Included as part of the PRECAUTIONS section.
See BOXED WARNING - WARNINGS: IMPORTANCE
OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE
Hypoventilation (Respiratory Depression)
Serious or fatal respiratory depression can occur even at
recommended doses in patients using ABSTRAL. Respiratory depression is more
likely to occur in patients with underlying respiratory disorders and elderly
or debilitated patients, usually following large initial doses, including
ABSTRAL, 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
ABSTRAL And Other Fentanyl Products
ABSTRAL is NOT equivalent to all other fentanyl products
used to treat breakthrough pain on a mcg per mcg basis. There are differences
in the pharmacokinetics of ABSTRAL relative to other fentanyl products which
could potentially result in clinically important differences in the amount of
fentanyl absorbed and could result in a fatal overdose.
When prescribing ABSTRAL to a patient, DO NOT convert on
a mcg to mcg basis from other fentanyl products. Directions for safely
converting patients to ABSTRAL from other fentanyl products are not currently
available except for Actiq [see Conversion from Actiq ]. This includes
oral, transdermal, or parenteral formulations of fentanyl. Therefore, for
opioid-tolerant patients starting treatment for breakthrough pain, the initial
dose of ABSTRAL is 100 mcg. Individually titrate each patient's dose to provide
adequate analgesia while minimizing side effects. [See DOSAGE AND
When dispensing ABSTRAL to a patient, DO NOT substitute
it for any other fentanyl product prescription.
Patients and their caregivers must be instructed that
ABSTRAL contains a medicine in an amount which can be fatal to a child. Even
though ABSTRAL is provided in child-resistant packaging, patients and their
caregivers must be instructed to keep tablets out of the reach of children.
[see HOW SUPPLIED/Storage and Handling, and PATIENT INFORMATION].
Taking ABSTRAL could be fatal in individuals for whom
it is not prescribed and for those who are not opioid-tolerant.
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 ABSTRAL 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 potent inhibitors of cytochrome P450 3A4 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 and the dose of ABSTRAL adjusted, 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 ABSTRAL of these
dangers and counsel them accordingly.
Chronic Pulmonary Disease
Because potent opioids can cause hypoventilation, titrate
ABSTRAL 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 ABSTRAL may further decrease
respiratory drive to the point of respiratory failure.
Head Injuries And Increased Intracranial Pressure
Administer ABSTRAL 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; use only if clinically warranted.
Intravenous administration of fentanyl may produce
bradycardia. Therefore, use ABSTRAL with caution in patients with
ABSTRAL is not recommended for use in patients who have
received MAO inhibitors within the past 14 days. 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], ABSTRAL is available only
through a restricted program called the TIRF REMS Access program. Under the
TIRF REMS Access program, outpatients, healthcare professionals 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 ABSTRAL, patient and prescriber
enrollment is not required.
Required components of the TIRF REMS Access program are:
- Healthcare professionals who prescribe ABSTRAL must
review the prescriber educational materials for the TIRF REMS Access program,
enroll in the program, and comply with the REMS requirements.
- To receive ABSTRAL, outpatients must understand the risks
and benefits and sign a Patient-Prescriber Agreement.
- Pharmacies that dispense ABSTRAL must enroll in the
program and agree to comply with the REMS requirements.
- Wholesalers and distributors that distribute ABSTRAL 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)
- Before initiating treatment
with Abstral, explain the statements below to patients and/or caregivers.
Instruct patients to read the Medication Guide each time Abstral 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 Abstral.
- Allow patients the opportunity
to ask questions and discuss any concerns regarding Abstral or the TIRF REMS
- As a component of the TIRF REMS Access program,
prescribers must review the contents of the Abstral Medication Guide with every
patient before initiating treatment with Abstral.
- Advise the patient that Abstral 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
- Advise the outpatient that only enrolled health care
providers may prescribe Abstral.
- Patient must sign the Patient-Prescriber Agreement to
acknowledge that they understand the risks of Abstral.
