FENTORA Comprimé (effervescent)

Canada - français - Health Canada

Achète-le

Ingrédients actifs:
Fentanyl (Citrate de fentanyl)
Disponible depuis:
TEVA CANADA LIMITED
Code ATC:
N02AB03
DCI (Dénomination commune internationale):
FENTANYL
Dosage:
800MCG
forme pharmaceutique:
Comprimé (effervescent)
Composition:
Fentanyl (Citrate de fentanyl) 800MCG
Mode d'administration:
Buccale
Unités en paquet:
28
Type d'ordonnance:
Stupéfiant (LRCDAS I)
Domaine thérapeutique:
OPIATE AGONISTS
Descriptif du produit:
Numéro de groupe d'ingrédients actifs (GIA) :0123302020; AHFS: 28:08.08
Statut de autorisation:
APPROUVÉ
Numéro d'autorisation:
02408058
Date de l'autorisation:
2013-06-11

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FENTORA

Page 1 of 59

PRODUCT MONOGRAPH

INCLUDING PATIENT MEDICATION INFORMATION

N

FENTORA

TM

fentanyl citrate

Buccal/Sublingual Effervescent Tablets

100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg fentanyl

Opioid Analgesic

Date of Revision:

May 28, 2020

Distributed by:

Teva Canada Limited

Toronto, Ontario M1B 2K9

Manufactured for:

Teva Canada Innovation

Montréal, Quebec H2Z 1S8

Submission Control No:

236380

FENTORA

Page 2 of 59

TABLE OF CONTENTS

PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3

SUMMARY PRODUCT INFORMATION ........................................................................3

INDICATIONS AND CLINICAL USE ..............................................................................3

CONTRAINDICATIONS ...................................................................................................4

WARNINGS AND PRECAUTIONS ..................................................................................5

ADVERSE REACTIONS ..................................................................................................14

DRUG INTERACTIONS ..................................................................................................21

DOSAGE AND ADMINISTRATION ..............................................................................25

OVERDOSAGE ................................................................................................................30

ACTION AND CLINICAL PHARMACOLOGY ............................................................31

STORAGE AND STABILITY ..........................................................................................36

DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................36

PART II: SCIENTIFIC INFORMATION ...............................................................................38

PHARMACEUTICAL INFORMATION ..........................................................................38

CLINICAL TRIALS ..........................................................................................................39

DETAILED PHARMACOLOGY .....................................................................................41

TOXICOLOGY .................................................................................................................42

REFERENCES ..................................................................................................................46

PART III: PATIENT MEDICATION INFORMATION .......................................................47

FENTORA

Page 3 of 59

N

FENTORA

TM

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form / Strength

Nonmedicinal

Ingredients

Buccal or

Sublingual

Fentanyl tablets containing:

100 micrograms fentanyl (as 157 mcg fentanyl citrate)

200 micrograms fentanyl (as 314 mcg fentanyl citrate)

400 micrograms fentanyl (as 628 mcg fentanyl citrate)

600 micrograms fentanyl (as 943 mcg fentanyl citrate)

800 micrograms fentanyl (as 1257 mcg fentanyl citrate)

citric acid,

magnesium

stearate, mannitol,

sodium bicarbonate,

sodium carbonate,

sodium starch

glycolate

INDICATIONS AND CLINICAL USE

Adults

FENTORA is indicated only for the management of breakthrough pain in cancer patients 18

years of age and older who are already receiving and who are tolerant to continuous opioid

therapy for their persistent baseline cancer pain.

Patients considered opioid tolerant are those who are taking at least 60 mg of oral morphine daily

or an equianalgesic dose of another opioid daily for a week or longer (see

WARNINGS AND

PRECAUTIONS

All patients starting treatment with FENTORA must begin with titration from the 100 mcg dose

(see

DOSAGE AND ADMINISTRATION

This product

must not

be used in opioid non-tolerant patients because life-threatening

respiratory depression and death could occur at any dose in patients not on a chronic regimen of

opioids. For this reason, FENTORA is contraindicated in the management of acute or post-

operative pain, including headache/migraine, dental pain or use in the emergency room.

Note: FENTORA is contraindicated in all post-operative pain, including post-operative cancer

pain if the patient is not already opioid tolerant. The addition of the qualifier “non cancer” may

be confusing as it could be interpreted to mean that FENTORA can be used for post-operative

pain after surgery for cancer or post-operatively for cancer pain, both of which can occur in

opioid non-tolerant patients. The term “post-operative” already implies that the pain is due to

surgery and not to cancer.

FENTORA is intended to be used only in the care of opioid tolerant cancer patients and only by

FENTORA

Page 4 of 59

healthcare professionals who are knowledgeable of and skilled in the use of opioids to treat

cancer pain.

Geriatrics (> 65 years of age):

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

minimizing risk.

In general, dose selection for an elderly patient should be cautious, reflecting the greater

frequency of decreased hepatic, renal, or cardiac function, concomitant disease or other drug

therapy (see

ACTION AND CLINICAL PHARMACOLOGY, Special Populations and

Conditions, Geriatrics

Pediatrics (< 18 years of age)

The safety and efficacy of FENTORA has not been studied in the pediatric population. Therefore

the use of FENTORA is not recommended in patients under 18 years of age.

CONTRAINDICATIONS

Opioid non-tolerant patients (use in acute or post-operative pain, including

headache/migraine, dental pain or use in the emergency room).

Patients who are hypersensitive to the active substance, fentanyl citrate, or other opioid

analgesics or to any ingredient in the formulation. For a complete listing, see the

DOSAGE

FORMS, COMPOSITION AND PACKAGING

section of the Product Monograph.

Anaphylaxis and hypersensitivity have been reported in association with the use of oral

transmucosal fentanyl products.

Patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel

obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any

type).

Patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).

Patients with acute or severe bronchial asthma, chronic obstructive airway, or status

asthmaticus.

Patients with acute respiratory depression, elevated carbon dioxide levels in the blood and

cor pulmonale.

Patients with acute alcoholism, delirium tremens, and convulsive disorders.

Patients with severe CNS depression, increased cerebrospinal or intracranial pressure, and

head injury.

Patients taking monoamine oxidase (MAO) inhibitors (or within 14 days of such therapy).

FENTORA

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WARNINGS AND PRECAUTIONS

SERIOUS WARNINGS AND PRECAUTIONS

Proper Patient Selection

FENTORA (fentanyl buccal/sublingual effervescent tablets) is intended to be used

only in the care of opioid tolerant patients with cancer and only by healthcare

professionals who are knowledgeable of, and skilled in, the use of opioids to treat

cancer pain.

FENTORA is an opioid analgesic indicated only for the management of

breakthrough pain in cancer patients 18 years of age and older who are already

receiving and who are tolerant to continuous opioid therapy for their persistent

baseline cancer pain.

Patients considered opioid-tolerant are those who have taken at

least 60 mg of oral morphine daily, at least 25 mcg/hr of transdermal fentanyl, at least 30

mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral

oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer.

FENTORA is contraindicated for use in opioid non-tolerant patients including those

using opioids intermittently, on an as needed basis.

Fentanyl products which are designed to manage breakthrough pain, including

FENTORA, should not be used in patients who are receiving partial opioid agonists

such as buprenorphine or agents with some opioid effects such as tramadol (see

DRUG INTERACTIONS, Drug-Drug Interactions).

Addiction, Abuse, and Misuse

FENTORA poses risks of opioid addiction, abuse, and misuse, which can lead to

overdose and death. Each patient's risk should be assessed prior to prescribing

FENTORA, and all patients should be monitored regularly for the development of

these behaviours or conditions (see WARNINGS AND PRECAUTIONS). FENTORA

should be stored securely to avoid theft or misuse.

Life-threatening Respiratory Depression: OVERDOSE

Fatal respiratory depression has occurred in patients treated with FENTORA,

including following use in opioid non-tolerant patients and improper dosing. The

substitution of FENTORA for any other fentanyl product may result in fatal

overdose. Infants exposed in-utero or through breast milk are at risk of life-

threatening respiratory depression upon delivery or when nursed. Patients should be

monitored for respiratory depression, especially during initiation of FENTORA or

following a dose increase.

FENTORA

Page 6 of 59

SERIOUS WARNINGS AND PRECAUTIONS

Due to the risk of respiratory depression, in opioid non-tolerant patients, FENTORA

is contraindicated in the management of acute or post-operative pain, including

headache/migraine, dental pain, or use in the emergency room.

Special care must be used when dosing with FENTORA. If the breakthrough pain

episode is not relieved, patients should wait at least 4 hours before taking another

dose (see DOSAGE AND ADMINISTRATION).

The concomitant use of FENTORA with cytochrome P450 3A4 inhibitors may result

in an increase in fentanyl plasma concentrations, and may cause potentially fatal

respiratory depression (see DRUG INTERACTIONS, Drug-Drug Interactions).

Accidental Exposure

Accidental ingestion of even one dose of FENTORA, especially by children, can result

in a fatal overdose of fentanyl (see DOSAGE AND ADMINISTRATION, Disposal,

for instructions on proper disposal).

Neonatal Opioid Withdrawal Syndrome

Prolonged maternal use of FENTORA during pregnancy can result in neonatal

opioid withdrawal syndrome, which may be life-threatening (see WARNINGS AND

PRECAUTIONS).

Interaction with Alcohol

The co-ingestion of alcohol with FENTORA should be avoided as it may result in

dangerous additive effects, causing serious injury or death (see WARNINGS AND

PRECAUTIONS and DRUG INTERACTIONS).

Medication Errors

When prescribing, do not convert patients on a mcg per mcg basis from any other

transmucosal fentanyl product to FENTORA. If patients are using other opioid-

containing products for breakthrough pain, they MUST be started on FENTORA at

the initial dose of 100 mcg.

Regardless of the opioid dose used for the baseline cancer pain, patients beginning

treatment with FENTORA must begin with titration from the 100 mcg dose (see

DOSAGE AND ADMINISTRATION).

When dispensing, do not substitute a FENTORA prescription for any other fentanyl

product. Substantial differences exist in the pharmacokinetic profile of FENTORA

compared to other fentanyl products that result in clinically important differences in

the extent of absorption of fentanyl. As a result of these differences, the substitution

of FENTORA for any other fentanyl product may result in fatal overdose.

FENTORA is NOT a generic version of any other fentanyl product.

FENTORA

Page 7 of 59

SERIOUS WARNINGS AND PRECAUTIONS

Patients and their caregivers must be instructed that FENTORA contains a medicine

in an amount which can be fatal to children, in individuals for whom it is not

prescribed, and in those who are not opioid tolerant. All units must be kept out of the

reach and sight of children and opened units properly discarded.

Further, instruct patients of the hazards related to taking opioids including fatal

overdose.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system

(CNS) depressants, including alcohol, may result in profound sedation, respiratory

depression, coma, and death (see WARNINGS AND PRECAUTIONS, Neurologic

and DRUG INTERACTIONS).

Reserve concomitant prescribing of FENTORA and benzodiazepines or other CNS

depressants for use in patients for whom alternative treatment options are

inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

General

It is important that the continuous opioid treatment used to treat the patient's persistent pain has

been stabilized before starting FENTORA therapy. In cases where patients regularly experience

more than 4 breakthrough pain episodes per day, increasing the opioid maintenance dose has to

be considered before starting the titration process.

Patients should be instructed not to give FENTORA (fentanyl) tablets to anyone other than

the patient for whom it was prescribed, as such inappropriate use may have severe medical

consequences, including death. FENTORA should be stored securely to avoid theft or

misuse.

FENTORA should only be prescribed by persons knowledgeable in the continuous

administration of potent opioids, in the management of patients receiving potent opioids

for the treatment of pain, and in the detection and management of respiratory depression,

including the use of opioid antagonists.

Patients should be cautioned not to consume alcohol while taking

FENTORA

as it may increase

the chance of experiencing serious adverse events, including death.

Hyperalgesia that will not respond to a further dose increase of fentanyl can occur at particularly

high doses. A fentanyl dose reduction or change in opioid may be required.

Abuse and Misuse

Like all opioids,

FENTORA

is a potential drug of abuse and misuse, which can lead to overdose

FENTORA

Page 8 of 59

and death. Therefore,

FENTORA

should be prescribed and handled with caution.

All patients receiving opioids should be routinely monitored for signs of misuse and abuse.

Opioids, such as

FENTORA

, should be used with particular care in patients with a history of

alcohol and illicit/prescription drug abuse. However, concerns about abuse, addiction, and

diversion should not prevent the proper management of pain.

FENTORA

is intended for oral use only. The tablets should be placed between the cheek and

gum, or under the tongue, and allowed to dissolve (see

DOSAGE AND ADMINISTRATION

Administration of FENTORA). Abuse of oral dosage forms can be expected to result in serious

adverse events, including death.

Carcinogenesis and Mutagenesis

TOXICOLOGY

section.

Cardiovascular

Fentanyl administration may result in severe hypotension in patients whose ability to maintain

adequate blood pressure is compromised by reduced blood volume, or concurrent administration

of drugs such as phenothiazines and other tranquilizers, sedative/hypnotics, tricyclic

antidepressants or general anesthetics. These patients should be monitored for signs of

hypotension after initiating or titrating the dose of FENTORA.

The use of

FENTORA

in patients with circulatory shock should be avoided as it may cause

vasodilation that can further reduce cardiac output and blood pressure.

