Auspar Fentanyl Citrate 150422 Pi

Attachment 1: Product information for AusPAR Fentora Fentanyl citrate Orphan Australia
Pty Ltd PM-2013-03632-1-1 Final 22 April 2015. This Product Information was approved at
the time this AusPAR was published.
PRODUCT INFORMATION
FENTORA
Fentanyl (as Citrate) Orally Disintegrating Tablets
100, 200, 400, 600 and 800 micrograms
NAME OF THE MEDICINE
Fentanyl citrate.
DESCRIPTION
FENTORA (fentanyl citrate) is a synthetic opioid analgesic related to pethidine and with similar
properties to morphine. Fentanyl citrate is a white, crystalline powder with a molecular weight of
528.6 and the molecular formula C22H28N2O,C6H8O7. Its chemical name is N-(1-Phenethyl-4-
piperidyl) propionanilide dihydrogen citrate. The CAS Registry Number for fentanyl citrate is
990-73-8.
The citrate salt is sparingly soluble to soluble in water; sparingly soluble in alcohol; slightly
soluble in chloroform; soluble to freely soluble in methyl alcohol.
FENTORA orally disintegrating tablets are available in five unit strengths equivalent to 100,
200, 400, 600 and 800 micrograms of fentanyl base. The excipients include mannitol, sodium
starch glycollate type A, sodium hydrogen carbonate, sodium carbonate anhydrous, anhydrous
citric acid , magnesium stearate.
FENTORA® – Product Information Page 1 of 24

PHARMACOLOGY
Pharmacodynamic properties
Fentanyl is an opioid analgesic, interacting predominantly with the opioid µ-receptor. Its primary
therapeutic actions are analgesia and sedation. Secondary pharmacological effects are respiratory
depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.
The analgesic effects of fentanyl are related to its plasma level. In general, the effective
concentration and the concentration at which toxicity occurs increase with increasing tolerance to
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).
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
as these patients will develop tolerance to respiratory depressant effects.
Pharmacokinetic Properties
Fentanyl is highly lipophilic and can be absorbed very rapidly through the oral mucosa and more
slowly by the conventional gastrointestinal route. It is subject to first-pass hepatic and intestinal
metabolism and the metabolites do not contribute to fentanyl’s therapeutic effects.
FENTORA employs a delivery technology which utilises an effervescent reaction which

enhances the rate and extent of fentanyl absorbed through the buccal mucosa. Transient pH
changes accompanying the effervescent reaction may optimise dissolution (at a lower pH) and
membrane permeation (at a higher pH).
Dwell time (defined as the length of time that the tablet takes to fully disintegrate following
buccal administration), does not affect early systemic exposure to fentanyl. In addition, a
comparativestudy evaluating the absorption of one 400 micrograms FENTORA tablet
administered either buccally (i.e., between the cheek and the gum) or sublingually met the
criteria of bioequivalence.
The effect of renal or hepatic impairment on the pharmacokinetics of FENTORA has not been
studied.
Absorption:
Following oromucosal 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 rapid absorption from the buccal mucosa, with peak plasma concentrations following
venous sampling generally attained within an hour after oromucosal administration.
Approximately 50% of the total dose administered is rapidly absorbed transmucosally and
becomes systemically available. The remaining half of the total dose is swallowed and slowly
absorbed from the gastrointestinal tract where 30% of it becomes systemically available by
bypassing hepatic and intestinal first-pass elimination.
The main pharmacokinetic parameters are shown in the following table.
Pharmacokinetic Parameters* in Adult Subjects Receiving FENTORA
Pharmacokinetic FENTORA 400 micrograms

parameter (mean)
Absolute 65% (±20%)
bioavailability
Fraction 48% (±31.8%)

absorbed transmucosally
Tmax (minute) ** 46.8 (20-240)
Cmax (ng/ml) 1.02 (± 0.42)
AUC0-tmax (ng.hr/ml) 0.40 (± 0.18)
AUC0-inf (ng.hr/ml) 6.48 (± 2.98)
* Based on venous blood samples (plasma). Fentanyl citrate concentrations obtained in serum
were higher than in plasma: Serum AUC and Cmax were approximately 20% and 30% higher
than plasma AUC and Cmax, respectively. The reason of this difference is unknown.
** Data for Tmax presented as median (range).
In pharmacokinetic studies that compared the absolute and relative bioavailability of FENTORA
and oral transmucosal fentanyl citrate (OTFC), the rate and extent of fentanyl absorption in
FENTORA demonstrated exposure that was between 30% to 50% greater than that for oral
transmucosal fentanyl citrate. If switching from another oral fentanyl citrate product,
independent dose titration with FENTORA is required as bioavailability between products
differs significantly. However, in these patients, a starting dose higher than 100 micrograms may
be considered.

