Included as part of the PRECAUTIONS section.
See BOXED WARNING
Respiratory depression is the chief hazard of opioid
agonists, including fentanyl, the active ingredient in FENTORA. 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
FENTORA is not bioequivalent with other fentanyl
products. Do not convert patients on a mcg per mcg basis from other fentanyl
products. There are no conversion directions available for patients on any
other fentanyl products other than Actiq. (Note: This includes oral,
transdermal, or parenteral formulations of fentanyl.) For patients being
converted from Actiq, it is necessary to follow the instructions found in Table
1 in Section 2.1, as Actiq and FENTORA are not equivalent on a microgram
per microgram basis. FENTORA is NOT a generic version of Actiq. All patients
should be titrated from the 100 mcg dose.
The initial dose of FENTORA should be 100 mcg. Titrate
each patient individually to provide adequate analgesia while minimizing side
effects. [see DOSAGE AND ADMINISTRATION]
When dispensing, DO NOT substitute a FENTORA
prescription for an Actiq prescription under any circumstances. FENTORA and
Actiq are not equivalent. Substantial differences exist in the
pharmacokinetic profile of FENTORA compared to other fentanyl products
including Actiq 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 FENTORA for the same dose of Actiq or any
other fentanyl product may result in a fatal overdose.
Patients and their caregivers must be instructed that
FENTORA contains a medicine in an amount which can be fatal to a child. Patients
and their caregivers must be instructed to keep tablets out of the reach of
children. [see HOW SUPPLIED/Storage and Handling]
Additive CNS Depressant Effects
The concomitant use of FENTORA 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. Consideration should be given to adjusting the
dose of FENTORA 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 FENTORA of these
dangers and counsel them accordingly.
Chronic Pulmonary Disease
Because potent opioids can cause respiratory depression,
titrate FENTORA with caution in patients with chronic obstructive pulmonary
disease or pre-existing medical conditions predisposing them to respiratory
depression. In such patients, even normal therapeutic doses of FENTORA may
further decrease respiratory drive to the point of respiratory failure.
Head Injuries and Increased Intracranial Pressure
Administer FENTORA 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.
Application Site Reactions
In clinical trials, 10% of all patients exposed to
FENTORA reported application site reactions. These reactions ranged from
paresthesia to ulceration and bleeding. Application site reactions occurring in
≥ 1% of patients were pain (4%), ulcer (3%), and irritation (3%).
Application site reactions tended to occur early in treatment were self-limited
and only resulted in treatment discontinuation for 2% of patients.
Intravenous fentanyl may produce bradycardia. Therefore,
use FENTORA with caution in patients with bradyarrhythmias.
FENTORA 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], FENTORA is available only
through a restricted program called the TIRF REMS Access program. Under the
TIRF REMS Access program, outpatients, healthcare professionals who prescribe
for outpatient use, 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 FENTORA, patient and prescriber
enrollment is not required.
Required components of the TIRF REMS Access program are:
- Healthcare professionals, who prescribe FENTORA for outpatient
use, must review the prescriber educational materials for the TIRF REMS Access
program, enroll in the program, and comply with the REMS requirements.
- To receive FENTORA, outpatients must understand the risks
and benefits and sign a Patient-Prescriber Agreement.
- Pharmacies that dispense FENTORA must enroll in the
program and agree to comply with the REMS requirements.
- Wholesalers and distributors that distribute FENTORA 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 FENTORA, explain the
statements below to patients and/or caregivers. Instruct patients to read the
Medication Guide each time FENTORA is dispensed because new information may be
- TIRF REMS Access Program
- Outpatients must be enrolled in the TIRF REMS Access
program before they can receive FENTORA.
- Allow patients the opportunity to ask questions and
discuss any concerns regarding FENTORA or the TIRF REMS Access program.
- As a component of the TIRF REMS Access program,
prescribers must review the contents of the FENTORA Medication Guide with every
patient before initiating treatment with FENTORA.
- Advise the patient that FENTORA 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 patient that only enrolled healthcare
providers may prescribe FENTORA.
- Patient must sign the Patient-Prescriber Agreement to
acknowledge that they understand the risks of FENTORA.
- Advise patients that they may be requested to participate
in a survey to evaluate the effectiveness of the TIRF REMS Access program.
