Included as part of the PRECAUTIONS section.
See BOXED WARNING - WARNING: RISK OF
RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL
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.
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
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
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.
Intravenous fentanyl may produce bradycardia. Therefore,
use Onsolis with caution in patients with bradyarrhythmias.
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
Patient Counseling Information
See FDA-Approved patient
labeling (Medication Guide).
- 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
- 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
- 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
- Instruct that if they are not taking an opioid medication
on a regular around-the-clock basis, they must not take Onsolis.
patients NOT to share Onsolis and that sharing Onsolis with anyone else could
result in the other individual's death due to overdose.
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.
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
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
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.
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
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
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
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
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
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.
Safety and efficacy in pediatric patients below the age
of 18 years have not been established.
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.