Differences in exposure with FENTORA were observed in a clinical study with patients with
grade 1 mucositis. Cmax and AUC0-8 were 1% and 25% higher in patients with mucositis
compared to those without mucositis, respectively. The differences observed were not
statistically or clinically significant.
Dose proportionality from 100 micrograms to 1000 micrograms of FENTORA has been

demonstrated.
Distribution
Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large
apparent volume of distribution. After buccal administration of FENTORA, fentanyl undergoes
initial rapid distribution that represents an equilibration of fentanyl between plasma and the
highly perfused tissues (brain, heart and lungs). Subsequently, fentanyl is redistributed between
the deep tissue compartment (muscle and fat) and the plasma.
The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha-1-acid
glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of
fentanyl increases with acidosis.

Metabolism
The metabolic pathways following buccal administration of FENTORA have not been
characterised in clinical studies. Fentanyl is metabolised in the liver and in the intestinal mucosa
to norfentanyl by CYP3A4 isoform. Norfentanyl is not pharmacologically active in animal
studies. More than 90% of the administered dose of fentanyl is eliminated by biotransformation
to N-dealkylated and hydroxylated inactive metabolites.
Elimination
Following the intravenous administration of fentanyl, less than 7% of the administered dose is
excreted unchanged in the urine, and only about 1% is excreted unchanged in the faeces. The
metabolites are mainly excreted in the urine, while faecal excretion is less important.
Following the administration of FENTORA, the terminal elimination phase of fentanyl is the
result of the redistribution between plasma and a deep tissue compartment. This phase of
elimination is slow, resulting in a median terminal elimination half-life t1/2 of approximately
22 hours following buccal administration of the effervescent formulation and approximately
18 hours following intravenous administration. The total plasma clearance of fentanyl following
intravenous administration is approximately 42 L/h.
CLINICAL TRIALS
The safety and efficacy of FENTORA have been evaluated in patients taking the drug at the
onset of the breakthrough pain episode. BTP is a transitory exacerbation of pain that occurs on a
background of otherwise controlled persistent pain. Pre-emptive use of FENTORA for
predictable pain episodes was not investigated in the clinical trials.
Two double-blind, randomized, placebo-controlled crossover studies have been conducted

involving a total of 248 patients with BTP and cancer who experienced on average 1 to 4
episodes of BTP per day while taking maintenance opioid therapy. Patients receiving
maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at
least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least
8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or
longer.
During an initial open-label phase, patients were titrated to an effective dose of FENTORA.
Patients who identified an effective dose entered the double-blind phase of the study. The
primary efficacy variable was the patient’s assessment of pain intensity. Patients assessed pain
intensity on a 11-point scale. For each BTP episode, pain intensity was assessed prior to and at
several time points after treatment.
Sixty-seven percent of the patients were able to be titrated to an effective dose.
In the pivotal clinical study (study 1), the primary endpoint was the average sum of differences
in pain intensity scores from dosing to 60 minutes, inclusive (SPID60), which was statistically
significant compared to placebo (p<0.0001).

Study 1: Mean (+/- SEM) Pain Intensity Difference at Each Time Point (Full Analysis Set)
SPID60 mean (+/- SD)

FENTORA=9.7(5.58) p<0.0001
Placebo=4.9(4.38)
+ p<0.0001 FENTORA versus placebo, in favor of FENTORA, by an analysis of variance

PID=pain intensity difference; SEM=standard error of the mean

Study 2: Mean (+/- SEM) Pain Intensity Difference at Each Time Point (Full Analysis Set)
SPID30 mean (+/- SD)

FENTORA=3.2(2.60) p<0.0001
Placebo=2.0(2.21)
* p<0.01 FENTORA versus placebo, in favor of FENTORA, by one-sample Wilcoxon signed rank test
+ p<0.0001 FENTORA versus placebo, in favor of FENTORA, by one-sample Wilcoxon signed rank test
PID=pain intensity difference; SEM=standard error of the mean
In the second pivotal study (study 2), the primary endpoint was SPID30, which was also
statistically significant compared to placebo (p<0.0001).
Statistically significant improvement in pain intensity difference was seen with FENTORA
versus placebo as early as 10 minutes in Study 1 and as early as 15 minutes (earliest time point
measured) in Study 2. These differences continued to be significant at each subsequent time
point in each individual study.
INDICATIONS
FENTORA is indicated for the treatment of breakthrough pain (BTP) in adults with cancer who
are already receiving maintenance opioid therapy for chronic cancer pain.
CONTRAINDICATIONS
FENTORA is contraindicated in:
Hypersensitivity to the active substance or to any of the excipients (see DESCRIPTION).

