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RECIVIT 800 MICROGRAMS SUBLINGUAL TABLETS

Active substance(s): FENTANYL CITRATE / FENTANYL CITRATE / FENTANYL CITRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Recivit 800 micrograms, sublingual tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Recivit 800 microgram sublingual tablets:
Each tablet contains 1260 micrograms of fentanyl citrate, equivalent to 800
micrograms of fentanyl.
Excipient with known effect:
Each tablet contains 0.651 mg sodium.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Sublingual tablet

Recivit 800 microgram sublingual tablets:
This medicine is presented in the form of a white, convex, triangular tablet,
height of 5.6 mm, printed with ‘8’ in black ink on one face.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Recivit is indicated for the treatment of breakthrough pain (BTP) in adults
with cancer who are already receiving maintenance opioid therapy for chronic
cancer pain.
BTP is a transitory exacerbation of pain that occurs on a background of
otherwise controlled persistent pain.
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.

4.2

Posology and method of 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 Recivit. The number
of tablet strengths available to the patients at any time should be minimised to
prevent confusion and potential overdose.
Recivit should be administered directly under the tongue at the deepest part.
Recivit should not be swallowed, but allowed to completely dissolve in the sublingual
cavity without chewing or sucking. Patients should be advised not to eat or drink
anything until the sublingual tablet is completely dissolved.

After 30 minutes, if remnants from the Recivit tablet remain, they may be
swallowed.
In patients who have a dry mouth, water may be used to moisten the buccal
mucosa before taking Recivit.
The tablet should not be stored once removed from the blister package as the
tablet integrity cannot be guaranteed and a risk of accidental exposure to a
tablet can occur (see also section 4.4 for warnings in children).
Patients should be advised to keep Recivit in a locked storage space.
Dose Titration
Before patients are titrated with Recivit, it is expected that their background persistent
pain will be controlled by use of opioid therapy and that they are typically
experiencing no more than 4 episodes of breakthrough pain per day.
The object of dose titration is to identify an optimal maintenance dose for ongoing
treatment of breakthrough pain episodes. This optimal dose should provide adequate
analgesia with an acceptable level of adverse reactions.
The optimal dose of Recivit will be determined by upward titration, on an individual
patient basis. Several doses are available for use during the dose titration phase. The
initial dose of Recivit used should be 133 micrograms, titrating upwards as necessary
through the range of available dosage strengths.
Patients should be carefully monitored until an optimal dose is reached.
Switching from other fentanyl containing products to Recivit must not occur at a 1:1
ratio because of different absorption profiles. If patients are switched from another
fentanyl containing product, a new dose titration with Recivit is required.
The following dose regimen is recommended for titration, although in all cases the
physician should take into account the clinical need of the patient, age and
concomitant illness.

All patients must start therapy with a single 133 micrograms sublingual tablet. If
adequate analgesia is not obtained within 15-30 minutes of administration of a single
tablet, a supplemental (second) 133 micrograms tablet may be administered. If
treatment of a breakthrough pain episode requires more than one dosage unit, an
increase in dose to the next higher available strength should be considered (Refer to
figure below). Dose escalation should continue in a stepwise manner until adequate
analgesia is achieved. The dose strength for the supplemental (second) tablet should
be increased from 133 to 267 micrograms at doses of 533 micrograms. This is
illustrated in the schedule below. No more than two (2) tablets should be administered
for a single episode of breakthrough pain during this titration phase.
RECIVIT TITRATION PROCESS
Starting dose
133 µg

Adequate pain relief achieved
within 15-30 minutes

Yes

No

Take a second tablet
(see table to determine
strength of second
tablet)

Use this dose for
Subsequent
breakthrough pain
episodes
Strength (micrograms)
of first tablet per
episode of
breakthrough pain
133
267
400
533
800

Increase first tablet
to next higher strength
for next breakthrough
pain episode
Strength (micrograms) of
supplemental (second) tablet
to be taken 15-30 minutes
after first tablet, if required
133
133
133
267
-

If adequate analgesia is achieved at the higher dose, but undesirable effects are
considered unacceptable, an intermediate dose may be administered (using the 67
micrograms or 133 micrograms tablet).
Doses higher than 800 micrograms have not been evaluated in clinical studies.
In order to minimise the risk of opioid-related adverse reactions and to identify the
appropriate dose, it is imperative that patients be monitored closely by health
professionals during the titration process.

Maintenance therapy
Once an appropriate dose has been established, which may be more than one tablet,
patients should be maintained on this dose and should limit consumption to a
maximum of four Recivit doses per day.
Dose re-adjustment

If the response (analgesia or adverse reactions) to the titrated Recivit dose
markedly changes, an adjustment of dose may be necessary to ensure that an
optimal dose is maintained.
If more than four episodes of breakthrough pain are consistently experienced
per day, then the dose of the long acting opioid used for persistent pain should
be re-evaluated. If the long acting opioid or dose of long acting opioid is
changed, the Recivit dose should be re-evaluated and re-titrated as necessary
to ensure the patient is on an optimal dose.
It is imperative that any dose re-titration of any analgesic is monitored by a health
professional.