Intravenous fentanyl may produce bradycardia. Therefore, use

FENTORA

with caution in

patients with bradyarrhythmias.

Dependence/Tolerance

As with other opioids, tolerance and physical dependence may develop upon repeated

administration of FENTORA and there is a potential for development of psychological

dependence.

Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic

exposure to an opioid, and are separate and distinct from abuse and addiction. Tolerance, as well

as physical dependence, may develop upon repeated administration of opioids, and are not by

themselves evidence of an addictive disorder or abuse.

Patients on prolonged therapy should be tapered gradually from the drug if it is no longer

required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of

therapy or upon administration of an opioid antagonist. Some of the symptoms that may be

associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea,

gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing,

tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in

sweating, palpitations, unexplained fever, weakness and yawning (see

ADVERSE

FENTORA

Page 9 of 59

REACTIONS, DOSAGE AND ADMINISTRATION, Adjustment or Reduction of Dosage

The administration of FENTORA should be guided by the response of the patient. Physical

dependence, per se, is not ordinarily a concern when one is treating a patient with cancer and

chronic pain, and fear of tolerance and physical dependence should not deter using doses that

adequately relieve the pain.

Use in Drug and Alcohol Addiction

FENTORA is an opioid with no approved use in the management of addictive disorders. Its

proper usage in individuals with drug or alcohol dependence, either active or in remission, is for

the management of breakthrough cancer pain requiring opioid analgesia. Patients with a history

of addiction to drugs or alcohol may be at higher risk of becoming addicted to FENTORA;

extreme caution and awareness is warranted to mitigate the risk.

Gastrointestinal Effects

FENTORA and other morphine-like opioids have been shown to decrease bowel motility.

Fentanyl may obscure the diagnosis or clinical course of patients with acute abdominal

conditions (see

CONTRAINDICATIONS

Neonatal Opioid Withdrawal Syndrome (NOWS)

Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the

neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults,

may be life-threatening.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep

pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset,

duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid

used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug

by the newborn.

FENTORA is not recommended to be used in pregnant women unless, in the judgement of the

physician, the potential benefits outweigh the risks. If FENTORA was used during pregnancy,

special attention to NOWS is warranted.

Neurologic

Serotonin toxicity / Serotonin syndrome:

Serotonin toxicity, also known as serotonin syndrome, is a potentially life-threatening condition

and has been reported with opioids, including FENTORA, particularly during combined use with

other serotonergic drugs. (See

DRUG INTERACTIONS

Serotonin toxicity is characterised by neuromuscular excitation, autonomic stimulation (e.g.

tachycardia, flushing) and altered mental state (e.g. anxiety, agitation, hypomania). In

accordance with the Hunter Criteria, serotonin toxicity diagnosis is likely when, in the presence

of at least one serotonergic agent, one of the following is observed:

Spontaneous clonus

Inducible clonus or ocular clonus with agitation or diaphoresis

FENTORA

Page 10 of 59

Tremor and hyperreflexia

Hypertonia and body temperature >38°C and ocular clonus or inducible clonus.

If concomitant treatment with FENTORA and other serotonergic agents is clinically warranted,

careful observation of the patient is advised, particularly during treatment initiation and dose

increases (see

DRUG INTERACTIONS

). If serotonin toxicity is suspected, discontinuation of

the serotonergic agents should be considered.

Endocrine

Adrenal Insufficiency

: Cases of adrenal insufficiency have been reported with opioid use, more

often following greater than one month of use. Presentation of adrenal insufficiency may include

non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness,

dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis

with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with

physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow

adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.

Other opioids may be tried as some cases reported use of a different opioid without recurrence of

adrenal insufficiency. The information available does not identify any particular opioids as being

more likely to be associated with adrenal insufficiency.

Interactions with Central Nervous System Depressants (including benzodiazepines and

alcohol):

Fentanyl should be used with caution and in a reduced dosage during concomitant

administration of other opioid analgesics, general anesthetics, phenothiazines and other

tranquilizers, sedative-hypnotics, tricyclic antidepressants, antipsychotics, antihistamines,

benzodiazepines, centrally-active anti-emetics and other CNS depressants. Respiratory

depression, hypotension and profound sedation, coma or death may result.

Observational studies have demonstrated that concomitant use of opioid analgesics and

benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics

alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with

the concomitant use of other CNS depressant drugs with opioid analgesics (see

DRUG

INTERACTIONS

). If the decision is made to prescribe a benzodiazepine or other CNS

depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and

minimum durations of concomitant use. In patients already receiving an opioid analgesic,

prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in

the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated

in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial

dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for

signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when

FENTORA is used with benzodiazepines or other CNS depressants (including alcohol and illicit

drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant

use of the benzodiazepine or other CNS depressant have been determined. Screen patients for

risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for

overdose and death associated with the use of additional CNS depressants including alcohol and

FENTORA

Page 11 of 59

illicit drugs (see

DRUG INTERACTIONS

FENTORA should not be consumed with alcohol as it may increase the chance of experiencing

dangerous side effects, including death (see

CONTRAINDICATIONS

ADVERSE

REACTIONS, Sedation

, and

DRUG INTERACTIONS

Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics.

Should pain suddenly subside, these effects may rapidly become manifest.

Head Injury

: The respiratory depressant effects of fentanyl, and the capacity to elevate

cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated

intracranial pressure produced by trauma. Also, fentanyl may produce confusion, miosis,

vomiting and other side effects which obscure the clinical course of patients with head injury. In

such patients, fentanyl must be used with extreme caution and only if it is judged essential (see

CONTRAINDICATIONS

Psychomotor Impairment

FENTORA may impair the mental and/or physical abilities needed for certain potentially

hazardous activities such as driving a car or operating machinery. Patients should be cautioned

accordingly. Patients should also be cautioned about the combined effects of fentanyl with other

CNS depressants, including other opioids, phenothiazine, sedative/hypnotics and alcohol.

Respiratory

Respiratory Depression

: Serious, life-threatening, or fatal respiratory depression has been

reported with the use of opioids, even when used as recommended. Respiratory depression from

opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death.

Management of respiratory depression may include close observation, removal of the tablet if

still in the mouth, supportive measures, and use of opioid antagonists, depending on the patient's

clinical status. Fentanyl should be used with extreme caution in patients with substantially

decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia (see

CONTRAINDICATIONS

While serious, life-threatening, or fatal respiratory depression can occur at any time during the

use of FENTORA, the risk is greatest during the initiation of therapy or following a dose

increase. Patients should be closely monitored for respiratory depression when initiating therapy

with FENTORA and following dose increases.

Life-threatening respiratory depression is more likely to occur in the elderly, cachectic, or

debilitated patients because they may have altered pharmacokinetics or altered clearance

compared to younger, healthier patients.

To reduce the risk of respiratory depression, proper dosing and titration of FENTORA are

essential (see

WARNINGS AND PRECAUTIONS, Special Populations, Special Risk

Groups

, and

DOSAGE AND ADMINISTRATION

FENTORA

Page 12 of 59

Use in Patients with Chronic Pulmonary Disease:

Monitor patients with significant chronic

obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased

respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory

depression, particularly when initiating therapy and titrating with FENTORA, as in these

patients, even usual therapeutic doses of FENTORA may decrease respiratory drive to the point

of apnea. The use of FENTORA is contraindicated in patients with acute or severe bronchial

asthma, chronic obstructive airway, or status asthmaticus (see

CONTRAINDICATIONS

Sleep Apnea

: Opioids can cause sleep-related breathing disorders such as sleep apnea

syndromes (including central sleep apnea [CSA]) and hypoxia (including sleep-related hypoxia).

Opioid use increases the risk of CSA in a dose-dependent fashion. Evaluate patients on an

ongoing basis for the onset of a new sleep apnea, or a worsening of an existing sleep apnea. In

these patients, consider reducing or stopping the opioid treatment if appropriate, using best

practices for tapering of opioids (see

WARNINGS AND PRECAUTIONS,

Dependence/Tolerance; DOSAGE AND ADMINISTRATION, Adjustment or Reduction of

Dosage

Concomitant Use of CYP3A4 Inhibitors

Concomitant use with 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 INTERACTIONS

Concomitant Use of MAO Inhibitors

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.

Sexual Function/Reproduction

Long-term use of opioids may be associated with decreased sex hormone levels and symptoms

such as low libido, erectile dysfunction, or infertility (see

ADVERSE REACTIONS, Post-

Marketing Experience

Special Populations

Special Risk Groups:

Fentanyl should be administered with caution to patients with a history of

alcohol and drug abuse and in a reduced dosage to debilitated patients, and in patients with

severely impaired pulmonary function, Addison's disease, hypothyroidism, myxedema, toxic

psychosis, prostatic hypertrophy or urethral stricture.

Pregnant Women:

Studies in humans have not been conducted. FENTORA crosses the

placental barrier and is not recommended to be administered to pregnant women unless, in the

judgment of the physician, potential benefits outweigh the risks (see

WARNINGS AND

PRECAUTIONS, Special Populations, Labour, Delivery and Nursing Women

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

FENTORA

Page 13 of 59

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 intravenous fentanyl.

Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the

neonate. Neonatal Opioid Withdrawal Syndrome (NOWS), unlike opioid withdrawal syndrome

in adults, can be life-threatening (see

WARNINGS AND PRECAUTIONS

Neonatal Opioid

Withdrawal Syndrome (NOWS), ADVERSE REACTIONS, Post-Marketing Experience

Pregnant women using opioids should not discontinue their medication abruptly as this can cause

pregnancy complication such as miscarriage or still-birth. Tapering should be slow and under

medical supervision to avoid serious adverse events to the fetus.

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 citrate was not teratogenic when administered to pregnant animals.

Studies were conducted assessing subcutaneous administration of fentanyl citrate to pregnant rats

at doses of 0, 25, 50, or 100 mcg/kg/day from gestation Day 6 through 17 and to pregnant rabbits

at doses of 50, 100, or 250 mcg/kg/day from gestation Day 6 through 18. The high dose in rats

was approximately 1.2 times the human dose of 800 mcg per pain episode on a mg/m

basis. The

high dose in rabbits was approximately 6 times the human dose of 800 mcg per pain episode on a

mg/m

basis. There were no fentanyl-related external, visceral, or skeletal malformations or

developmental variations noted (see

TOXICOLOGY

Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to

pregnant rats from Day 7 to 21, was not teratogenic. The high dose was approximately 6-times

the human dose of 800 mcg per pain episode on a mg/m

basis). Intravenous administration of

fentanyl (10 or 30 mcg/kg/day) 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.

Labour, Delivery and Nursing Women:

Since opioids can cross the placental barrier and are

excreted in breast milk, FENTORA is not recommended to be used in nursing women and during

labour and delivery unless, in the judgement of the physician, the potential benefits outweigh the

risks. Life-threatening respiratory depression can occur in the infant if opioids are administered

to the mother. Naloxone, a drug that counters the effects of opioids, should be readily available if

FENTORA is used in this population.

Pediatrics (< 18 years of age):

The safety and efficacy of FENTORA have not been studied in

the pediatric population. Therefore, use of FENTORA is not recommended in patients under 18

years of age.

FENTORA

Page 14 of 59

Geriatrics (> 65 years of age):

In general, dose selection for an elderly patient should be

cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of

concomitant disease or other drug therapy (see

DOSAGE AND ADMINISTRATION

ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions,

Geriatrics

Of the 358 patients with cancer in clinical studies of FENTORA, 76 (21%) 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 minimizing risk.

Patients with Hepatic Impairment:

FENTORA should be administered with caution to patients

with liver dysfunction. The influence of liver impairment on the pharmacokinetics of FENTORA

has not been determined. However, the clearance of intravenously administered fentanyl is

decreased in hepatic disease due to alterations in metabolic clearance and plasma proteins (see

DOSAGE AND ADMINISTRATION

ACTION AND CLINICAL

PHARMACOLOGY

Patients with Renal Impairment:

The influence of renal impairment on the pharmacokinetics

of FENTORA has not been determined. FENTORA should be administered with caution to

patients with renal impairment due to the potential for reduced renal excretion of fentanyl (see

DOSAGE AND ADMINISTRATION

ACTION AND CLINICAL

PHARMACOLOGY

Patients with Biliary/Pancreatic Disease:

Fentanyl may cause spasm of the sphincter of Oddi and FENTORA should be used with caution

in patients with biliary tract disease, including acute pancreatitis. Opioids may cause increases in

serum amylase concentration.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Commonly observed adverse events seen with FENTORA (fentanyl buccal/sublingual

effervescent tablet) are similar to those of other opioid analgesics, and represent an extension of

pharmacological effects of the drug class. These include, but are not limited to, nausea, vomiting,

constipation, fatigue, headache, and dizziness.

The major hazards of opioids include respiratory and central nervous system depression and to a

lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest. Opioid side

effects should be expected and managed accordingly.

FENTORA

Page 15 of 59

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating

rates

The clinical trials of FENTORA were designed to evaluate safety and efficacy in treating

patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as

sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their

persistent pain.

The safety of FENTORA has been evaluated in 2 double-blind, placebo-controlled studies and 1

12-month, open-label study which comprised 358 opioid-tolerant cancer patients with

breakthrough pain. Over a third (37%) of the patients received study drug for at least 3 months

and 80 (22%) patients received study drug for at least 6 months.