Patients without maintenance opioid therapy (see CLINICAL TRIALS) as there is an increased
risk of respiratory depression.
Severe respiratory depression or severe obstructive lung conditions.
Treatment of acute pain other than breakthrough pain (e.g. postoperative pain, headache,
migraine).
Simultaneous use of monoamine-oxidase (MAO) inhibitors, or within 2 weeks after the cessation
of the use of MAO inhibitors.
PRECAUTIONS
In order to minimise the risks of opioid-related undesirable effects and to identify the effective
dose, it is imperative that patients be monitored closely by health professionals during the
titration process.
It is important that the long acting opioid treatment used to treat the patient’s persistent pain has
been stabilised before FENTORA therapy begins and that the patient continues to be treated with
the long acting opioid treatment whilst taking FENTORA.
When switching from another oral fentanyl citrate product, independent dose titration is required
as bioavailability between products differ significantly.
Special Risk Patients

Respiratory depression
As with all opioids, there is a risk of clinically significant respiratory depression associated with
the use of fentanyl. Improper patient selection (e.g., use in patients without maintenance opioid
therapy) and/or improper dosing have resulted in fatal outcome with FENTORA as well as with
other fentanyl products.
FENTORA should only be used for conditions specified in INDICATIONS.
CNS Depression
Use of FENTORA in combination with other CNS depressants can result in increased risk to
patients. (see INTERACTIONS WITH OTHER MEDICINES).
Chronic obstructive pulmonary disease

Particular caution should be used when titrating FENTORA in patients with non-severe chronic
obstructive pulmonary disease or other medical conditions predisposing them to respiratory
depression, as even normally therapeutic doses of FENTORA may further decrease respiratory
drive to the point of respiratory failure.
Increased intracranial pressure, impaired consciousness

FENTORA should only be administered with extreme caution in patients who may be
particularly susceptible to the intracranial effects of CO2 retention, such as those with evidence
of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical
course of a patient with a head injury and should be used only if clinically warranted.
Cardiovascular
Intravenous fentanyl may produce bradycardia. In clinical trials with FENTORA, no clear
evidence for bradycardia was observed. However, FENTORA should be used with caution in
patients with pre-existing bradyarrhythmias.
Careful consideration should be given to patients with hypovolaemia and hypotension.
Hepatic and Renal Impairment

FENTORA should be administered with caution to patients with hepatic or renal impairment.
The influence of hepatic and renal impairment on the pharmacokinetics of the medicinal product
has not been evaluated, however, when administered intravenously the clearance of fentanyl has
been shown to be altered in hepatic and renal impairment due to alterations in metabolic
clearance and plasma proteins. After administration of FENTORA, impaired hepatic and renal
function may both increase the bioavailability of swallowed fentanyl and decrease its systemic
clearance, which could lead to increased and prolonged opioid effects.
Therefore, special care should be taken during the titration process in patients with moderate or
severe hepatic or renal impairment.
Serotonin Syndrome
Caution is advised when fentanyl is coadministered with drugs that affect the serotoninergic
neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the
concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs)
and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair
metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur
within the recommended dose.
Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma),
autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular
abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, treatment with fentanyl should be discontinued.
Tolerance, dependence

Tolerance and physical and/or psychological dependence may develop upon repeated
administration of opioids such as fentanyl. However, iatrogenic addiction following therapeutic
use of opioids is rare.
Application site
Application site reactions, including gum bleeding, irritation, pain and ulcer have been reported
in post-marketing use. Therefore caution is advised for patients with mucositis and local
tolerability issues.
Controlled sodium diet

This medicinal product contains 10 mg sodium per 100 micrograms tablet, and 20 mg sodium
per 400, 600 and 800 micrograms tablet. To be taken into consideration by patients on a
controlled sodium diet.
Anaphylaxis and hypersensitivity