- 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 ABSTRAL
contains medicine in an amount that could be fatal in children, in individuals
for whom ABSTRAL is not prescribed, and in those who are not opioid tolerant. Patients
and their caregivers must be instructed to keep ABSTRAL, both used and unused
dosage units, out of the reach of children. Patients and their caregivers must
be instructed to dispose of any unneeded tablets remaining from a prescription
as soon as possible [see HOW SUPPLIED/Storage and Handling, and WARNINGS
- Instruct patients and their caregivers to read the
Medication Guide each time ABSTRAL is dispensed because new information may be
- Instruct patients not to take Abstral 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
Abstral 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 Abstral.
- You must not take more than 2 doses of ABSTRAL for each
episode of breakthrough cancer pain.
- You must wait two hours before treating a new episode of
breakthrough pain with ABSTRAL.
- Instruct patients NOT to share Abstral and that sharing
Abstral with anyone else could result in the other individual's death due to
- Advise patients that Abstral contains fentanyl, which is
a pain medication similar to hydromorphone, methadone, morphine, oxycodone, and
- Advise patients that the active ingredient in Abstral,
fentanyl, is a drug that some people abuse. Abstral 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 Abstral.
- Instruct patients to use Abstral exactly as prescribed by
their doctor and not to take Abstral more often than prescribed.
- Caution patients that Abstral 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 Abstral of these
dangers and counsel accordingly.
- Warn patients not to combine Abstral 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 Abstral to ask their doctor about
the effects that Abstral (or any medicine) may have on them and their unborn
Disposal of Unopened ABSTRAL Blister Packages When No
- Advise patients and their household members to dispose of
any unopened packs remaining from a prescription as soon as they are no longer
- Instruct patients that, to dispose of any unused ABSTRAL
tablets, remove them from the blister cards and flush them down the toilet. Do
not dispose of the ABSTRAL blister cards or cartons down the toilet.
- Detailed instructions for the proper storage,
administration, disposal, and important instructions for managing an overdose
of ABSTRAL are provided in the ABSTRAL Medication Guide. Ensure patients 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 units that remain in the home after the drug
is no longer needed, instruct them to call the toll-free number for Galena
Biopharma, Inc. 1-888-227-8725 or seek assistance from their local 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 micronucleus
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 ABSTRAL.
Use In Specific Populations
There are no adequate and well-controlled studies in
Use ABSTRAL 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 intravenously or 160 mcg/kg
subcutaneously. Conversion to human equivalent doses indicates this is within the
range of the human recommended dosing for ABSTRAL.
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 6times the human dose of 800 mcg
per pain episode on a mcg/m² basis). Intravenous administration of
fentanyl (10 mcg/kg or 30 mcg/kg) to pregnant female rats from gestation day 6
to 18, was embryo- or feto-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 crosses the placenta. Therefore do not
use ABSTRAL during labor and delivery (including caesarean section) since it
may cause respiratory depression in the fetus or in the newborn infant.
Fentanyl is excreted in human milk; therefore, do not use
ABSTRAL in women who are nursing 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 ABSTRAL.
The safety and efficacy of ABSTRAL have not been
established in patients below 18 years of age.
Of the 270 opioid tolerant patients with breakthrough
cancer pain in the Phase 3 clinical studies of Abstral, 58 (21%) 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 ABSTRAL clinical trials.
Elderly patients have been shown to be more sensitive to
the effects of fentanyl when administered intravenously, compared with the
younger adult population. Therefore, exercise caution when individually
titrating ABSTRAL in elderly patients to provide adequate efficacy while
Patients With Renal And Hepatic Impairment
Insufficient information exists to make recommendations regarding
the use of ABSTRAL in patients with impaired renal or hepatic function.
Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme
system and the inactive metabolite is mostly eliminated in urine. If the drug
is used in these patients, use the drug with caution because of the reduced
hepatic metabolism and renal excretion capacity in such patients.
Both male and female opioid-tolerant cancer patients were
studied for the treatment of breakthrough cancer pain. No clinically relevant
gender differences were noted either in efficacy or in observed adverse