- Patients and their caregivers must be instructed that
children, especially small children, exposed to FENTORA are at high risk of
FATAL RESPIRATORY DEPRESSION. Patients and their caregivers must be
instructed to keep FENTORA tablets out of the reach of children. [see HOW
SUPPLIED/Storage and Handling and WARNINGS AND PRECAUTIONS]
- Instruct patients not to take FENTORA 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
that FENTORA 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
- Instruct patients that, if they are not taking an opioid
medication on a scheduled basis (around-the-clock), they should not take
- Instruct patients that the titration phase is the only
period in which they may take more than ONE tablet to achieve a desired dose
(e.g., two 100 mcg tablets for a 200 mcg dose).
- Instruct patients that, if the breakthrough pain episode
is not relieved after 30 minutes, they may take ONLY ONE ADDITIONAL DOSE OF
FENTORA USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should
take a maximum of two doses of FENTORA for any breakthrough pain episode.
- Instruct patients that they MUST wait at least 4 hours
before treating another episode of breakthrough pain with FENTORA.
- Instruct patients NOT to share FENTORA and that sharing
FENTORA with anyone else could result in the other individual's death due to
- Make patients aware that FENTORA contains fentanyl which
is a strong pain medication similar to hydromorphone, methadone, morphine,
oxycodone, and oxymorphone.
- Instruct patients that the active ingredient in FENTORA,
fentanyl, is a drug that some people abuse. FENTORA 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.
- Instruct patients not to open the blister until ready to
use FENTORA and not to store the tablet in a temporary container such as a pill
box, once it has been removed from the blister package.
- Instruct patients that FENTORA tablets are not to be
swallowed whole; this will reduce the effectiveness of the medication. Tablets
are to be placed between the cheek and gum above a molar tooth or under the
tongue and allowed to dissolve. After 30 minutes if remnants of the tablet
still remain, patients may swallow it with a glass of water.
- Caution patients to talk to their doctor if breakthrough
pain is not alleviated or worsens after taking FENTORA.
- Instruct patients to use FENTORA exactly as prescribed by
their doctor and not to take FENTORA more often than prescribed.
- Caution patients that FENTORA 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 FENTORA of these
dangers and counsel them accordingly.
- Warn patients to not combine FENTORA 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
- Inform female patients that if they become pregnant or
plan to become pregnant during treatment with FENTORA, they should ask their
doctor about the effects that FENTORA (or any medicine) may have on them and their
- 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 Unopened FENTORA Blister Packages When No
Patients and members of their household must be advised
to dispose of any unopened blister packages remaining from a prescription as
soon as they are no longer needed.
To dispose of unused FENTORA, remove FENTORA tablets from
blister packages and flush down the toilet. Do not flush the FENTORA blister
packages or cartons down the toilet.
Detailed instructions for the proper storage,
administration, disposal, and important instructions for managing an overdose
of FENTORA are provided in the FENTORA Medication Guide. Instruct patients to
read this information in its entirety and provide an opportunity to have their
In the event that a caregiver requires additional
assistance in disposing of excess unusable tablets that remain in the home
after a patient has expired, instruct them to call the Teva Pharmaceuticals
toll-free number (1-800-8965855) or seek assistance from their local DEA
Carcinogenesis, Mutagenesis, Impairment of Fertility
Fentanyl was evaluated for carcinogenic potential in a
104-week rat study and in a 6-month Tg.AC transgenic mouse study. In rats,
doses up to 50 mcg/kg in males and 100 mcg/kg in females were administered
subcutaneously and no treatment-related neoplasms were observed (doses are
equivalent to 2.3- and 3.4-times the exposure of a single human dose of 800 mcg
per pain episode, respectively, based on an AUC comparison). In mice, at
topical doses up to 50 mcg/dose/day, no increase in the occurrence of
treatment-related neoplasms was observed.
Fentanyl citrate was not mutagenic in the Ames reverse
mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis
assay. Fentanyl citrate was not clastogenic in the in vivo mouse micronucleus
Impairment of Fertility
In a fertility study, female rats were administered
fentanyl subcutaneously for 14 days prior to mating with untreated males at
doses up to 300 mcg/kg and no effects on female fertility were observed. The
systemic exposure at the dose of 300 mcg/kg was approximately 8.6-times the
exposure of a single human dose of 800 mcg per pain episode, based on an AUC
comparison. Males were administered fentanyl subcutaneously for 28 days prior
to mating with untreated females at doses up to 300 mcg/kg. At 300 mcg/kg, adverse
effects on sperm parameters, which affected fertility, were observed. These
effects included decreased percent mobile sperm, decreased sperm concentrations
as well as an increase in the percent abnormal sperm. The dose in males at
which no effects on fertility were observed was 100 mcg/kg, which is
approximately 5.7- times the exposure of a single human dose of 800 mcg per
pain episode, based on an AUC comparison.