Anaphylaxis and hypersensitivity have been reported in association with the use of oral
transmucosal fentanyl products.
Effects on fertility
When male rats treated with fentanyl for 28 days prior to and during mating were mated with
untreated females, adverse effects on sperm parameters, which reduced fertility, were observed
at a high subcutaneous dose of 300 µg/kg/day that also resulted in mortalities. No effects on
fertility were observed following administration of the same dose to females mated with
untreated males. Estimated fentanyl exposure (plasma AUC) at this dose was about 10-fold that
observed following a single dose of 800 µg fentanyl in humans and about 2-fold that observed
after four daily doses of 800 µg fentanyl. Corresponding exposure ratios at the no observed
effect level for fertility (100 µg/kg/day) were 3 and 0.6
Use in pregnancy (Category C)
Fentanyl crosses the placenta in humans and has been found in fetal blood at concentrations
about 40% of those found in maternal blood. There are no adequate data from the use of fentanyl
in pregnant women. In studies in which fentanyl was administered to rats and rabbits at
respective subcutaneous doses of up to 100 and 250 µg/kg/day during the period of
organogenesis, no increased incidence of fetal malformations or variations was observed, but
fetal weights were reduced in rats at the maternotoxic dose of 100 µg/kg/day. Respective
fentanyl exposures (plasma AUC) at these doses in rats and rabbits were about 3- and 5-fold that
observed following a single dose of 800 µg fentanyl in humans, and less than or equal to that
observed in humans after four daily doses of 800 µg fentanyl.
In a study in which rats received subcutaneous fentanyl from early gestation to weaning, reduced
pup survival, growth and development were observed at clearly maternotoxic doses (100 and 400
µg/kg/day). Fentanyl exposure (plasma AUC) at the no-effect dose for pup developmental
toxicity (50 µg/kg/day) was similar to that observed following a single dose of 800 µg fentanyl
in humans and about 0.2-fold that observed after four daily doses of 800 µg fentanyl.
FENTORA should not be used in pregnancy unless clearly necessary.
Use in labour and delivery
It is advised not to use fentanyl during labour and delivery (including caesarean section) because
fentanyl passes through the placenta and may cause respiratory depression in the foetus. If
FENTORA is administered, an antidote for the child should be readily available.
Use in Lactation
Following long-term treatment, fentanyl may cause withdrawal in the new-born infant.
Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breast-
fed child. Fentanyl should not be used by breastfeeding women and breastfeeding should not be
restarted until at least 48 hours after the last administration of fentanyl.
Paediatric Use
FENTORA is not recommended for use in children and adolescents below 18 years due to a lack
of data on safety and efficacy.
Use in the Elderly
In clinical studies patients older than 65 years tended to titrate to a lower effective dose than
younger patients. It is recommended that increased caution should be exercised in titrating the
dose of FENTORA in elderly patients.
Genotoxicity
Fentanyl showed no evidence of genotoxic potential in assays for gene mutations (Ames reverse
mutation test, mouse lymphoma thymidine kinase assay), chromosomal damage (Chinese
hamster ovary cells, mouse micronucleus test) and other genotoxic effects (unscheduled DNA
synthesis in rat hepatocytes, mammalian cell transformation assay). The genotoxic potential of
fentanyl is considered to be low.
Carcinogenicity
Carcinogenicity studies (26-week dermal bioassay in Tg.AC transgenic mice; two-year

subcutaneous study in rats) did not induce any findings indicative of oncogenic potential. At the
highest doses tested in these studies (50 µg/day in mice, 50 µg/kg/day in male rats and 100
µg/kg/day in female rats), systemic exposure (plasma Cmax in mice and AUC in rats) was about 3-
fold (mice and female rats) and about 2-fold (male rats) that observed following a single dose of
800 µg fentanyl in humans.
Effects on ability to drive and use machines
No studies of the effects on the ability to drive and use machines have been performed.
However, opioid analgesics impair the mental and/or physical ability required for the
performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Patients
should be advised not to drive or operate machinery if they experience somnolence, dizziness, or
visual disturbance while taking FENTORA and not to drive or operate machinery until they
know how they react.
INTERACTIONS WITH OTHER MEDICINES
Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system
(CYP3A4), therefore potential interactions may occur when FENTORA is given concurrently
with agents that affect CYP3A4 activity. Coadministration with agents that induce 3A4 activity
may reduce the efficacy of FENTORA. The concomitant use of FENTORA with strong CYP3A4
inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, and
nelfinavir) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem,
erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in
increased fentanyl plasma concentrations, potentially causing serious adverse drug reactions
including fatal respiratory depression. Patients receiving FENTORA concomitantly with
moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of
time. Dosage increase should be done with caution.
The concomitant use of other central nervous system depressants, including other opioids,
sedatives or hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle
relaxants, sedating antihistamines and alcohol may produce additive depressant effects.
FENTORA is not recommended for use in patients who have received monoamine oxidase
(MAO) inhibitors within 14 days because severe and unpredictable potentiation by MAO
inhibitors has been reported with opioid analgesics.
The concomitant use of partial opioid agonists/antagonists (e.g. buprenorphine, nalbuphine,

pentazocine) is not recommended. They have high affinity to opioid receptors with relatively low
intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may
induce withdrawal symptoms in opioid dependant patients.
Serotoninergic Drugs
Coadministration of fentanyl with a serotoninergic agent, such as a Selective Serotonin Re-
uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a
Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a
potentially life-threatening condition.
ADVERSE EFFECTS

