instructed to safely dispose of used SUBSYS units.

  1. After administration of SUBSYS, place the used spray unit into one of the disposable bags provided with your prescription.
  2. Seal the bag and discard into a trash container out of the reach of children.
Disposal Of Unopened SUBSYS Unit Dose Systems When No Longer Needed

Patients and members of their household must be advised to dispose of any unopened units remaining from a prescription as soon as they are no longer needed.

To dispose of the unopened SUBSYS units:

  1. Using a pair of scissors, cut the blister package on the line marked by an image of a pair of scissors and the instruction “cut to open” printed on the blister. Peel back the blister material to remove the SUBSYS unit from the package.
  2. Remove a charcoal-lined disposal pouch from the aluminum foil package by tearing open the package at the notch.
  3. Hold the charcoal-lined disposal pouch with the opening facing up. Put the nozzle of the SUBSYS spray unit upside-down into the opening of the charcoal-lined disposal pouch.
  4. Squeeze your fingers and thumb together to spray SUBSYS into the charcoal-lined disposal pouch.
  5. Dispose of the empty spray unit in a disposal bag.
  6. Repeat the above steps for each unused SUBSYS spray unit. The charcoallined disposal pouch may be used for disposing of the contents of up to 10 spray units. Make sure all unused spray units have been sprayed into a charcoal-lined disposal pouch.
  7. To seal a used charcoal-lined disposal pouch, remove the backing from the adhesive strip. Fold the flap down and press to seal the charcoal-lined disposal pouch.
  8. Place the sealed charcoal-lined disposal pouch into a disposal bag.
  9. To seal the disposal bag, remove the backing from the adhesive strip. Fold the flap down and press to seal.
  10. Discard the sealed disposal bag in the trash out of the reach of children.

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.

In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Insys Therapeutics, Inc. (1-877-978-2797) or seek assistance from their local DEA office.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fentanyl.

Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. typhimurium or E. coli or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay.

Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg intravenously and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for SUBSYS.

Use In Specific Populations


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.

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.

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.

Pediatric Use

Safety and efficacy in pediatric patients below the age of 18 years have not been established.

Geriatric Use

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 CNS effects when titrating SUBSYS in elderly patients.

Patients With Renal Or Hepatic Impairment

Insufficient information exists to make recommendations regarding the use of SUBSYS in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via the human CYP450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, monitor patients closely for signs of respiratory and central nervous system depression.


Both male and female opioid tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant gender differences were noted either in dosage requirement or in observed adverse reactions.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 2/25/2016


Report Problems to the Food and Drug Administration


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Get the latest treatment options.