The adverse event data presented here reflect the actual percentage of patients experiencing each

adverse effect among patients who received FENTORA for breakthrough pain along with a

concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use

of other opioids, duration of FENTORA therapy or cancer-related symptoms.

Common Clinical Trial Adverse Drug Reactions (> 5%)

Table 1 lists, by maximum dose received, adverse events with an overall frequency of 5% or

greater within the total population that occurred during titration. The ability to assign a dose-

response relationship to these adverse events is limited by the titration schemes used in these

studies.

FENTORA

Page 16 of 59

Table 1

Adverse Events which Occurred During Titration at a Frequency of ≥ 5%

Number (%) of patients

a

Maximum Titration Dose of FENTORA

System organ class

MedDRA preferred term, n (%)

100 mcg

(N=43)

200 mcg

(N=36)

400 mcg

(N=66)

600 mcg

(N=65)

800 mcg

(N=147)

Total

(N=358

b

)

Gastrointestinal disorders

Nausea

5 (12)

6 (17)

15 (23)

15 (23)

18 (12)

59 (16)

Vomiting

1 (2)

2 (6)

4 (6)

9 (14)

3 (2)

19 (5)

General disorders and administration site

conditions

Fatigue

3 (7)

2 (6)

6 (9)

3 (5)

6 (4)

20 (6)

Nervous system disorders

Dizziness

4 (9)

2 (6)

12 (18)

21 (32)

24 (16)

64 (18)

Headache

1 (2)

3 (8)

5 (8)

8 (12)

11 (7)

28 (8)

Somnolence

1 (2)

2 (6)

6 (9)

8 (12)

4 (3)

21 (6)

Patients are counted only once in each preferred term category and only once in each system organ class category.

Successful dose was missing for 1 patient.

MedDRA=Medical Dictionary for Regulatory Activities.

Table 2 lists, by successful dose, adverse events with an overall frequency of ≥ 5% within the

total population that occurred after a successful dose had been determined.

FENTORA

Page 17 of 59

Table 2

Adverse Events which Occurred During Long-Term Treatment at a

Frequency of ≥ 5%

Number (%) of patients

a

Successful Dose of FENTORA

System organ class

MedDRA preferred term, n (%)

100 mcg

(N=21)

200 mcg

(N=33)

400 mcg

(N=53)

600 mcg

(N=58)

800 mcg

(N=74)

Total

(N=239)

Blood and lymphatic system disorders

Anemia

7 (33)

5 (15)

5 (9)

7 (12)

7 (9)

31 (13)

Neutropenia

1 (5)

2 (6)

1 (2)

5 (9)

6 (8)

15 (6)

Gastrointestinal disorders

Nausea

9 (43)

5 (15)

18 (34)

20 (34)

19 (26)

71 (30)

Vomiting

8 (38)

7 (21)

11 (21)

13 (22)

12 (16)

51 (21)

Constipation

7 (33)

5 (15)

6 (11)

8 (14)

8 (11)

34 (14)

Abdominal pain

2 (10)

4 (12)

5 (9)

9 (16)

5 (7)

25 (10)

Diarrhoea

4 (19)

1 (3)

5 (9)

6 (10)

6 (8)

22 (9)

Stomatitis

1 (5)

3 (9)

4 (8)

2 (3)

3 (4)

13 (5)

Dyspepsia

1 (5)

1 (3)

3 (6)

2 (3)

5 (7)

12 (5)

General disorders and administration site

conditions

Fatigue

4 (19)

3 (9)

10 (19)

11 (19)

12 (16)

40 (17)

Oedema peripheral

8 (38)

4 (12)

4 (8)

8 (14)

8 (11)

32 (13)

Asthenia

4 (19)

5 (15)

2 (4)

6 (10)

10 (14)

27 (11)

Pyrexia

1 (5)

6 (18)

1 (2)

7 (12)

4 (5)

19 (8)

Infections and infestations

Pneumonia

2 (10)

5 (15)

4 (8)

4 (7)

6 (8)

21 (9)

Urinary tract infection

2 (6)

2 (4)

5 (9)

6 (8)

15 (6)

Investigations

Weight decreased

2 (10)

1 (3)

4 (8)

4 (7)

7 (9)

18 (8)

Metabolism and nutrition disorders

Dehydration

4 (19)

4 (8)

7 (12)

9 (12)

24 (10)

Anorexia

2 (10)

2 (6)

6 (11)

5 (9)

8 (11)

23 (10)

Hypokalemia

2 (6)

2 (3)

9 (12)

13 (5)

Musculoskeletal and connective tissue

disorders

Arthralgia

1 (3)

6 (11)

5 (9)

5 (7)

17 (7)

Back pain

3 (14)

3 (6)

7 (12)

3 (4)

16 (7)

Pain in extremity

1 (5)

2 (4)

4 (7)

4 (5)

11 (5)

Neoplasms benign, malignant, and unspecified

(including cysts and polyps)

Cancer pain

3 (14)

1 (3)

3 (6)

4 (7)

1 (1)

12 (5)

Nervous system disorders

Headache

2 (10)

1 (3)

5 (9)

9 (16)

14 (19)

31 (13)

Dizziness

5 (24)

3 (9)

5 (9)

8 (14)

7 (9)

28 (12)

FENTORA

Page 18 of 59

Number (%) of patients

a

Successful Dose of FENTORA

System organ class

MedDRA preferred term, n (%)

100 mcg

(N=21)

200 mcg

(N=33)

400 mcg

(N=53)

600 mcg

(N=58)

800 mcg

(N=74)

Total

(N=239)

Psychiatric disorders

Depression

2 (10)

1 (3)

7 (13)

7 (12)

7 (9)

24 (10)

Confusional state

4 (19)

1 (3)

2 (4)

4 (7)

5 (7)

16 (7)

Anxiety

2 (6)

3 (6)

6 (10)

4 (5)

15 (6)

Insomnia

2 (10)

1 (3)

5 (9)

2 (3)

4 (5)

14 (6)

Respiratory, thoracic and mediastinal

disorders

Dyspnoea

1 (5)

5 (15)

1 (2)

8 (14)

3 (4)

18 (8)

Cough

2 (10)

3 (6)

5 (9)

6 (8)

16 (7)

Preferred terms are sorted by descending order of incidence within system organ class. Patients are counted only once

in each preferred term category and only once in each system organ class category.

MedDRA=Medical Dictionary for Regulatory Activities.

A small number of patients (n=11) with Grade 1 oral mucositis were included in clinical trials

designed to support the safety of FENTORA. There was no evidence of excess toxicity in this

subset of patients. Additionally, in an open-label study in opioid-tolerant patients with cancer,

the safety profiles were found to be comparable in patients with (n = 8) and without (n = 8) oral

mucositis (Grade 1) after administration of a single dose of FENTORA 200 mcg.

Application site reactions:

In the 3 clinical trials, 9% 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 (3%), ulcer (3%),

irritation (2%), and paresthesia (1%). Application site reactions tended to occur early in

treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients.

Sedation:

Sedation is a common side effect of opioid analgesics, especially in opioid naïve

individuals. (FENTORA is contraindicated for use in opioid non-tolerant patients.) Sedation

may also occur partly because patients often recuperate from prolonged fatigue after the relief of

persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to

five days and, if the sedation is not severe, will not require any treatment except reassurance. If

excessive sedation persists beyond a few days, the dose of the opioid should be reduced and

alternate causes investigated. Some of these are: concurrent CNS depressant medication,

hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is

necessary to reduce the dose, it can be carefully increased again after three or four days if it is

obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by

postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the

patient lies down.

Nausea and Vomiting:

Nausea is a common side effect on initiation of therapy with opioid

analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of

the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea

declines following continued treatment with opioid analgesics. When instituting therapy with an

FENTORA

Page 19 of 59

opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the

cancer patient, investigation of nausea should include such causes as constipation, bowel

obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and

concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to

dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by

other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These

symptoms respond to chronic treatment with gastrointestinal prokinetic agents.

Constipation:

Practically all patients become constipated while taking opioids on a persistent

basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is

essential to caution the patients in this regard and to institute an appropriate regimen of bowel

management at the start of prolonged opioid therapy. Stimulant laxatives, stool softeners, and

other appropriate measures should be used as required. As fecal impaction may present as

overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy

prior to initiating treatment for diarrhea.

The following adverse effects occur less frequently with opioid analgesics and include those

reported in FENTORA clinical trials, whether related or not to fentanyl.

Less Common Clinical Trial Adverse Drug Reactions

(≥ 1% and < 5%)

The following adverse events were reported in the administration of FENTORA at a frequency

between ≥ 1% and < 5%:

Blood and lymphatic system disorders:

Leukopenia, lymphadenopathy, pancytopenia,

thrombocytopenia

Cardiac disorders:

Atrial fibrillation, tachycardia

Gastrointestinal disorders:

Abdominal distension, abdominal pain upper, ascites, dry mouth,

dyspepsia, dysphagia, food poisoning, gastrooesophageal reflux disease, gingival pain,

glossodynia, mouth ulceration, oral mucosal discolouration, stomach discomfort

General disorders and administration site conditions:

Application site irritation, application

site pain, application site paraesthesia, application site ulcer, chest pain, chills, gait disturbance,

oedema, pain

Hepatobiliary disorders:

Jaundice

Infections and infestations:

Bronchitis, cellulitis, gastroenteritis viral, influenza,

nasopharyngitis, oral candidiasis, sepsis, sinusitis, tooth abscess, upper respiratory tract infection

Injury, poisoning and procedural complications:

Contusion, fall, spinal compression fracture

Investigations:

Alanine aminotransferase increased, aspartate aminotransferase increased, blood

alkaline phosphatase increased, blood glucose increased, breath sounds abnormal, haematocrit

decreased, haemoglobin decreased, platelet count decreased

FENTORA

Page 20 of 59

Metabolism and nutrition disorders:

Decreased appetite, electrolyte imbalance, fluid retention,

hypercalcaemia, hypoalbuminaemia, hypomagnesaemia, hyponatraemia, oral intake reduced

Musculoskeletal and connective tissue disorders:

Bone pain, chest wall pain, flank pain,

muscle spasms, muscular weakness, myalgia, neck pain, osteoporosis, pain in extremity,

shoulder pain

Neoplasms benign, malignant and unspecified (incl cysts and polyps):

Breast cancer, breast

cancer metastatic, cancer pain, cervix carcinoma, colon cancer, colon cancer metastatic, lung

cancer metastatic, lung neoplasm malignant, non-small cell lung cancer, pancreatic carcinoma

Nervous system disorders:

Balance disorder, dysgeusia, hypoaesthesia, lethargy, migraine,

neuropathy, neuropathy peripheral, paraesthesia, tremor, sedation

Psychiatric disorders:

Disorientation, euphoric mood, hallucination, insomnia, nervousness

Renal and urinary disorders:

Dysuria, renal failure

Respiratory, thoracic and mediastinal disorders:

Dyspnoea exertional, epistaxis, haemoptysis,

pharyngolaryngeal pain, pleural effusion, productive cough, pulmonary embolism, respiratory

failure, wheezing

Skin and subcutaneous tissue disorders:

Alopecia, cold sweat, erythema, hyperhidrosis, night

sweats, pruritus, rash

Vascular disorders:

Deep vein thrombosis, flushing, hot flush, hypertension, hypotension,

pallor

Post-marketing Experience

Spontaneous reports received are consistent with the safety profile observed in clinical trials. The

following additional adverse reactions have been identified during the post-marketing

experience:

General disorders and administration site conditions:

Drug tolerance, drug withdrawal

syndrome, neonatal withdrawal syndrome, opioid use disorder.

Immune system disorders:

hypersensitivity reactions (including rash, erythema, lip and face

swelling, and urticaria).

Nervous system disorders:

Loss of consciousness.

Psychiatric disorders:

Delirium.

Respiratory, thoracic, and mediastinal disorders

: Respiratory arrest

FENTORA

Page 21 of 59

Androgen deficiency

: Chronic use of opioids may influence the hypothalamic-pituitary-gonadal

axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile

dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of

hypogonadism is unknown because the various medical, physical, lifestyle, and psychological

stressors that may influence gonadal hormone levels have not been adequately controlled for in

studies conducted to date. Patients presenting with symptoms of androgen deficiency should

undergo laboratory evaluation.

DRUG INTERACTIONS

Overview

CYP3A4 Inhibitors:

Fentanyl is metabolized mainly via the human CYP3A4 isoenzyme

system; therefore potential interactions may occur when FENTORA is given concurrently with

agents that affect CYP3A4 activity. The concomitant use of FENTORA with CYP3A4 inhibitors

(e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone,

saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice,

verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma

concentrations, which could increase or prolong adverse drug effects and may cause potentially

fatal respiratory depression. Patients receiving FENTORA who begin therapy with, or increase

the dose of, CYP3A4 inhibitors should be carefully monitored for signs of opioid toxicity over

an extended period of time. Dosage increase should be done cautiously (see

WARNINGS AND

PRECAUTIONS

CYP3A4 Inducers:

The concomitant use of FENTORA with CYP3A4 inducers (e.g.,

barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine,

phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, or troglitazone) may

result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of

FENTORA. Patients receiving FENTORA who stop therapy with, or decrease the dose of,

CYP3A4 inducers should be monitored for signs of increased FENTORA activity and the dose

of FENTORA should be adjusted accordingly.