The adverse events seen with FENTORA are typical opioid side effects. Frequently, these will
cease or decrease in intensity with continued use of the medicinal product, as the patient is
titrated to the most appropriate dose. However, the most serious adverse reactions are
respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory
depression, hypotension and shock. All patients should be closely monitored for these.
Because the clinical studies of FENTORA were designed to evaluate safety and efficacy in
treating BTP, all patients were also taking concomitant opioids, such as sustained-release
morphine or transdermal fentanyl, for their persistent pain. Thus it is not possible to definitively
separate the effects of FENTORA alone.
The table below summarises the adverse events occurring during the titration and posttitration
periods in at least 5% of patients with cancer and breakthrough pain from three Phase 3 studies
in patients with cancer and BTP:
MedDRA system organ Percentage of patients (%)

class
Preferred term, n (%) Titration Posttitration period Overall (N=358)
period (N=239)
(N=358)
Patients with at least 1 206 (58) 217 (91) 305 (85)
adverse event
Blood and lymphatic system disorders
Anaemia 6 (2) 31 (13) 40 (11)
Neutropenia 3 (<1) 15 (6) 18 (5)
Gastrointestinal disorders
Nausea 59 (16) 71 (30) 110 (31)
Vomiting 19 (5) 51 (21) 63 (18)
Constipation 15 (4) 34 (14) 48 (13)
Diarrhoea 8 (2) 22 (9) 29 (8)
Abdominal pain 5 (1) 25 (10) 27 (8)
Stomatitis 8 (2) 13 (5) 20 (6)
Dyspepsia 1 (<1) 12 (5) 13 (4)
General disorders and administration site conditions
Fatigue 20 (6) 40 (17) 58 (16)
Oedema peripheral 5 (1) 32 (13) 38 (11)
Asthenia 6 (2) 27 (11) 34 (9)
Pyrexia 4 (1) 19 (8) 23 (6)
Infections and infestations
Pneumonia 3 (<1) 21 (9) 24 (7)
Urinary tract infection 4 (1) 15 (6) 18 (5)
Investigations
Weight decreased 4 (1) 18 (8) 22 (6)
Metabolism and nutrition disorders
Dehydration 10 (3) 24 (10) 33 (9)
Anorexia 3 (<1) 23 (10) 25 (7)
Hypokalaemia 5 (1) 13 (5) 18 (5)
Musculoskeletal and connective tissue disorders
Arthralgia 3 (<1) 17 (7) 22 (6)

Back pain 5 (1) 16 (7) 20 (6)

Pain in extremity 2 (<1) 11 (5) 14 (4)
Neoplasms benign, malignant, and unspecified (including cysts and polyps)
Cancer pain 3 (<1) 12 (5) 15 (4)
Nervous system disorders
Dizziness 64 (18) 28 (12) 83 (23)
Headache 28 (8) 31 (13) 52 (15)
Somnolence 21 (6) 22 (9) 41 (11)
Psychiatric disorders
Depression 1 (<1) 24 (10) 25 (7)
Anxiety 4 (1) 15 (6) 20 (6)
Confusional state 4 (1) 16 (7) 18 (5)
Insomnia 2 (<1) 14 (6) 16 (4)
Respiratory, thoracic and mediastinal disorders
Dyspnoea 6 (2) 18 (8) 23 (6)
Cough 3 (<1) 16 (7) 19 (5)
The following adverse reactions have been reported with FENTORA during clinical studies and
post marketing experience. Adverse reactions are listed below by system organ class and
frequency (frequencies are defined as: very common ≥1/10, common ≥1/100 to <1/10,
uncommon ≥ 1/1,000 to <1/100, rare (1/10,000 to <1/1,000), not known (cannot be estimated
from the available data); within each frequency group, undesirable effects are presented in order
of decreasing seriousness:
Very Common Uncommon Rare Not known

common
Investigations Weight Platelet count
decreased decreased
Heart rate
increased
Haematocrit
decreased
Haemoglobin
decreased
Cardiac Tachycardia Bradycardia
disorders
Blood and Anaemia Thrombocyto
lymphatic Neutropenia -penia
system
disorders


common
Nervous Dizziness Dysgeusia Depressed Cognitive Loss of
system Headache Somnolence level of disorder consciousnes
disorders Lethargy consciousnes Motor s
Tremor s dysfunction Convulsion
Sedation Disturbance
Hypoaesthesia in attention
Migraine Balance
disorder
Dysarthria
Eye disorders Visual Abnormal
disturbance sensation in
Ocular eye
hyperaemia Photopsia
Blurred
vision
Visual acuity
reduced
Ear and Vertigo
labyrinth Tinnitus
disorders Ear
discomfort
Respiratory, Dyspnoea Respiratory Respiratory
thoracic and Pharyngolaryn depression arrest
mediastinal -geal pain Sleep apnoea
disorders syndrome