Use In Specific Populations
Pregnancy – Category C
There are no adequate and well-controlled studies in
pregnant women. FENTORA 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 characteristic of neonatal abstinence syndrome in newborn infants.
Symptoms of neonatal respiratory or neurological depression were no more
frequent than expected in most studies of infants born to women treated acutely
during labor with intravenous or epidural fentanyl. Transient neonatal muscular
rigidity has been observed in infants whose mothers were treated with
Fentanyl is embryocidal 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 FENTORA.
Fentanyl (25, 50 or 100 mcg/kg) was administered
subcutaneously to pregnant rats during the period of organogenesis (Gestation
Day, GD 6-17). Maternal toxicity and a decrease in fetal weights were observed
at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is
equivalent to 1.4-times the exposure of a single human dose of 800 mcg per pain
episode, based on an AUC comparison). Fentanyl (50, 100 or 250 mcg/kg) was also
administered subcutaneously to pregnant rabbits during the period of
organogenesis (GD 6-18). Maternal toxicity was noted at doses > 100 mcg/kg.
No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to
7.5times the exposure of a single human dose of 800 mcg per pain episode, based
on an AUC comparison).
Published studies concur with the conducted studies
regarding the lack of teratogenic potential for fentanyl. One literature report
showed that administration of fentanyl (10, 100, or 500 mcg/kg) to pregnant
rats from GD 7-21, via implanted microosmotic minipumps, was not teratogenic
(the high dose was approximately 6-times the single human dose of 800 mcg per pain
episode on a mg/m² basis). Another report showed that intravenous
administration of fentanyl (10 or 30 mcg/kg) to pregnant rats from GD 6-18 was
embryotoxic in the 30 mcg/kg group, but was not teratogenic. Conversion to
human equivalent doses indicates this is within the range of the human
recommended dosing for FENTORA.
In a postnatal development study, pregnant rats were
treated from GD 6 through lactation day (LD) 20 with subcutaneous doses of
fentanyl (25, 50, 100 and 400 mcg/kg). Maternal toxicity was noted at doses
> 100 mcg/kg. A reduction in pup growth and delayed attainment of
developmental indices were observed at > 100 mcg/kg. No difference in the
number of live pups/litter was seen at birth, however, pup survival at LD 4 was
reduced to 48% at 400 mcg/kg and by LD 21 pup survival was reduced to 30% and
26% at 100 and 400 mcg/kg, respectively. During lactation, fentanyl-related
clinical signs (decreased activity, skin cold to touch, and moribund
appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg
group. Pups from this group also had significantly reduced body weights
throughout the lactation period. The dose of fentanyl administered to rats at
which no developmental toxicity in the F1 generation was seen was 50 mcg/kg
which is approximately equal the exposure of a single human dose of 800 mcg per
pain episode, based on an AUC comparison.
Labor and Delivery
Fentanyl readily passes across the placenta to the fetus;
therefore, do not use FENTORA for analgesia 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
FENTORA 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 FENTORA.
The safety and efficacy of FENTORA have not been
established in pediatric patients below the age of 18 years.
Of the 304 patients with cancer in clinical studies of
FENTORA, 69 (23%) were 65 years of age and older.
Patients over the age of 65 years tended to titrate to
slightly lower doses than younger patients.
Patients over the age of 65 years reported a slightly
higher frequency for some adverse events specifically vomiting, constipation,
and abdominal pain. Therefore, caution should be exercised in individually
titrating FENTORA in elderly patients to provide adequate efficacy while
Patients with Renal or Hepatic Impairment
Insufficient information exists to make recommendations
regarding the use of FENTORA in patients with impaired renal or hepatic
function. Fentanyl is metabolized primarily via human cytochrome P450 3A4
isoenzyme system and 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.
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.
The pharmacokinetic effects of race with the use of
FENTORA have not been systematically evaluated. In studies conducted in healthy
Japanese subjects, systemic exposure was generally higher than that observed in