MAO Inhibitors:

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.

Serious Drug Interactions

The concomitant use of FENTORA with cytochrome P450 3A4 inhibitors may result in

an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory

depression.

FENTORA is not recommended for use in patients who have received MAO inhibitors

within 14 days.

FENTORA

Page 22 of 59

Serotonergic Drugs:

Co-administration of fentanyl with a serotonergic agent, such as a

Selective Serotonin Re-uptake Inhibitor or a Serotonin Norepinephrine Re-uptake Inhibitor, may

increase the risk of serotonin syndrome, a potentially life threatening condition (see

WARNINGS AND PRECAUTIONS

Interaction with Benzodiazepines and Other Central Nervous System (CNS) Depressants:

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS

depressants (e.g. other opioids, sedatives/hypnotics, antidepressants, anxiolytics, tranquilizers,

muscle relaxants, general anesthetics, antipsychotics, phenothiazines, neuroleptics,

antihistamines, antiemetics, and alcohol) and beta-blockers, increases the risk of respiratory

depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs

for use in patients for whom alternative treatment options are inadequate. Limit dosages and

durations to the minimum required. Follow patients closely for signs of respiratory depression

and sedation (see

WARNINGS AND PRECAUTIONS, Neurologic, Interactions with

Central Nervous System Depressants (including benzodiazepines and alcohol) and

Psychomotor Impairment

). FENTORA should not be consumed with alcohol as it may

increase the chance of experiencing dangerous side effects.

FENTORA

Page 23 of 59

Drug-Drug Interactions

Table 3

Established or Potential Drug-Drug Interactions

Drug Class

[Examples]

Effect

Clinical Comment

Inhibitors of CYP3A4

[indinavir, nelfinavir, ritonavir,

clarithromycin, itraconazole,

ketoconazole, nefazodone,

saquinavir, telithromycin,

aprepitant, diltiazem,

erythromycin, fluconazole,

grapefruit juice, verapamil,

cimetidine]

The concomitant use of FENTORA and

CYP3A4 inhibitors can increase the

plasma concentration of fentanyl,

resulting in increased or prolonged

opioid effects. These effects could be

more pronounced with concomitant use

of FENTORA and CYP3A4 inhibitors,

particularly when an inhibitor is added

after a stable dose of FENTORA is

achieved.

After stopping a CYP3A4 inhibitor, as

the effects of the inhibitor decline, the

fentanyl plasma concentration will

decrease, resulting in decreased opioid

efficacy or a withdrawal syndrome in

patients who had developed physical

dependence to fentanyl.

If concomitant use is

necessary, consider dosage

reduction of FENTORA until

stable drug effects are

achieved. Monitor patients for

respiratory depression and

sedation at frequent intervals.

If a CYP3A4 inhibitor is

discontinued, consider

increasing the FENTORA

dosage until stable drug

effects are achieved. Monitor

for signs of opioid withdrawal.

CYP3A4 Inducers

[barbiturates, carbamazepine,

efavirenz, glucocorticoids,

modafinil, nevirapine,

oxcarbazepine, phenobarbital,

phenytoin, pioglitazone, rifabutin,

rifampin, St. John's wort,

troglitazone]

The concomitant use of FENTORA and

CYP3A4 inducers can decrease the

plasma concentration of fentanyl,

resulting in decreased efficacy or onset

of a withdrawal syndrome in patients

who have developed physical

dependence to fentanyl.

After stopping a CYP3A4 inducer, as the

effects of the inducer decline, the

fentanyl plasma concentration will

increase, which could increase or

prolong both the therapeutic effects and

adverse reactions, and may cause serious

respiratory depression.

If concomitant use is

necessary, consider increasing

the FENTORA dosage until

stable drug effects are

achieved. Monitor for signs of

opioid withdrawal. If a

CYP3A4 inducer is

discontinued, consider

FENTORA dosage reduction

and monitor for signs of

respiratory depression.

CNS Depressants

[Benzodiazepines and other

sedatives/hypnotics, anxiolytics,

tranquilizers, muscle relaxants,

general anesthetics, antipsychotics,

other opioids, alcohol]

Due to additive pharmacologic effect, the

concomitant use of benzodiazepines or

other CNS depressants including alcohol,

increases the risk of respiratory

depression, profound sedation, coma,

and death.

Reserve concomitant

prescribing of these drugs for

use in patients for whom

alternative treatment options

are inadequate. Limit dosages

and durations to the minimum

required. Follow patients

closely for signs of respiratory

depression and sedation.

FENTORA

Page 24 of 59

Drug Class

[Examples]

Effect

Clinical Comment

Serotonergic Drugs

[Selective serotonin reuptake

inhibitors (SSRIs), serotonin and

norepinephrine reuptake inhibitors

(SNRIs), tricyclic antidepressants

(TCAs), triptans, 5- HT3 receptor

antagonists, drugs that affect the

serotonin neurotransmitter system

(e.g., mirtazapine, trazodone,

tramadol), certain muscle relaxants

(e.g. cyclobenzaprine), monoamine

oxidase (MAO) inhibitors (those

intended to treat psychiatric

disorders and also others, such as

linezolid and intravenous

methylene blue).]

Co-administration of fentanyl with a

serotonergic agent may increase the risk

of serotonin syndrome, a potentially life

threatening condition (see

WARNINGS

AND PRECAUTIONS, Serotonin

Syndrome

If concomitant use is

warranted, carefully observe

the patient, particularly during

treatment initiation and dose

adjustment. Discontinue

FENTORA if serotonin

syndrome is suspected.

Mixed Agonist/Antagonist and

Partial Agonist Opioid Analgesics

[Butorphanol, nalbuphine,

pentazocine, buprenorphrine]

May reduce the analgesic effect of

FENTORA and/or precipitate

withdrawal symptoms.

Avoid concomitant use.

Muscle Relaxants

Fentanyl may enhance the

neuromuscular blocking action of

skeletal muscle relaxants and produce an

increased degree of respiratory

depression.

Monitor patients for signs of

respiratory depression that

may be greater than otherwise

expected and decrease the

dosage of FENTORA and/or

the muscle relaxant as

necessary.

Diuretics

Opioids can reduce the efficacy of

diuretics by inducing the release of

antidiuretic hormone.

Monitor patients for signs of

diminished diuresis and/or

effects on blood pressure and

increase the dosage of the

diuretic as needed.

Anticholinergic Drugs

The concomitant use of anticholinergic

drugs may increase risk of urinary

retention and/or severe constipation,

which may lead to paralytic ileus.

Monitor patients for signs of

urinary retention or reduced

gastric motility when

FENTORA is used

concomitantly with

anticholinergic drugs.

Drug-Food Interactions

Grapefruit and grapefruit juice, which are CYP3A4 inhibitors, may result in a potentially

dangerous increase in fentanyl plasma concentrations.

Drug-Herb Interactions

Interactions with herbal products have not been established.

FENTORA

Page 25 of 59

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Interactions with lifestyle products have not been established. The concomitant use of alcohol

should be avoided (see

WARNINGS AND PRECAUTIONS, General

DOSAGE AND ADMINISTRATION

FENTORA is intended to be used only in the care of patients who are already receiving and

who are tolerant to continuous opioid therapy.

Dosing Considerations

Adults:

FENTORA (fentanyl buccal/sublingual effervescent tablets) is indicated only for the

management of breakthrough pain in cancer patients 18 years of age and older who are already

receiving and who are tolerant to continuous opioid therapy for their persistent baseline cancer

pain. Patients considered opioid tolerant are those who are taking continuous medicine consisting

of at least 60 mg of oral morphine daily, at least 25 mcg/hr of transdermal fentanyl, at least 30

mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral

oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer.

Individually titrate FENTORA to a dose that provides adequate analgesia with tolerable side

effects (see

DOSAGE AND ADMINISTRATION

Recommended Dose

and Dosage

Adjustment

It is important to minimize the number of strengths available to patients at any time to prevent

confusion and possible overdose.

Recommended Dose

and Dosage Adjustment

Adults:

FENTORA is not bioequivalent with other fentanyl products. Do not convert patients on a

mcg per mcg basis from other fentanyl products. (Note: This includes oral, transdermal, or

parenteral formulations of fentanyl.) All patients should be titrated from the 100 mcg dose.

The maximum single dose should not exceed 800 mcg. FENTORA should only be used

ONCE per breakthrough cancer pain episode, i.e. FENTORA should not be redosed within

an episode.

During any episode of breakthrough cancer pain, if adequate pain relief

is not achieved

after

FENTORA, the patient may use a rescue medication (other than FENTORA, after 30 minutes) as

directed by their healthcare provider.

FENTORA

Page 26 of 59

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain

with FENTORA.

Use of FENTORA should be limited to four episodes of breakthrough pain per day. If the

patient experiences greater than four breakthrough pain episodes per day, the dose of the

continuous opioid used for persistent pain should be re-evaluated.

Patients with Hepatic Impairment:

Special care should be taken during the titration process in patients with liver dysfunction.

Patients with Renal Impairment:

Special care should be taken during the titration process in patients with kidney dysfunction.

Geriatrics:

Respiratory depression has occurred in the elderly when opioids were co-administered with other

agents that can depress respiration. Patients over the age of 65 years tended to titrate to slightly

lower doses of FENTORA than younger patients and 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 minimizing risk (see

WARNINGS AND PRECAUTIONS

ACTION AND

CLINICAL PHARMACOLOGY

FENTORA

Page 27 of 59

Starting Dose:

All patients MUST begin treatment using 100 mcg FENTORA.

Dose Titration:

Dose titration is the key to success with opioid analgesic therapy.

Proper optimization of doses

scaled to the relief of the individual's pain should aim at administration of the lowest dose

which will achieve the overall treatment goal of satisfactory pain relief with acceptable side

effects.

The dose of FENTORA is not predicted from the daily maintenance dose of opioid used to

manage the persistent cancer pain and

MUST

be determined by dose titration.

Dosage adjustments should be based on the patient's clinical response.

Adjustment or Reduction of Dosage:

Physical dependence with or without psychological dependence tends to occur with chronic

administration of opioids, including FENTORA. Withdrawal (abstinence) symptoms may occur

following abrupt discontinuation of therapy. These symptoms may include body aches, diarrhea,

gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose, sneezing, tremors or

shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating,

palpitations, unexplained fever, weakness and yawning.

Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer

required for pain control. In patients who are appropriately treated with opioid analgesics and

who undergo gradual withdrawal from the drug, these symptoms are usually mild (see

WARNINGS AND PRECAUTIONS). Tapering should be individualised and carried out under

medical supervision.

From the initial dose, patients should be closely followed by the prescriber and the dosage

strength changed until the patient reaches a dose that provides adequate analgesia with tolerable

side effects. Patients should record their use of FENTORA over several episodes of breakthrough

pain and discuss their experience with their physician to determine if a dosage adjustment is

warranted.

Patients who need to titrate to a higher dose, can be instructed to use two 100 mcg tablets (one on

each side of the mouth in the buccal cavity) with their next breakthrough pain episode. If this

dosage is not successful, the patient may be instructed to place two 100 mcg tablets on each side

of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate using multiples of the

200 mcg FENTORA tablet for doses above 400 mcg (600 mcg and 800 mcg). Do not use more

than 4 tablets simultaneously.

Doses above 800 mcg FENTORA should not be used

Once adequate pain relief is achieved with a dose between 100 and 800 mcg FENTORA, the

patient should get a prescription for FENTORA of the dose determined by titration (i.e., 100,

200, 400, 600 or 800 mcg) to treat subsequent episodes.

FENTORA

Page 28 of 59

To reduce the risk of overdose during titration, patients should have only one strength of

FENTORA tablets available at any time.

During any episode of breakthrough cancer pain, if adequate pain relief

is not achieved

after

FENTORA, the patient may use a rescue medication (other than FENTORA, after 30 minutes) as

directed by their healthcare provider.

Maintenance Dosing:

Once titrated to an effective dose, patients should use

only ONE

FENTORA tablet of the

appropriate strength per breakthrough pain episode.

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain

with FENTORA.

During any episode of breakthrough cancer pain, if adequate pain relief

is not achieved

after

FENTORA, the patient may use a rescue medication (other than FENTORA, after 30 minutes) as

directed by their healthcare provider.

Dosage adjustment of FENTORA may be required in some patients. Generally, the FENTORA

dose should be increased only when a single administration of the current dose fails to

adequately treat the breakthrough pain episode for several consecutive episodes.

If the patient experiences greater than four breakthrough pain episodes per day, the dose of the

continuous opioid used for persistent pain should be re-evaluated.

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Page 29 of 59

Discontinuation of Therapy:

For patients requiring discontinuation of all opioid therapy, the recent FENTORA dose should be

taken into consideration for a gradual downward opioid titration to avoid the possibility of abrupt

withdrawal effects (see

WARNINGS AND PRECAUTIONS

If patients continue to take their background opioid therapy for persistent pain, FENTORA

therapy may usually be immediately discontinued if no longer required for breakthrough pain.