common
Gastro- Nausea Constipation Ileus Oral
intestinal Vomiting Stomatitis Mouth mucosal
disorders Dry mouth ulceration blistering
Diarrhoea Oral Dry lip
Abdominal hypoaesthesi
pain a
Gastro- Oral
oesophageal discomfort
reflux disease Oral mucosal
Stomach discolouratio
discomfort n
Dyspepsia Oral soft
Toothache tissue
disorder
Glossodynia
Tongue
blistering
Gingival pain
Tongue
ulceration
Tongue
disorder
Oesophagitis
Chapped lips
Tooth
disorder
Renal and Urinary
urinary retention
disorders
Skin and Pruritus Cold sweat Onychorrhex
subcutaneous Hyperhidrosis Facial is
tissue Rash swelling
disorders Generalised
pruritus
Alopecia
Musculoskele Myalgia Muscle
tal and Back pain twitching
connective Muscular
tissue weakness
disorders
Endocrine Hypogonadis
disorders m


common
Metabolism Anorexia
and nutrition
disorders
Infections and Oral Pharyngitis Oral pustule
infestations candidiasis
Injury, Fall
poisoning and
procedural
complications
Vascular Hypotension Flushing
disorders Hypertension Hot flush
General Application Peripheral Malaise
disorders and site oedema Sluggishness
administration reactions Fatigue Chest
site conditions including Asthenia discomfort
bleeding, Drug Feeling
pain, ulcer, withdrawal abnormal
irritation, syndrome Feeling
paraesthesia Chills jittery
, Thirst
anaesthesia, Feeling cold
erythema, Feeling hot
oedema,
swelling
and vesicles
Hepatobiliary Biliary
disorders dilatation
Psychiatric Depression Euphoric
disorders Anxiety mood
Confusional Nervousness
state Hallucination
Insomnia Visual
hallucination
Mental status
changes
Drug
dependence
(addiction)
Disorientatio
n
Immune Hypersensiti
system vity
disorders

Tolerance, physical and/or psychological dependence may develop upon repeated administration
of opioids such as fentanyl.
Opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety and shivering have
been observed in studies with FENTORA.
Loss of consciousness and respiratory arrest have been observed in the context of overdose.
Hypersensitivity reactions have been reported in post-marketing experience, including rash,
erythema, lip and face swelling, and urticarial.
DOSAGE AND ADMINISTRATION
Treatment should be initiated by and remain under the guidance of a physician experienced in
the management of opioid therapy in cancer patients. Physicians should keep in mind the
potential of abuse of fentanyl. Patients should be instructed not to use two different formulations
of fentanyl concurrently for the treatment of breakthrough pain, and to dispose of any fentanyl
product prescribed for BTP when switching to FENTORA. The number of tablet strengths
available to the patients at any time should be minimised to prevent confusion and potential
overdose.
Dose titration
FENTORA should be individually titrated to an “effective” dose that provides adequate

analgesia and minimises undesirable effects. In clinical studies, the effective dose of FENTORA
for BTP was not predictable from the daily maintenance dose of opioid. Patients should be
carefully monitored until an effective dose is reached.
Titration in patients not switching from other fentanyl containing products

The initial dose of FENTORA should be 100 micrograms, titrating upwards as necessary through
the range of available tablets strengths (100, 200, 400, 600, 800 micrograms).
Titration in patients switching from other fentanyl containing products

Due to different absorption profiles, switching must not be done at a 1:1 ratio. If switching from
another oral fentanyl citrate product, independent dose titration with FENTORA is required as
bioavailability between products differs significantly, especially when a different route of
administration is used. However, in these patients, a starting dose higher than 100 micrograms
may be considered.
Method of titration
During titration, if adequate analgesia is not obtained within 30 minutes after the start of
administration of a single tablet, a second FENTORA tablet of the same strength may be used.
If treatment of a BTP episode requires more than one tablet, an increase in dose to the next
higher available strength should be considered to treat the next BTP episode.
During titration, multiple tablets may be used: up to four 100 micrograms or up to four 200
micrograms tablets may be used to treat a single episode of BTP during dose titration according
to the following schedule:
 If the initial 100 micrograms tablet is not efficacious, the patient can be instructed to treat the
next episode of BTP with two 100 micrograms tablets. It is recommended that one tablet
should be placed in each side of the mouth. If this dose is considered to be the effective
dose, treatment of successive episodes of BTP may be continued with a single 200
micrograms tablet of FENTORA.
 If a single 200 micrograms tablet of FENTORA (or two 100 micrograms tablets) is not
considered to be efficacious the patient can be instructed to use two 200 micrograms tablets
(or four 100 micrograms tablets) to treat the next episode of BTP. It is recommended that two
tablets should be placed in each side of the mouth. If this dose is considered to be the
effective dose, treatment of successive episodes of BTP may be continued with a single 400
micrograms tablet of FENTORA.
 For titration to 600 micrograms and 800 micrograms, tablets of 200 micrograms should be
used.
Doses above 800 micrograms were not evaluated in clinical studies.
No more than two tablets should be used to treat any individual BTP episode, except when
titrating using up to four tablets as described above.
Patients should wait at least 4 hours before treating another BTP episode with FENTORA during
titration. The frequency may be increased under clinical supervision.

