April 27, 2017
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Included as part of the PRECAUTIONS section.



Respiratory Depression (Hypoventilation)

Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in Onsolis. 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.

Onsolis Dispensing

When dispensing, do not substitute an Onsolis prescription for any other fentanyl product. Substantial differences exist in the pharmacokinetic profile of Onsolis compared to other fentanyl products (e.g., see Figure 1) that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of Onsolis for any other fentanyl product may result in fatal overdose. Onsolis is NOT a generic version of any other transmucosal fentanyl product.

Patient/Caregiver Instructions

Patients and their caregivers must be instructed that Onsolis contains a medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid-tolerant. Patients and their caregivers must be instructed to keep Onsolis out of the reach of children. [see HOW SUPPLIED, Storage and Handling, and PATIENT INFORMATION].

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.

Additive CNS Depressant Effects

The concomitant use of Onsolis 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., hypoventilation, hypotension, and profound sedation). Concomitant use with inhibitors of the cytochrome P450 3A4 (CYP3A4) 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 Onsolis 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 Onsolis of these dangers and counsel them accordingly.

Chronic Pulmonary Disease

Because potent opioids can cause respiratory depression, titrate Onsolis with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to hypoventilation. In such patients, even normal therapeutic doses of Onsolis may further decrease respiratory drive to the point of respiratory failure.

Head Injuries And Increased Intracranial Pressure

Administer Onsolis 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 Onsolis with caution in patients with bradyarrhythmias.

MAO Inhibitors

Onsolis 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 for misuse, abuse, addiction, and overdose [see Drug Abuse and Dependence], Onsolis is available only through a restricted program 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 Onsolis, patient and prescriber enrollment is not required.

Required components of the TIRF REMS Access program are:

Healthcare professionals who prescribe Onsolis must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.

  • To receive Onsolis, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
  • Pharmacies that dispense Onsolis must enroll in the program and agree to comply with the REMS requirements.
  • Wholesalers and distributors that distribute Onsolis 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 ONSOLIS, explain the statements below to patients and/or caregivers. Instruct patients to read the Medication Guide each time ONSOLIS is dispensed because new information may be available.
  • TIRF REMS Access Program
    • Outpatients must be enrolled in the TIRF REMS Access program before they can receive Onsolis.
    • Allow patients the opportunity to ask questions and discuss any concerns regarding Onsolis or the TIRF REMS Access program.
    • As a component of the TIRF REMS Access program, prescribers must review the contents of the Onsolis Medication Guide with every patient before initiating treatment with Onsolis.
    • Advise the patient that Onsolis 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.
    • Patient must sign the Patient-Prescriber Agreement to acknowledge that they understand the risks of Onsolis.
    • Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the TIRF REMS Access Program.
  • Instruct patients and their caregivers that Onsolis contains medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. Patients and their caregivers must be instructed to keep Onsolis out of the reach of children. Patients and members of their household must be instructed to dispose of any unneeded films remaining from a prescription as soon as possible [see HOW SUPPLIED and Storage and Handling].
  • Instruct patients not to take Onsolis 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.
  • Instruct patients on the meaning of opioid tolerance and Onsolis is only to be used as a supplemental pain medication for patients with pain requiring regular opioids, who have developed tolerance to the opioid medication and who need additional opioid treatment of breakthrough pain episodes.
  • Instruct that if they are not taking an opioid medication on a regular around-the-clock basis, they must not take Onsolis.
  • Instruct patients NOT to share Onsolis and that sharing Onsolis with anyone else could result in the other individual's death due to overdose.
  • Advise patients that Onsolis contains fentanyl, which is a pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
  • Instruct patients that they must wait at least 2 hours before treating a new episode of breakthrough pain with Onsolis.
  • Advise patients that the active ingredient in Onsolis, fentanyl, is a drug that some people abuse. Onsolis is to be taken only by the patient for whom it was prescribed, and protected from theft or misuse in the work or home environments.
  • Instruct patients to talk to their doctor if breakthrough pain is not alleviated or worsens after taking Onsolis.
  • Instruct patients to use Onsolis exactly as prescribed by their doctor and not to take Onsolis more often than prescribed.
  • Caution patients that Onsolis 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 Onsolis of these dangers and counsel accordingly.
  • Warn patients not to combine Onsolis with alcohol, sleep aids, or tranquilizers except by order of the prescribing physician, because dangerous additive effects may occur resulting in serious injury or death.
  • Inform female patients that if they become pregnant or plan to become pregnant during treatment with Onsolis to ask their doctor about the effects that Onsolis (or any medicine) may have on them and their unborn 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.
Disposal Of Unneeded Onsolis Films

Patients and members of their household must be instructed on the safe disposal of any unneeded films remaining from a prescription as soon as they are no longer needed.

To dispose of the unneeded Onsolis films:

  • Remove the Onsolis film from its foil package.
  • Drop the Onsolis film into the toilet.
  • Repeat steps 1 and 2 for each Onsolis film. Flush the toilet after all unneeded films have been put into the toilet.

Do not flush the Onsolis foil packages or cartons down the toilet [see HOW SUPPLIED and Storage and Handling].

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of Onsolis are provided in the 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 unneeded films that remain in the home after a patient has expired, instruct them to call BioDelivery Sciences International, Inc. at 1-877-579-4578 or seek assistance from their local Drug Enforcement Agency (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 IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for Onsolis.

Use In Specific Populations

Pregnancy – Category C

There are no adequate and well-controlled studies in pregnant women.

Onsolis 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 IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for Onsolis.

Fentanyl citrate was not teratogenic when administered to pregnant animals. In published studies, pregnant rats were treated with fentanyl (10, 100, or 500 mcg/kg/day) via implanted microosmotic minipumps from Day 7 to 21 of their 21-day gestation period. Fentanyl was not teratogenic at doses up to 500 mcg/kg/day [approximately 3-times the maximum recommended human dose (MRHD) of 1200 mcg for Onsolis per breakthrough cancer pain episode]. 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 Onsolis during labor and delivery (including caesarean section) since it may cause respiratory depression in the fetus or in the newborn infant.

Nursing Mothers

Fentanyl is excreted in human milk; therefore, Onsolis should not be used 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 Onsolis.

Pediatric Use

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

Geriatric Use

Of the 306 opioid tolerant patients with breakthrough cancer pain in clinical studies of Onsolis, 98 (32.0%) were 65 years of age and older. There was no difference in the median titrated dose in patients aged 65 years and older compared to those < 65 years. No clinically meaningful difference was noted in the safety profile of the group 65 years of age and older as compared to younger patients in Onsolis 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, exercise caution when individually titrating Onsolis in elderly patients to provide adequate efficacy while minimizing risk.

Patients With Renal Or Hepatic Impairment

Insufficient information exists to make recommendations regarding the use of Onsolis in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via the human CYP3A4 isoenzyme system and the inactive metabolite is mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

It is recommended that Onsolis be titrated to clinical effect for all patients with special care taken in patients with severe renal or hepatic disease.


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: 1/11/2017


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