Physical dependence with or without psychological dependence tends to occur with chronic

administration of opioids, including

FENTORA

. Withdrawal (abstinence) symptoms may occur

following abrupt discontinuation of therapy. These symptoms may include body aches, diarrhea,

gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose, sneezing, tremors or

shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating,

palpitations, unexplained fever, weakness and yawning.

Patients should be informed that reducing and/or discontinuing opioids decreases their tolerance

to these drugs. If treatment needs to be re-initiated, the patient must start at the lowest dose and

titrate up to avoid overdose (

see DOSAGE AND ADMINISTRATION, Recommended Dose

and Dosage Adjustment, Starting Dose

Dose Titration

Administration of FENTORA

Opening the Blister Package

Instruct patients not to open the blister until ready to administer FENTORA.

Separate a single blister unit from the blister card by bending and tearing apart at the

perforations.

Bend the blister unit along the line where indicated.

Peel back the blister backing to expose the tablet.

Patients should NOT attempt to push

the tablet through the blister as this may cause damage to the tablet.

Do not store the tablet once it has been removed from the blister package as the tablet

integrity may be compromised and, more importantly, because this increases the risk of

accidental exposure to the tablet.

Tablet Administration

Once the tablet is removed from the blister unit, the patient should

immediately

place the entire

FENTORA tablet in the buccal cavity (above a rear molar, between the upper cheek and gum), or

sublingually.

Patients should not split the tablet.

The FENTORA tablet should not be sucked, chewed or swallowed, as this will result in lower

plasma concentrations than when taken as directed.

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Page 30 of 59

The FENTORA tablet should be left between the cheek and gum until it has disintegrated, which

usually takes approximately 14-25 minutes. After 30 minutes, if remnants from the FENTORA

tablet remain, they may be swallowed with a glass of water.

It is recommended that patients alternate sides of the mouth when administering subsequent

doses of FENTORA.

FENTORA may also be administered sublingually.

Disposal

FENTORA

should be kept in a safe place, out of the sight and reach of children before, during

and after use. FENTORA should not be used in front of children, since they may copy these

actions.

FENTORA should never be disposed of in household trash.

Disposal via a pharmacy take

back program is recommended. Unused or expired FENTORA should be properly disposed of

as soon as it is no longer needed to prevent accidental exposure to others, including children or

pets. If temporary storage is required before disposal, a sealed child-proof container, such as a

biohazard waste container or a lockable medication box could be obtained from a pharmacy.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Symptoms:

The manifestations of FENTORA overdosage are expected to be similar in nature to

intravenous fentanyl and other opioids, and are an extension of its pharmacological actions with

the most serious significant effect being respiratory depression.

Immediate Management:

Immediate management of opioid overdose includes removal of the

FENTORA tablet, if still in the mouth, ensuring a patent airway, physical and verbal stimulation

of the patient, and assessment of level of consciousness, as well as ventilatory and circulatory

status.

Treatment of Overdosage (Accidental Ingestion) in the Opioid Non-Tolerant Person:

Provide ventilatory support, obtain intravenous access, and employ naloxone or other opioid

antagonists as clinically indicated. The duration of respiratory depression following overdose

may be longer than the effects of the opioid antagonist’s action (e.g., the half-life of naloxone

ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the

product monograph of the individual opioid antagonist for details about such use.

Treatment of Overdose in Opioid Tolerant Patients:

Provide ventilatory support and obtain

intravenous access as clinically indicated. Judicious use of naloxone or another opioid antagonist

may be warranted in some instances, but it is associated with the risk of precipitating an acute

withdrawal syndrome.

FENTORA

Page 31 of 59

General Considerations for Overdose:

Management of severe FENTORA overdose includes:

securing a patent airway, assisting or controlling ventilation, establishing intravenous access, and

GI decontamination by lavage and/or activated charcoal, once the patient’s airway is secure. In

the presence of respiratory depression or apnea, ventilation should be assisted or controlled and

oxygen administered as indicated.

Patients with overdose should be carefully observed and appropriately managed until their

clinical condition is well-controlled.

Although muscle rigidity interfering with respiration has not been seen following the use of

FENTORA, this is possible with fentanyl and other opioids. If it occurs, manage by the use of

assisted or controlled ventilation, by an opioid antagonist, and as a final alternative, by a

neuromuscular blocking agent.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Fentanyl is a pure opioid agonist whose principal therapeutic action is analgesia. Other members

of the class known as opioid agonists include substances such as morphine, oxycodone,

hydromorphone, codeine, and hydrocodone.

Pharmacodynamics

Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation,

respiratory depression, constipation, miosis, cough suppression, and analgesia. Like all pure

opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed

agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with

increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the

ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may

include somnolence and respiratory depression.

Secondary

actions

include

increase

tone

decrease

contractions

gastrointestinal smooth muscle, which results in prolongation of gastrointestinal transit time and

may be responsible for the constipation typically seen with opioids.

Analgesia:

The analgesic effects of fentanyl are related to the blood level of the drug, if proper

allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-

life). In opioid-naive individuals, analgesia occurs at blood levels of 1 to 2 ng/mL, while blood

levels of 10-20 ng/mL would produce surgical anaesthesia and profound respiratory depression.

In general, the effective concentration and the concentration at which toxicity occurs increase

with increasing tolerance with any and all opioids. The rate of development of tolerance varies

widely among individuals. As a result, the dose of FENTORA should be individually titrated to

achieve the desired effect.

Central Nervous System:

Fentanyl produces respiratory depression by direct action on brain

FENTORA

Page 32 of 59

stem respiratory centres. The respiratory depression involves both a reduction in the

responsiveness of the brain stem centres to increases in CO

tension and to electrical stimulation.

Fentanyl depresses the cough reflex by direct effect on the cough centre in the medulla.

Antitussive effects may occur with doses lower than those usually required for analgesia.

Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but

are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce

similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of

oxycodone overdose.

Gastrointestinal Tract and Other Smooth Muscle:

Fentanyl causes a reduction in motility

associated with an increase in smooth muscle tone in the antrum of the stomach and in the

duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are

decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased

to the point of spasm resulting in constipation. Other opioid-induced effects may include a

reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and

transient elevations in serum amylase.

Cardiovascular System:

Fentanyl may produce release of histamine with or without associated

peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilatation may

include pruritus, flushing, red eyes, hyperhidrosis and/or orthostatic hypotension.

Endocrine System:

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes.

Some changes that can be seen include an increase in serum prolactin, and decreases in plasma

cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal

changes.

Immune System: In vitro

and animal studies indicate that opioids have a variety of effects on

immune functions, depending on the context in which they are used. The clinical significance of

these findings is unknown.

Respiratory System:

All opioid µ-receptor agonists, including fentanyl, produce dose-

dependent respiratory depression. The risk of respiratory depression is less in patients receiving

chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects.

Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral

transmucosal fentanyl citrate product administration and may persist for several hours.

Serious or fatal respiratory depression can occur even at recommended doses. Fentanyl depresses

the cough reflex as a result of its CNS activity. Although not observed with oral transmucosal

fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses

may interfere with respiration by causing rigidity in the muscles of respiration. Therefore,

physicians and other healthcare providers should be aware of this potential complication.

FENTORA

Page 33 of 59

Concentration – Efficacy Relationships

The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is

made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life).

In general, the effective concentration and the concentration at which toxicity occurs increase

with increasing tolerance with any and all opioids. The rate of development of tolerance varies

widely among individuals. As a result, the dose of FENTORA should be individually titrated to

achieve the desired effect (see

DOSAGE AND ADMINISTRATION, Recommended Dose

and Dosage Adjustment

). The minimum effective analgesic concentration of fentanyl for any

individual patient may increase over time due to an increase in pain, the development of a new

pain syndrome and/or the development of analgesic tolerance.

Concentration – Adverse Reaction Relationship

There is a relationship between increasing fentanyl plasma concentration and increasing

frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and

respiratory depression. In opioid-tolerant patients, the situation may be altered by the

development of tolerance to opioid-related adverse reactions (see

DOSAGE AND

ADMINISTRATION

Pharmacokinetics

Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following

administration of FENTORA increases linearly in an approximate dose-proportional manner

over the 100- to 800-mcg dose range.

Absorption:

Following buccal administration of FENTORA, fentanyl is readily absorbed with an absolute

bioavailability of 65%. The absorption profile of FENTORA is largely the result of an initial

absorption from the buccal mucosa, with peak plasma concentrations following venous sampling

generally attained within an hour after buccal administration. Approximately 50% of the total

dose administered is absorbed transmucosally and becomes systemically available. The

remaining half of the total dose is swallowed and undergoes more prolonged absorption from the

gastrointestinal tract.

Mean pharmacokinetic parameters are presented in Table 4. Mean plasma concentration versus

time profiles are presented in Figure 1.

FENTORA

Page 34 of 59

Table 4

Pharmacokinetic Parameters* Following Single 100, 200, 400, and 800 mcg

Doses of FENTORA in Healthy Subjects

Pharmacokinetic

Parameter

(mean±SD)

100 mcg

200 mcg

400 mcg

800 mcg

C

max

(ng/mL)

0.25 ± 0.14

0.40 ± 0.18

0.97 ± 0.53

1.59 ± 0.90

T

max

minute**

(range)

45.0

(25.0 – 181.0)

40.0

(20.0 – 180.0)

35.0

(20.0 – 180.0)

40.0

(25.0 – 180.0)

AUC

0-inf

(nghr/mL)

0.98 ± 0.37

2.11 ± 1.13

4.72 ± 1.95

9.05 ± 3.72

AUC

0-tmax

(nghr/mL)

0.09 ± 0.06

0.13 ± 0.09

0.34 ± 0.23

0.52 ± 0.38

T

1/2

, hr**

2.63

(1.47 – 13.57)

4.43

(1.85 – 20.76)

11.09

(3.44 – 20.59)

11.70

(4.63 – 28.63)

* Based on venous sampling.

** Data for T

presented as median (range)

Figure 1

Mean Plasma Concentration Versus Time Profiles Following Single 100, 200,

400, and 800 mcg Doses of FENTORA in Healthy Subjects

Dwell time (defined as the length of time that the tablet takes to fully disintegrate following

buccal administration), does not appear to affect early systemic exposure to fentanyl.

The effect of mucositis (Grade 1) on the pharmacokinetic profile of FENTORA was studied in a

group of patients with (N = 8) and without mucositis (N = 8) who were otherwise matched. A

single 200 mcg tablet was administered, followed by sampling at appropriate intervals. Mean

summary statistics (standard deviation in parentheses, except T

where range was used) are

FENTORA

Page 35 of 59

presented in Table 5.

Table 5

Pharmacokinetic Parameters in Patients with Mucositis

Patient status

C

max

(ng/mL)

T

max

(min)

AUC

0-tmax

(nghr/mL)

AUC

0-8

(nghr/mL)

Mucositis

1.25 ± 0.78

25.0 (15 – 45)

0.21 ± 0.16

2.33 ± 0.93

No mucositis

1.24 ± 0.77

22.5 (10 – 121)

0.25 ± 0.24

1.86 ± 0.86

Distribution:

Fentanyl is highly lipophilic. The plasma protein binding of fentanyl is 80-85%. The main

binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to

some extent. The mean oral volume of distribution at steady state (Vss/F) was 25.4 L/kg.

Metabolism:

The metabolic pathways following buccal administration of FENTORA have not been

characterized in clinical studies. The progressive decline of fentanyl plasma concentrations

results from the uptake of fentanyl in the tissues and biotransformation in the liver. Fentanyl is

metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4

isoform. In animal studies, norfentanyl was not found to be pharmacologically active.

Excretion:

Disposition of fentanyl following buccal administration of FENTORA has not been

characterized in a mass balance study. Fentanyl is primarily (more than 90%) eliminated by

biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the

administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged

in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less

important.

The total plasma clearance of fentanyl following intravenous administration is approximately

42 L/h.

Special Populations and Conditions

Pediatrics:

Individuals under 18 years of age should not take

FENTORA

tablets.

Geriatrics:

No formal study has been performed to assess FENTORA pharmacokinetics in

elderly subjects or patients. Patients over the age of 65 years tended to titrate to slightly lower

doses than younger patients (see

WARNINGS AND PRECAUTIONS, Special Populations,

Geriatrics (> 65 years of age)

Gender:

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.

Systemic exposure was higher for women than men (mean C

and AUC values were

approximately 20% and 17% higher, respectively). The observed differences between men and

FENTORA

Page 36 of 59

women were largely attributable to differences in weight.

Race:

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 non-Japanese subjects (mean C

and AUC values

were approximately 50% and 20% higher, respectively). The observed differences were largely

attributed to the lower mean weight of the Japanese subjects compared to non-Japanese subjects

(57.4 kg versus 73 kg).

Hepatic Impairment:

Insufficient information exists to make recommendations regarding the

use of FENTORA in patients with impaired 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 of

fentanyl.

Renal Impairment:

Insufficient information exists to make recommendations regarding the use

of FENTORA in patients with impaired renal 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 renal excretion of fentanyl.

STORAGE AND STABILITY

FENTORA (fentanyl buccal/sublingual effervescent tablets) is supplied in individually sealed,

child-resistant blister packages. The amount of fentanyl contained in FENTORA can be fatal to a

child.

Patients and their caregivers must be instructed to keep FENTORA out of the reach

of children.

Store in original package at 20 to 25ºC, with excursions permitted between 15° and 30°C, until

ready to use.