Maintenance therapy
Once an effective dose has been established during titration, patients should continue to take this
dose as a single tablet of that given strength. Breakthrough pain episodes may vary in intensity
and the required FENTORA dose might increase over time due to progression of the underlying
cancer disease. In these cases, a second tablet of the same strength may be used. If a second
tablet of FENTORA was required for several consecutive times, the usual maintenance dose is to
be readjusted (see below).
Patients should wait at least 4 hours before treating another BTP episode with FENTORA during
maintenance therapy. The frequency may be increased under clinical supervision.
Dose readjustment
The maintenance dose of FENTORA should be increased when a patient requires more than one
tablet per BTP episode for several consecutive BTP episodes. For dose-readjustment the same
principles apply as outlined for dose titration (see above).
Dose readjustment of the background opioid therapy may be required if patients consistently
present with more than four BTP episodes per 24 hours. If the dose of background opioid
therapy is increased, the dose of FENTORA to treat BTP may need to be reviewed.
It is imperative that any dose re-titration of any analgesic is monitored by a health professional.
Discontinuation of therapy
FENTORA therapy may usually be immediately discontinued if no longer required for BTP
only, in patients who continue to take their chronic opioid therapy for persistent pain.
For patients requiring discontinuation of all opioid therapy, account should be taken of the
FENTORA dose in consideration of a gradual downward opioid titration to avoid the possibility
of abrupt withdrawal effects.
Patients with xerostomia:
Patients experiencing xerostomia are advised to drink water to moisten the buccal cavity prior to
administration of FENTORA. If this recommendation does not result in an appropriate
effervescence, then a switch of therapy may be advised.
Method of administration:
FENTORA tablet once exposed to moisture utilises an effervescent reaction to deliver the active
substance. Therefore patients should be instructed not to open the blister until ready to place the
tablet in the buccal cavity.
Opening the blister package

Patients should be instructed NOT to attempt to push the tablet through the blister because this
could damage the orally disintegrating tablet. The correct method of releasing the tablet from the
blister is:
One of the blister units should be separated from the blister card by tearing it apart at the
perforations. The blister unit should then be flexed along the line printed on the backing foil
where indicated. The backing foil should be peeled back to expose the tablet.
Patients should be instructed not to attempt to crush or split the tablet.
The tablet should not be stored once removed from the blister package as the tablet integrity can
not be guaranteed and a risk of accidental exposure to a tablet can occur.
Tablet administration
Patients should remove the tablet from the blister unit and immediately place the entire
FENTORA tablet in the buccal cavity (near a molar between the cheek and gum). Alternatively,
the tablet could be placed sublingually (under the tongue at the deepest part) (see
Pharmacokinetics properties).
The FENTORA tablet should not be sucked, chewed or swallowed, as this will result in lower
plasma concentrations than when taken as directed.
FENTORA should be placed and retained within the buccal cavity or sublingual cavity for a
period sufficient to allow disintegration of the tablet 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.
The length of time that the tablet takes to fully disintegrate following oromucosal administration
does not appear to affect early systemic exposure to fentanyl.
Patients should not consume any food and drink when a tablet is in the buccal cavity.
In case of buccal mucosa irritation, a change in tablet placement within the buccal cavity should
be recommended.
Instructions for use, handling and disposal
Patients and their carers must be instructed that FENTORA contains an active substance in an
amount that can be fatal, especially to a child. Therefore they must keep all tablets out of the
reach and sight of children.
Patients and carers must be advised to dispose of any unopened tablets remaining from a
prescription as soon as they are no longer needed.
Any used or unused but no longer required product or waste material should be returned to a
pharmacy for safe disposal. Medicines should not be disposed of via wastewater or household
waste.
OVERDOSAGE
For information on the management of overdose, contact the Poison Information Centre on
131126 (Australia).
Acute Toxicity and Symptoms

The symptoms of fentanyl overdose are expected to be similar in nature to those of intravenous
fentanyl and other opioids, and are an extension of its pharmacological actions, with the most
serious significant effects being altered mental status, loss of consciousness, hypotension,
respiratory depression, respiratory distress, and respiratory failure, which have resulted in death.
Management and Treatment