Protect FENTORA from moisture. Do not use if the blister package has been tampered with.

DOSAGE FORMS, COMPOSITION AND PACKAGING

FENTORA (fentanyl buccal/sublingual effervescent tablets) are flat-faced, round, beveled-edge

in shape; are white in color; and are available in strengths of 100 mcg, 200 mcg, 400 mcg,

600 mcg and 800 mcg fentanyl, as fentanyl citrate. Each tablet strength is marked with a unique

identifier and is contained in a uniquely coloured carton/blister package, as described in the table

below.

Dosage Strength

Debossing

Carton/Blister Package

Colour

100 mcg

Blue

200 mcg

Orange

FENTORA

Page 37 of 59

400 mcg

Sage green

600 mcg

Magenta (pink)

800 mcg

Yellow

Note: Carton/blister package colours are a secondary aid in product identification. Please be

sure to confirm the printed dosage before dispensing.

Composition:

The FENTORA tablet is a solid formulation of fentanyl citrate. All tablet strengths are expressed

as the amount of fentanyl free base, e.g. the 100 mcg strength contains 100 mcg of fentanyl free

base.

Inactive Ingredients:

Citric acid, magnesium stearate, mannitol, sodium bicarbonate,

sodium carbonate, and sodium starch glycolate.

Packaging:

Each carton contains 7 blister cards with 4 white tablets in each card. The blisters are child-

resistant, encased in peelable foil, and provide protection from moisture. Each tablet is debossed

on one side with

, and the other side of each dosage strength is uniquely identified by the

debossing on the tablet as described in the table above. In addition, the dosage strength is

indicated on the blister package and the carton. See blister package and carton for product

information.

FENTORA

Page 38 of 59

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name

Fentanyl citrate

Chemical name:

N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1)

Molecular formula and molecular mass:

O ꞏ C

Free base: 336.5

Citrate salt: 528.6

Structural formula:

Physicochemical properties of fentanyl citrate, including solid state:

Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1)

that is freely soluble in organic solvents and sparingly soluble in water (1:40). The pKa of the

tertiary nitrogens are 7.3 and 8.4.

Drug Product

FENTORA employs the OraVescent

drug delivery technology, which generates a reaction that

releases carbon dioxide when the tablet comes in contact with saliva. It is believed that transient

pH changes accompanying the reaction may optimize dissolution (at a lower pH) and absorption

through the membrane (at a higher pH) of fentanyl through the buccal mucosa.

FENTORA

Page 39 of 59

CLINICAL TRIALS

Study Demographics and Trial Design

The efficacy of FENTORA was demonstrated in two double-blind, placebo-controlled, cross-

over studies in opioid tolerant patients with cancer and breakthrough pain.

In these studies, patients were titrated in an open-label manner to a successful dose of

FENTORA. A successful dose was defined as the dose in which a patient obtained adequate

analgesia with tolerable side effects. Patients who identified a successful dose were randomized

to a sequence of 10 treatments with 7 being the successful dose of FENTORA and 3 being

placebo. Patients used one tablet of study drug (either FENTORA or Placebo) per breakthrough

pain episode.

Patients assessed pain intensity on a scale that rated the pain as 0=none to 10=worst possible

pain. With each episode of breakthrough pain, pain intensity was assessed first and then

treatment was administered. Pain intensity (0-10) was measured at 15, 30, 45 and 60 minutes for

Study 1 and at 5, 10, 15, 30, 45, 60, 90, and 120 minutes for Study 2, after the start of

administration. The sum of differences in pain intensity scores at 15 and 30 minutes from

baseline (SPID

) was the primary efficacy measure in Study 1 and the sum of differences in pain

intensity scores at 5 through 60 minutes from baseline (SPID

) was the primary efficacy

measure in Study 2.

Study results

Sixty-five percent (65%) of patients in Study 1 and 70% of patients in Study 2, who entered the

respective study, achieved a successful dose during the titration phase. The distribution of

successful doses is shown in Table 6. The median dose for both studies was 400 mcg.

Table 6

Successful Dose of FENTORA Following Initial Titration

FENTORA Dose

Study 1 (N=80)

n (%)

Study 2 (N=87)

n (%)

100 mcg

13 (16)

7 (8)

200 mcg

11 (14)

10 (12)

400 mcg

21 (26)

16 (18)

600 mcg

10 (13)

24 (28)

800 mcg

25 (31)

30 (34)

For Study 1, the LS mean (SE) SPID

for FENTORA-treated episodes was 3.0 (0.12) while for

placebo-treated episodes it was 1.8 (0.18), and for Study 2, the LS mean (SE) SPID

FENTORA-treated episodes was 9.8 (0.26) while for placebo-treated episodes it was 5.0 (0.38).

FENTORA

Page 40 of 59

Figure 2

Mean Summed Pain Intensity Differences (SPID) at Each Time Point

during the Double-Blind Treatment Period (Study 1)

Figure 3

Mean Summed Pain Intensity Differences (SPID) at Each Time Point

during the Double-Blind Treatment Period (Study 2)

FENTORA

Page 41 of 59

Statistically significant improvement in pain intensity difference was seen with FENTORA

versus placebo as early as 15 minutes (earliest time point measured) in Study 1 and as early as

10 minutes in Study 2. These differences continued to be significant at each subsequent time

point in each individual study.

Long-term Open-label Study

Efficacy and safety of FENTORA was supported in a long-term, open-label study in opioid-

tolerant patients with cancer and breakthrough pain, in which patients were treated for up to 23

months.

DETAILED PHARMACOLOGY

Pharmacodynamics

Fentanyl citrate is a potent opioid analgesic with pharmacological effects similar to morphine.

Fentanyl (N-[1-phenethyl-4-piperidyl]propionanilide) is chemically related to the

phenylpiperidines, with potent agonist properties at µ-opioid receptors located in various regions

throughout the central nervous system. Fentanyl possesses analgesic activity with a potency

estimated to be about 80-fold higher than that of morphine.

In addition to analgesia, interaction with the µ-opioid receptor is also believed to be responsible

for the respiratory depression associated with opioids. Narcotic antagonists, such as naloxone,

have been shown to be useful in reversing fentanyl overdose or in stimulating recovery after high

dose fentanyl-induced anesthesia.

Safety pharmacology evaluations of fentanyl citrate were performed on major organ systems

including the cardiovascular, respiratory and central nervous systems.

Safety Pharmacology

Cardiovascular Effects:

A cardiovascular safety evaluation study was performed to evaluate the

potential effects of fentanyl citrate on arterial blood pressure, heart rate and electrocardiography,

including the appropriate intervals, following subcutaneous dosing at doses of 0 (vehicle), 0.001,

0.01, or 0.05 mg/kg in conscious unrestrained Beagle dogs. Four male Beagle dogs, surgically

implanted with telemetry transducers, were used for this study. Administration of 0.001 and 0.01

mg/kg fentanyl citrate had no effect on arterial blood pressure, heart rate or lead II ECG

parameters. Administration of 0.5 mg/kg fentanyl citrate produced a decrease in heart rate

between 15 and 45 minutes post-dosing and also at 360 minutes post-dosing. Correspondingly,

the RR and PR interval, QRS duration and QT interval increased in comparison with the vehicle

control data. The increases in QT interval were comparable to the baseline (pre-dose) values in

the 0.05 mg/kg group and, in this regard, the changes noted in QT were not associated to test

article administration. At the 120-minute post-dose interval, the mean value for QTcQ was

notably higher relative to the respective pre-dose value and statistically significantly higher than

the concurrent vehicle control value. Due to this isolated (acute) occurrence of this increase as

well as the variability of increase within dogs in this group (13 to 34% elevated from the

respective individual pre-dose values), the toxicological significance of this finding was

considered to be equivocal. The decrease in heart rate contributed to a number of escape

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complexes. Administration of 0.05 mg/kg fentanyl citrate was also associated with an increase

in QTc interval and QRS duration at 120 minutes post dosing.

Respiratory Effects:

A respiratory safety pharmacology study was performed to assess potential

adverse effects of fentanyl citrate on respiration rate and tidal volume in conscious rats. Male

Sprague-Dawley rats (n=8 rats/group) were given a single subcutaneous dose of 0 (vehicle),

0.003, 0.03 or 0.3 mg/kg fentanyl citrate, or a single intravenous dose of 20 mg/kg morphine

(reference control). In this study, subcutaneous administration of 0.003 and 0.03 mg/kg had no

adverse effect on respiration rate or tidal volume, when compared to the vehicle control group.

A subcutaneous dose of 0.3 mg/kg produced a significant decrease in respiration rate at 30

minutes and 5 h post-dosing and a significant decrease in tidal volume at 30 minute post-dosing,

when compared to the vehicle control group. The effect on respiration rate is considered to be

consistent with an exaggerated pharmacological effect (CNS) of fentanyl citrate.

Central Nervous System:

Potential effects of fentanyl citrate on the central nervous system

(CNS) were evaluated using the Irwin test. Groups of 6 male Sprague-Dawley rats were

administered fentanyl citrate via subcutaneous injection at doses of 0 (vehicle), 0.003, 0.03 or 0.3

mg/kg. Subcutaneous administration of 0.003 mg/kg produced no changes in behavior as

compared to the vehicle control group, where as a dose of 0.03 mg/kg produced signs of

stereotypic behavior (cage licking) at the 30 minute post-dosing interval. The high dose of 0.3

mg/kg fentanyl citrate produced signs that were indicative of a generalized depression of the

central nervous system, i.e., signs associated with decreased locomotor activity, decreased grip

strength, decreased body tone, and decreased pain response. These signs of CNS depression

were consistent with an exaggerated pharmacologic effect of fentanyl citrate. The effects

observed following administration of 0.3 mg/kg fentanyl citrate were transient with signs of

recovery having occurred approximately 5 h post-dosing and complete recovery being noted

approximately 24 h post-dosing.

TOXICOLOGY

The toxicity profile of fentanyl by various routes of administration is well-established.

Single and Repeat-dose Toxicity

Acute toxicity studies showed that the fentanyl mortality dose response curve in mice was

biphasic following both subcutaneous and intravenous dosing. The mechanism for this biphasic

response is not known, but the mortality observed at the low end of the dose-response curve was

considered to be associated with respiratory depression. Median lethal fentanyl doses (LD

following intravenous and subcutaneous administration of fentanyl to mice were 11.2 and

62 mg/kg, respectively.

In rats, the mean acute LD

following intravenous administration was calculated to be 6 mg/kg,

following subcutaneous administration was calculated to be 3.1 to 12 mg/kg and following oral

administration was calculated to be 18 mg/kg.

In dogs, an extensive investigation of the cardiovascular, neurological and metabolic side effects

was evaluated using 8 opioids. The findings, which applied to all opioids tested, indicated an

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inverse relationship between analgesic potency and hemodynamic, neurological and metabolic

toxicity. In general, the more potent and shorter acting the opioid, the higher the margin of

safety.

A number of repeat-dosing studies, ranging in duration from 2 to 13 weeks, using fentanyl by

parenteral routes in mice, rat, rabbit and dog have been reported. In rats, deaths occurred

following oral doses of 10 mg/kg/day or more or at intramuscular doses of 0.1 or 0.4 mg/kg/day.

The main findings in the majority of these studies were adverse effects on CNS (decreased

activity, impaired righting reflex, prostration) and weight gain, and there was no clear-cut

evidence to suggest direct organ or tissue toxicity although the range of parameters examined

was limited. Fentanyl was well tolerated in rabbits in transcutaneous route studies of up to

90 days' duration and no deaths occurred in dogs administered the drug by the intramuscular

route, at a maximum dose of 0.4 mg/kg/day for 4 weeks. In FVB/N mice, dermal application up

to 500 mcg/mouse for 28 days (in support of dose selection for a 26-week carcinogenicity study

in transgenic mice, Tg.AC strain) resulted in hyperactivity and slightly lower body weight gains

relative to concurrent control values.

Genotoxicity

Fentanyl citrate was evaluated in a standard battery of genotoxicity studies, an in vitro bacterial

reverse mutation assay, an in vitro mammalian cell (L5178Y mouse lymphoma cells)

mutagenicity assay, and an in vivo

mouse micronucleus assay.

In the in vitro mutation studies, there was no evidence of mutagenicity in

Salmonella

typhimurium

test strains TA98, TA100, TA1535, and TA1537 and

Escherichia coli

test strain

uvrA

, in the presence and absence of metabolic activation (Aroclor-induced rat liver S9).

Fentanyl was negative for induction of micronucleated polychromatic erythrocytes (MNPCE) in

an in vivo mouse bone marrow cytogenetic assay. In vitro and in vivo genotoxicity studies did

not show any evidence for a genotoxic potential for fentanyl.

Carcinogenicity

A 26-week Tg.AC transgenic mouse dermal carcinogenicity study was conducted with fentanyl.

The mice were treated with daily dermal applications of 5, 15 or 50 mcg/dose/day of fentanyl in

acetone. A positive control group was included and was dosed dermally with 1.25 mcg TPA in

acetone, three times per week. There were no treatment-related increases in the incidence of

dermal papilloma formation at the site of application, and no increase in the occurrence of

neoplastic lesions. The positive control produced the expected significant increase in the

incidence of dermal papillomas at the site of application, thereby validating the results of this

26-week dermal carcinogenicity study.

A 104-week subcutaneous carcinogenicity study in rats was conducted with fentanyl citrate.

Dose levels evaluated in this study were 0, 12.5, 25, and 50 mcg/kg/day for male rats, and 0, 25,

50 and 100 mcg/kg/day for female rats (dose levels expressed as fentanyl base). Fentanyl did not

produce any microscopic findings that were indicative of oncogenic potential following lifetime

exposure.

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Reproductive and Developmental Toxicity

Developmental and reproductive toxicity studies consisting of a fertility and general reproductive

performance study in rats, studies to assess embryo-fetal development in rats and rabbits, and a

study in rats to determine pre- and postnatal development, including an evaluation of behavior,

learning and reproductive function in the F

offspring have been performed.

In the fertility and early embryonic development study in rats where treated male rats were

mated with untreated female rats and treated female rats were mated with untreated males, a

male mediated effect was observed in the untreated females mated with males given

subcutaneous doses of 300 mcg/kg/day for 28 days prior to mating. The observed effects in

these untreated females included significant decreases in implantation sites, significant increases

in pre-implantation loss and decreases in viable embryos. These effects were related to severe

changes in sperm parameters including a significant decrease in the percentage of mobile sperm

and sperm concentrations, and a significant increase in the percentage of abnormal sperm. These

effects were considered to be indirect effects of fentanyl treatment in these male rats. Due to the

marked sedation noted in these males, it is likely that the testis was pushed into the inguinal

canal, thereby affecting the temperature of the testis leading to adverse effects on

spermatogenesis in these males. No reproductive effects were seen in treated females mated

with untreated males.

Embryo-fetal developmental toxicity studies were also conducted in rats and rabbits. Although

the expected exaggerated pharmacological effects of fentanyl were observed in both studies,

there were no fentanyl-related malformations or developmental variations observed in pregnant

female rats at subcutaneous doses up to 100 mcg/kg/day, or in pregnant rabbits at subcutaneous

doses up to 250 mcg/kg/day, when administered during the period of organogenesis.

In a pre- and post-natal developmental toxicity study which evaluated the effect of fentanyl

citrate on the pregnant/lactating female rat and on development of the conceptus and offspring

following exposure of the female from implantation through weaning, mortality and exaggerated

pharmacological effects were observed at doses of 100 and 400 mcg/kg/day. Based upon the

significant maternal toxicity observed at 400 mcg/kg/day, several adverse effects were observed

in the F

litters. The number of live pups/litter was significantly decreased on post-natal day 4 at

400 mcg/kg/day. Clinical signs observed in these F

pups during the lactation included decreased

activity, skin cold to touch, and moribundity. In this group, pup body weights were lower

throughout lactation, and continued to be lower throughout the premating, mating and gestation

period. In the 400 mcg/kg/day group, a delay in static righting reflex and eye opening, and

reduced auditory response were observed. Sexual maturation was delayed in these high-dose

pups. Motor activity parameters were also affected by treatment with 400 mcg/kg/day. No

effects on reproductive and fertility parameters were observed in the F

pups, although the mean

implantation sites were reduced in the F

pups from the 400 mcg/kg/day group.

Test article-related clinical signs in F

pups during the lactation period consisted of decreased

activity, skin cold to touch, and moribundity. Pup body weights by sex and both sexes combined

were significantly reduced throughout the lactation period (PND 0-21) and continued to be lower

throughout the premating, mating, and gestation period at 400 mcg/kg/day. Male pup body

weights were significantly lower on PND 4 (pre- and post- culling) at 100 mcg/kg/day. A test

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Page 45 of 59

article-related delay in static righting reflex and eye opening and reduced auditory response were

observed in pups at 400 mcg/kg/day. Additionally, vaginal opening and preputial separation

were significantly delayed at 400 mcg/kg/day. Some motor activity parameters were also

affected at 400 mcg/kg/day. No effect on F

reproductive and fertility parameters were seen in

any of the dosing groups; however, mean implantation sites per animal were significantly

reduced at 400 mcg/kg/day. A dose-related systemic exposure of pregnant female rats to

fentanyl and norfentanyl was demonstrated following once-daily subcutaneous administration of

25, 50, 100 or 400 mcg/kg/day fentanyl base for up to approximately 5 weeks (i.e. from GD 6 to

LD 20). Based on the results of this pre- and postnatal developmental toxicity study, the no-

observed-adverse-effect level (NOAEL) for maternal, reproductive, and developmental toxicity

was considered to be 50 mcg/kg/day.

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REFERENCES

Darwish M, Kirby M, Jiang JG. Effect of Buccal Dwell Time on the Pharmacokinetic

Profile of Fentanyl Buccal Tablet. Expert Opin Pharmacother 2007; 8(13):2011-2016.

Darwish M, Kirby M, Robertson P, Tracewell W, Jiang JG. Absolute and Relative

Bioavailability of Fentanyl Buccal Tablet and Oral Transmucosal Fentanyl Citrate. J Clin

Pharmacol 2007; 47:343-350.

Darwish M, Kirby M, Robertson P, Tracewell W, Jiang JG. Absorption of Fentanyl from

Fentanyl Buccal Tablet in Cancer Patients with or without Oral Mucositis: A Pilot Study.

Clin Drug Invest 2007; 27(9):605-611.

Darwish M, Kirby M, Robertson P, Tracewell W, Jiang JG. Pharmacokinetic Properties

of Fentanyl Effervescent Buccal Tablets: A Phase I, Open-Label, Crossover Study of

Single-Dose 100, 200, 400, and 800 µg in Healthy Adult Volunteers. Clinical

Therapeutics 2006; 28(5):707-714.

Darwish M, Tempero K, Kirby M, Thompson J. Pharmacokinetics and Dose

Proportionality of Fentanyl Effervescent Buccal Tablets in Healthy Volunteers. Clin

Pharmacokinet 2005; 44(12):1279-1286.

Darwish M, Tempero K, Kirby M, Thompson J. Relative Bioavailability of the Fentanyl

Effervescent Buccal Tablet (FEBT) 1080 µg Versus Oral Transmucosal Fentanyl Citrate

1600 µg and Dose Proportionality of FEBT 270 to 1300 µg: A Single-Dose,

Randomized, Open-Label, Three-Period Study in Healthy Adult Volunteers. Clinical

Therapeutics 2006; 28(5):715-724.

Portney RK, Taylor D, Messina J, Tremmel L. A Randomized, Placebo-controlled Study

of Fentanyl Buccal Tablet for Breakthrough Pain in Opioid-treated Patients with Cancer.

Clin J Pain 2006; 22(9):805-811.

Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl Buccal Tablet for Relief of

Breakthrough Pain in Opioid-Tolerant Patients with Cancer-Related Chronic Pain. J

Support Oncol 2007; 5(7):327-334.

Weinstein SM, Messina J, Xie F. Fentanyl Buccal Tablet for the Treatment of

Breakthrough Pain in Opioid-Tolerant Patients with Chronic Cancer Pain. Cancer 2009;

2571-2579.

Zeppetella G, Messina J, Xie F, Slatkin NE. Consistent and Clinically Relevant Effects

with Fentanyl Buccal Tablet in the Treatment of Patients Receiving Maintenance Opioid

Therapy and Experiencing Cancer-Related Breakthrough Pain. Pain Practice 2010.

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READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

PATIENT MEDICATION INFORMATION

N

FENTORA

TM

fentanyl buccal

sublingual effervescent tablets

Read this carefully before you start taking

FENTORA

and each time you get a refill. This leaflet

is a summary and will not tell you everything about this drug. Talk to your healthcare

professional about your medical condition and treatment and ask if there is any new information

about

FENTORA

Serious Warnings and Precautions

Do not use FENTORA unless you are regularly using another opioid pain medicine

continuously for your cancer pain and your body is used to these medicines (this

means you are opioid tolerant). You can ask your healthcare professional if you are

opioid tolerant.

Even if you take FENTORA as prescribed you are at a risk for opioid addiction,

abuse and misuse. This can lead to overdose and death.

You may get life-threatening breathing problems while taking FENTORA. This is

less likely to happen if you take it as prescribed by your doctor. Babies are at risk

of life-threatening breathing problems if their mothers take opioids while pregnant

or nursing.

You should never give anyone your FENTORA. They could die from taking it. If a

person has not been prescribed FENTORA, taking even one dose can cause a fatal

overdose. This is especially true for children and for an adult who is not already

taking opioids continuously.

In an emergency, try to remove FENTORA from the mouth.

If you stop taking your regular opioid pain medicine for your cancer pain, you must

stop using FENTORA. You may no longer be opioid-tolerant. Talk to your

healthcare professional about how to treat your pain.

You or a family member should call your doctor or get emergency medical help

immediately if you have trouble breathing, drowsiness with slow breathing, slow

shallow breathing (little chest movement with breathing) or feel faint, dizzy,

confused, or have other unusual symptoms. These can be symptoms of an overdose

with FENTORA. Your dose of FENTORA may be too high for you. These

FENTORA

Page 48 of 59

symptoms may lead to serious problems or death if not treated immediately. If you

have any of the above symptoms, do not take another dose of FENTORA.

Use FENTORA exactly as prescribed by your healthcare professional.

You must begin treatment with FENTORA at the lowest dose of 100 mcg.

You must not use more than ONE dose of FENTORA for each episode of

breakthrough cancer pain.

You must wait at least 4 hours before treating a new episode of breakthrough

pain with FENTORA.

You must not treat more than 4 episodes of breakthrough pain per day. Talk

to your healthcare professional if you have more than 4 episodes of

breakthrough cancer pain per day. The dose of your around-the-clock opioid

pain medicine may need to be changed.

Do not switch from FENTORA to other medicines that contain fentanyl without

talking with your healthcare professional. The amount of fentanyl in a dose of

FENTORA is not the same as the amount of fentanyl in other medicines that

contain fentanyl. Your healthcare professional will prescribe a starting dose of

FENTORA that may be different than other fentanyl containing medicines you may

have been taking.

If you took FENTORA while you were pregnant, whether for short or long periods

of time or in small or large doses, your baby

can suffer life-threatening withdrawal

symptoms after birth. This can occur in the days after birth and for up to 4 weeks

after delivery. If your baby has any of the following symptoms:

has changes in their breathing (such as weak, difficult or fast breathing)

is unusually difficult to comfort

has tremors (shakiness)

has increased stools, sneezing, yawning, vomiting, or fever

Seek immediate medical help for your baby.

Keep FENTORA in a safe place away from children and pets. Do not use

FENTORA in front of children.

Taking FENTORA with other opioid medicines, benzodiazepines, alcohol, or other

central nervous system depressants (including street drugs) can cause severe

drowsiness, decreased awareness, breathing problems, coma, and death.

What is FENTORA used for?

FENTORA is used to manage sudden bursts of pain described as “breakthrough pain” in adults

with cancer who are already taking other opioid pain medicines regularly for cancer pain.

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FENTORA is started only after you have been taking other opioid pain medicines and your body

has become used to them (you are “opioid–tolerant”). Do not use FENTORA if you are not

opioid-tolerant. Do not use FENTORA if you are under 18 years of age.

How does FENTORA work?

FENTORA is a painkiller belonging to the class of drugs known as opioids. It relieves pain by

acting on specific nerve cells of the spinal cord and brain.

What are the ingredients in FENTORA?

Medicinal ingredients: Fentanyl citrate

Non-medicinal ingredients: Citric acid, magnesium stearate, mannitol, sodium bicarbonate,

sodium carbonate, sodium starch glycolate

FENTORA comes in the following dosage forms:

FENTORA is a tablet that you place between your gum and cheek or under the tongue. These

tablets are called “Buccal/Sublingual Effervescent Tablets” and they come in strengths of 100,

200, 400, 600 and 800 micrograms of fentanyl. Each tablet strength comes in a box and blister

pack with a different colour, as shown below:

Tablet

Strength

Box and Blister

Colour

100 mcg

Blue

200 mcg

Orange

400 mcg

Sage green

600 mcg

Magenta (pink)

800 mcg

Yellow

Do not use FENTORA if:

your doctor did not prescribe it for you

you are not taking other opioid pain medicines for your cancer pain. Your body must

already be used to taking opioid pain medicine when you take FENTORA.

you are allergic to fentanyl citrate or any of the other ingredients in FENTORA.

you have severe asthma, trouble breathing, or other breathing problems

you have any heart problems

you have bowel blockage or narrowing of the stomach or intestines

you have severe pain in your abdomen

you have a head injury

you are at risk for seizures

you suffer from alcoholism

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you are taking or have taken within the past 2 weeks a Monoamine Oxidase inhibitor

(MAOi) (such as phenelzine sulphate, tranylcypromine sulphate, moclobemide or

selegiline).

you are going to have, or recently had, a planned surgery

you are in labour

you are breastfeeding

To help avoid side effects and ensure proper use, talk to your healthcare professional

before you take FENTORA. Talk about any health conditions or problems you may have,

including if you:

have a history of illicit or prescription drug or alcohol abuse

have severe kidney, liver or lung disease

have low blood pressure

have a history of sleep apnea

have past or current depression

suffer from migraines

suffer from chronic or severe constipation

have problems with your thyroid, adrenal or prostate gland

have, or had in the past, hallucinations or other severe mental problems

are pregnant or planning to become pregnant

Other warnings you should know about:

Opioid dependence and addiction:

There are important differences between physical

dependence and addiction. It is important that you talk to your doctor if you have questions or

concerns about abuse, addiction or physical dependence.