Immediate management of opioid overdose includes removal of the FENTORA orally
disintegrating tablet, if still in the mouth, ensuring a patent airway, physical and verbal
stimulation of the patient, assessment of the level of consciousness, ventilatory and circulatory
status, and assisted ventilation (ventilatory support) if necessary.
For treatment of overdose (accidental ingestion) in the opioid-naive person, intravenous

access should be obtained and naloxone or other opioid antagonists should be employed 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 Information of
the individual opioid antagonist for details about such use.
For treatment of overdose in opioid-maintained patients, intravenous access should be

obtained. The 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.
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, it should be managed
by the use of assisted ventilation, by an opioid antagonist, and as a final alternative, by a
neuromuscular blocking agent.
PRESENTATION AND STORAGE CONDITIONS
FENTORA orally disintegrating tablets are available in five unit strengths equivalent to 100,
200, 400, 600 and 800 micrograms of fentanyl base. The orally disintegrating tablets are flat-
faced, round, beveled-edge tablet, embossed one side with a “C” and on the other side with “1”
for FENTORA 100 micrograms, with “2” for FENTORA 200 micrograms, with “4” for
FENTORA 400 micrograms, with “6” for FENTORA 600 micrograms, or with “8” for
FENTORA 800 micrograms.
FENTORA is supplied in aluminium laminated blister of PVC/aluminium foil/Polyamide/PVC

with paper/polyester/aluminium foil lidding.
Blister packs are supplied in cartons of 4 or 28 tablets.
Storage conditions
Store below 250C. Store in the original package in order to protect from moisture.
NAME AND ADDRESS OF THE SPONSOR
Orphan Australia Pty Ltd

(a member of the Aspen Australia group of companies)
34-36 Chandos Street
St Leonards NSW 2065

Australia
POISON SCHEDULE OF THE MEDICINE
S8
DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC

GOODS (the ARTG)
XX XXXX XXX

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Attachment 1: Product information for AusPAR Fentora Fentanyl citrate Orphan Australia

NAME OF THE MEDICINE

FENTORA® – Product Information Page 1 of 24

FENTORA employs a delivery technology which utilises an effervescent reaction which

Pharmacokinetic Parameters* in Adult Subjects Receiving FENTORA

Pharmacokinetic FENTORA 400 micrograms

Fraction 48% (±31.8%)

Tmax (minute) ** 46.8 (20-240)

Cmax (ng/ml) 1.02 (± 0.42)

AUC0-tmax (ng.hr/ml) 0.40 (± 0.18)

AUC0-inf (ng.hr/ml) 6.48 (± 2.98)

FENTORA® – Product Information Page 3 of 24

Dose proportionality from 100 micrograms to 1000 micrograms of FENTORA has been

FENTORA® – Product Information Page 4 of 24

Two double-blind, randomized, placebo-controlled crossover studies have been conducted

Sixty-seven percent of the patients were able to be titrated to an effective dose.

FENTORA® – Product Information Page 5 of 24

SPID60 mean (+/- SD)

+ p<0.0001 FENTORA versus placebo, in favor of FENTORA, by an analysis of variance

FENTORA® – Product Information Page 6 of 24

SPID30 mean (+/- SD)

FENTORA is contraindicated in:

Hypersensitivity to the active substance or to any of the excipients (see DESCRIPTION).

Severe respiratory depression or severe obstructive lung conditions.

Special Risk Patients

FENTORA should only be used for conditions specified in INDICATIONS.

Chronic obstructive pulmonary disease

Increased intracranial pressure, impaired consciousness

FENTORA® – Product Information Page 8 of 24

Careful consideration should be given to patients with hypovolaemia and hypotension.

Hepatic and Renal Impairment

If serotonin syndrome is suspected, treatment with fentanyl should be discontinued.

FENTORA® – Product Information Page 9 of 24

Controlled sodium diet

Anaphylaxis and hypersensitivity

Use in pregnancy (Category C)

FENTORA should not be used in pregnancy unless clearly necessary.

Use in labour and delivery

Use in the Elderly

Carcinogenicity studies (26-week dermal bioassay in Tg.AC transgenic mice; two-year

Effects on ability to drive and use machines

INTERACTIONS WITH OTHER MEDICINES

The concomitant use of partial opioid agonists/antagonists (e.g. buprenorphine, nalbuphine,

FENTORA® – Product Information Page 12 of 24

MedDRA system organ Percentage of patients (%)

FENTORA® – Product Information Page 13 of 24

Back pain 5 (1) 16 (7) 20 (6)

Very Common Uncommon Rare Not known

FENTORA® – Product Information Page 14 of 24

Very Common Uncommon Rare Not known

FENTORA® – Product Information Page 15 of 24

Very Common Uncommon Rare Not known

FENTORA® – Product Information Page 16 of 24

Very Common Uncommon Rare Not known

FENTORA® – Product Information Page 17 of 24

DOSAGE AND ADMINISTRATION

FENTORA should be individually titrated to an “effective” dose that provides adequate

Titration in patients not switching from other fentanyl containing products

Titration in patients switching from other fentanyl containing products

Doses above 800 micrograms were not evaluated in clinical studies.