Pregnancy, nursing, labour and delivery:

Opioids can be transferred to your baby through

breast milk, or while still in the womb. FENTORA can then cause life-threatening breathing

problems in your unborn baby or nursing infant. Your doctor will determine if the benefits of

using FENTORA outweigh the risks to your unborn baby or nursing infant.

If you are pregnant and are taking FENTORA, it is important that you don’t stop taking your

medication all of a sudden. If you do, it can cause a miscarriage or a still-birth. Your doctor will

monitor and guide you on how to slowly stop taking FENTORA. This may help avoid serious

harm to your unborn baby.

Driving and using machines:

Before you do tasks which may require special attention, you

should wait until you know how you react to FENTORA. FENTORA can cause:

drowsiness

dizziness or

lightheadedness

This can usually occur after you take your first dose and when your dose is increased.

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Disorder of the adrenal gland:

You may develop a disorder of the adrenal gland called adrenal

insufficiency. This means that your adrenal gland is not making enough of certain hormones.

You may experience symptoms such as:

nausea, vomiting

feeling tired, weak or dizzy

decreased appetite

You may be more likely to have problems with your adrenal gland if you have been taking

opioids for longer than one month. Your doctor may do tests, give you another medication, and

slowly take you off FENTORA.

Serotonin Syndrome:

FENTORA can cause Serotonin Syndrome, a rare but potentially life-

threatening condition. It can cause serious changes in how your brain, muscles and digestive

system work. You may develop Serotonin Syndrome if you take FENTORA with certain anti-

depressants, migraine or muscle relaxants medications.

Serotonin Syndrome symptoms include:

fever, sweating, shivering, diarrhea, nausea, vomiting;

muscle shakes, jerks, twitches or stiffness, overactive reflexes, loss of coordination;

fast heartbeat, changes in blood pressure;

confusion, agitation, restlessness, hallucinations, mood changes, unconsciousness, and

coma.

Sexual Function/Reproduction:

Long term use of opioids may lead to a decrease in sex

hormone levels. It may also lead to low libido (desire to have sex), erectile dysfunction or being

infertile.

Sleep apnea:

Opioids can cause a problem called sleep apnea (stopping breathing from time to

time while sleeping). Tell your doctor if you have a history of sleep apnea or if anyone notices

that you stop breathing from time to time while sleeping.

Tell your healthcare professional

about all the medicines you take, including any drugs,

vitamins, minerals, natural supplements or alternative medicines.

The following may interact with FENTORA:

Alcohol. This includes prescription and non-prescription medications that contain

alcohol.

Do not

drink alcohol while you are taking FENTORA. It can lead to:

drowsiness

unusually slow or weak breathing

serious side effects or

a fatal overdose

other sedative drugs which may enhance the drowsiness caused by FENTORA

other opioid analgesics (drugs used to treat pain)

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Page 52 of 59

general anesthetics (drugs used during surgery)

benzodiazepines (drugs used to help you sleep or that help reduce anxiety)

antidepressants (for depression and mood disorders).

Do not

take FENTORA with MAO

inhibitors (MAOi) or if you have taken MAOi’s in the last 14 days.

drugs used to treat migraines (e.g. triptans)

drugs used to treat serious mental or emotional disorders (such as schizophrenia)

antihistamines (drugs used to treat allergies)

anti-emetics (drugs used for the prevention of vomiting)

drugs used to treat muscle spasms and back pain

CYP3A4 inhibitors and inducers. (Ask your healthcare professional about these drugs if

you think you may be taking them.)

grapefruit juice

St. John’s Wort

How to take FENTORA:

Usual Adult Starting Dose:

All patients MUST begin treatment using one 100 microgram FENTORA tablet.

To find the right dose for you, your doctor will instruct you on how to safely increase your dose

until you reach a dose that gives you enough pain relief. If there are any side effects, they should

be acceptable to you.

Your dose is tailored/personalized just for you. Be sure to follow your doctor’s dosing

instructions exactly.

Do not increase or decrease your dose without consulting your doctor.

Review your pain regularly with your doctor to determine if you still need FENTORA. Be sure

to use FENTORA only for the condition for which it was prescribed.

If your pain increases or you develop any side effect as a result of taking FENTORA, tell your

doctor immediately.

Your doctor will give you a prescription to treat up to four breakthrough pain episodes per

day by using the right dose.

Do not split, suck, chew, or swallow FENTORA tablets. You will get less relief for your

breakthrough cancer pain. Use FENTORA tablets whole.

Wait 30 minutes after using FENTORA. If any FENTORA tablet is left in your mouth, you may

drink a glass of water to help you swallow the left-over medicine.

You must not use more than one dose of FENTORA for each episode of breakthrough cancer

pain.

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Page 53 of 59

If your breakthrough pain does not get better after the single dose of FENTORA, call

your healthcare professional for instructions.

Do not use another dose of FENTORA

for the same episode of breakthrough pain.

Wait at least

4

hours before treating a new episode of breakthrough cancer pain with FENTORA.

Take only one dose of FENTORA for an episode of breakthrough pain. You must wait

4

hours from the time of that dose to take another dose of FENTORA for a

new

episode of

breakthrough pain.

It is important for you to keep taking your opioid pain medicine regularly while using

FENTORA.

Talk to your healthcare professional if your dose of FENTORA does not relieve your

breakthrough cancer pain. Your healthcare professional will decide if your dose of FENTORA

needs to be changed. Do not skip to a higher dose unless instructed to do so by your doctor.

Do not treat more than 4 breakthrough pain episodes per day with FENTORA. Talk to your

healthcare professional if you have more than 4 episodes of breakthrough cancer pain per day.

The dose of your regular opioid pain medicine may need to be changed.

If you begin to feel dizzy, sick to your stomach, or very sleepy before the tablet is completely

dissolved, rinse your mouth with water and spit the remaining pieces of the tablet into a sink or

toilet right away. Rinse the sink or flush the toilet to dispose of any remaining tablet pieces.

FENTORA Dosing Instructions:

When you get an episode of breakthrough cancer pain, use the dose of FENTORA

prescribed by your healthcare professional as follows:

FENTORA comes packaged as a blister card containing 4 blister units. Each blister unit contains

1 FENTORA tablet.

Do not open a blister until ready to use.

Separate one of the blister units from the blister card by tearing apart at the perforations.

Figure 1

Bend the blister unit along the line where indicated. The product strength of your

FENTORA tablets will be printed in the box below and in

Figure 1

FENTORA

Page 54 of 59

Figure 1

Peel back foil on blister unit to expose tablet (see

Figure 2

Figure 2

Do not push the tablet

through the foil on the blister unit because this could damage the

tablet.

When removed from the blister unit, FENTORA tablet must be used right away.

Do not split the FENTORA tablet.

Use FENTORA tablets whole

You can place a FENTORA tablet in your mouth:

above a back molar tooth between the upper cheek and gum.

Leave the tablet in

place until it dissolves.

A FENTORA tablet generally takes 14 to 25 minutes to

dissolve (see

Figure 3

FENTORA

Page 55 of 59

Figure 3

on the floor of your mouth, under your tongue (see

Figures 4a, 4b, 4c, 4d

When placing the tablet under your tongue, first lift your tongue (

4b

), then place

the tablet under your tongue (

4c

), and lower your tongue over the tablet (

4d

Figure 4a

Figure 4b

Figure 4c

Figure 4d

Leave the tablet in place until it dissolves.

A FENTORA tablet generally takes 14 to

25 minutes to dissolve.

After 30 minutes, if there is any FENTORA left in your mouth, you may drink a glass of

water to help you swallow the left-over medicine.

If you cannot use FENTORA in this manner, tell your healthcare professional. Your

healthcare professional will tell you what to do. Do not split the tablet.

Do not split, suck, chew or swallow FENTORA tablets.

You will get less relief for

your breakthrough cancer pain.

Stopping your Medication

If you have been taking FENTORA for more than a few days you should not stop taking it all of

a sudden. Your doctor will monitor and guide you on how to slowly stop taking FENTORA.

You should do it slowly to avoid uncomfortable symptoms such as having:

body aches

diarrhea

goosebumps

loss of appetite

nausea

feeling nervous or restless

runny nose

FENTORA

Page 56 of 59

sneezing

tremors or shivering

stomach cramps

rapid heart rate (tachycardia)

having trouble sleeping

an unusual increase in sweating

heart palpitations

an unexplained fever

weakness

yawning

By reducing or stopping your opioid treatment, your body will become less used to opioids. If

you start treatment again, you will need to start at the lowest dose. You may overdose if you

restart at the last dose you took before you slowly stopped taking FENTORA.

Refilling your Prescription for FENTORA:

A new written prescription is required from your doctor each time you need more FENTORA.

Therefore, it is important that you contact your doctor before your current supply runs out.

Only obtain prescriptions for this medicine from the doctor in charge of your treatment. Do not

seek prescriptions from other doctors unless you switch to another doctor for your pain

management.

Overdose:

If you think you have taken too much FENTORA, contact your healthcare professional, hospital

emergency department or regional Poison Control Centre immediately, even if there are no

symptoms.

Signs of overdose may include:

unusually slow or weak breathing

dizziness

confusion

extreme drowsiness

In cases of possible overdose try to remove any FENTORA tablets still remaining in the

mouth.

What are possible side effects from using FENTORA?

These are not all the possible side effects you may feel when taking FENTORA. If you

experience any side effects not listed here, contact your healthcare professional.

FENTORA

Page 57 of 59

Side effects may include:

Drowsiness

Insomnia

Dizziness

Fainting

Nausea, vomiting, or a poor appetite

Dry mouth

Headache

Problems with vision

Weakness, uncoordinated muscle movement

Itching

Sweating

Constipation

Low sex drive, impotence (erectile dysfunction), infertility

Talk with your doctor or pharmacist about ways to prevent constipation when you start using

FENTORA.

Serious side effects and what to do about them

Symptom / effect

Talk to your healthcare professional

Stop taking drug

and get immediate

medical help

Only if severe

In all cases

RARE

Overdose:

hallucinations,

confusion, inability to walk

normally, slow or weak

breathing, extreme sleepiness,

sedation or dizziness, floppy

muscles/low muscle tone, cold

and clammy skin.

Respiratory Depression:

Slow, shallow or weak breathing

or shortness of breath.

Allergic Reaction:

rash, hives,

swelling of the face, lips, tongue

or throat, difficulty swallowing

or breathing

Bowel Blockage (impaction):

abdominal pain, severe

constipation, nausea

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Page 58 of 59

Withdrawal:

nausea, vomiting,

diarrhea, anxiety, shivering, cold

and clammy skin, body aches,

loss of appetite, sweating.

Fast, Slow or Irregular

Heartbeat:

heart

palpitations.

Low Blood Pressure:

dizziness,

fainting, light-headedness.

Serotonin toxicity

: a reaction

which may cause feelings of

agitation or restlessness,

flushing, muscle twitching,

involuntary eye movements,

heavy sweating, high body

temperature (>38°C ), or rigid

muscles

If you have a troublesome symptom or side effect that is not listed here or becomes bad enough

to interfere with your daily activities, talk to your healthcare professional.

Reporting Side Effects

We encourage you to report serious or unexpected side effects to Health Canada. The

information is used to check for new safety concerns about health products. As a consumer,

your report contributes to the safe use of health products for everyone.

3 ways to report

Online at MedEffect: https://www.canada.ca/en/health-canada/services/drugs-health-

products/medeffect-canada.html

By calling 1-866-234-2345 (toll-free);

By completing a Consumer Side Effect Reporting Form and sending it by:

Fax to 1-866-678-6789 (toll-free), or

Mail to:

Canada Vigilance Program

Health Canada, Postal Locator 0701E

Ottawa, ON

K1A 0K9

Postage paid labels and the Consumer Side Effect Reporting Form are available

at MedEffect (https://www.canada.ca/en/health-canada/services/drugs-health-

products/medeffect-canada.html).

NOTE: Should you require information related to the management of side effects, contact your

health professional. The Canada Vigilance Program does not provide medical advice.

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Page 59 of 59

Storage:

Keep unused or expired FENTORA in a secure place to prevent theft, misuse or

accidental exposure.

Store FENTORA in original package at 20 - 25

C. If necessary, you may store

FENTORA between 15

and 30

C, until ready to use.

Keep FENTORA in the original blister unit. FENTORA should be used immediately

after opening the child-resistant package. Do not remove FENTORA from its blister

packaging for storage in a temporary container, such as a pill box.

Keep FENTORA dry.

Keep FENTORA under lock, out of sight and reach of children and pets.

Never take medicine in front of small children as they will want to copy you.

Accidental ingestion by a child is dangerous and may result in death. If a child

accidentally takes FENTORA, get emergency help right away.

Disposal:

FENTORA should never be thrown into household trash, where children and pets may

find it.

It should be returned to a pharmacy for proper disposal.

If you want more information about FENTORA:

Talk to your healthcare professional

Find the full product monograph that is prepared for healthcare professionals and includes

this consumer medication information by visiting the Health Canada website

(https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-

products/drug-product-database.html); the manufacturer’s website

http://www.tevacanadainnovation.ca, or by calling 1-855-513-8382.

This leaflet was prepared by Teva Canada Innovation

Last revised: May 28, 2020.

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