Discontinuation of therapy
Recivit should be discontinued immediately if the patient no longer
experiences breakthrough pain episodes. The treatment for the persistent
background pain should be kept as prescribed. If discontinuation of all opioid
therapy is required, the patient must be closely followed by the doctor in order
to manage the risk of abrupt withdrawal effects.
Use in elderly patients
Dose titration needs to be approached with particular care and patients observed
carefully for signs of fentanyl toxicity (see section 4.4).
Use in patients with renal and hepatic impairment
Patients with kidney or liver dysfunction should be carefully observed for signs of
fentanyl toxicity during the Recivit titration phase (see section 4.4).
Use in paediatric population
Recivit is not indicated for use in children and adolescents below 18 years due to a
lack of data on safety and efficacy (see also section 4.4).

4.3

Contraindications






Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1.
Patients without maintenance opioid therapy (see section 4.1) as there is an
increased risk of respiratory depression.
Simultaneous use of monoamine-oxidase (MAO) inhibitors, or within 2 weeks
after the cessation of the use of MAO inhibitors.
Severe respiratory depression or severe obstructive lung conditions.
Treatment of acute pain other than breakthrough pain.

4.4

Special warnings and precautions for use
Patients and their carers must be instructed that Recivit contains an active
substance in an amount that can be fatal to a child, and therefore to keep all
tablets out of the reach and sight of children and non-patients at all times.
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 Recivit therapy begins and that the
patient continues to be treated with the long acting opioid treatment whilst
taking Recivit.
As with all opioids, there is a risk of clinically significant respiratory
depression associated with the use of fentanyl. Particular caution should be
used when titrating Recivit in patients with non-severe chronic obstructive
pulmonary disease or other medical conditions predisposing them to
respiratory depression, as even normally therapeutic doses of Recivit may
further decrease respiratory drive to the point of respiratory failure.
Recivit 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.
Cardiac disease
Fentanyl may produce bradycardia. Fentanyl should be used with caution in
patients with previous or preexisting bradyarrhythmias.
In addition, Recivit 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 Recivit,
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.
Careful consideration should be given to patients with hypovolaemia and
hypotension.

Recivit has not been studied in patients with mouth wounds or mucositis.
There may be a risk of increased systemic drug exposure in such patients and
therefore extra caution is recommended during dose titration.
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.
Serotonin Syndrome
Caution is advised when Recivit 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 Reuptake 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 Recivit should be
discontinued.
This medicinal product contains 0.651 mg sodium per tablet. To be taken into
consideration by patients on a controlled sodium diet.
4.5

Interaction with other medicinal products and other forms of interaction
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.

Recivit is contraindicated 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.
Fentanyl is metabolized by the CYP3A4 isoenzyme in the liver and intestinal
mucosa. Inhibitors of CYP3A4 such as


macrolide antibiotics (e.g. erythromycin, clarithromycin,
telithromycin),

azole antifungals (e.g. ketoconazole, itraconazole, and fluconazole),

certain protease inhibitors (e.g. ritonavir, indinavir, nelfinavir,
saquinavir),

calcium channel blockers (e.g. diltiazem or verapamil),

anti-emetics (e.g. aprepitant or dronabinol),

antidepressants (e.g. fluoxetin),

antacids (e.g. cimetidin)
or alcohol may increase the bioavailability of swallowed fentanyl and may
also decrease its systemic clearance which may result in increased or
prolonged opioid effects and may cause potentially fatal respiratory
depression. Similar effects could be seen after concurrent ingestion of
grapefruit juice, which is known to inhibit CYP3A4. Hence caution is advised
if fentanyl is given concomitantly with CYP3A4 inhibitors. Patients receiving
Recivit 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.
The concomitant use of Recivit with potent CYP3A4 inducers such as

barbiturates and other sedatives (e.g. phenobarbital),

anti-epileptics (e.g. carbamazepine, phenytoin, oxcarbazepine),

certain antivirals (e.g. efavirenz, nevirapine),

anti-inflammatory or immunosuppressive agents (e.g. glucocorticoids),

anti-diabetics (e.g. pioglitazone),

antibiotics for tuberculosis treatment (e.g. rifabutin, rifampin),

psychotropic substances (e.g. modafinil),

antidepressants (e.g. St. John's wort),
may result in a decrease in fentanyl plasma concentrations, which could
decrease the efficacy of Recivit. Patients receiving Recivit who stop therapy
with, or decrease the dose of, CYP3A4 inducers should be monitored for signs
of increased Recivit activity, or toxicity, and the dose of Recivit should be
adjusted accordingly.
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.
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.
4.6

Pregnancy and lactation
Pregnancy

There are no adequate data from the use of fentanyl in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The
potential risk for humans is unknown. Recivit should not be used in pregnancy
unless clearly necessary.
Following long-term treatment, fentanyl may cause withdrawal in the newborn infant.
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 or in the new-born infant. If Recivit is
administered, an antidote for the child should be readily available.
Breastfeeding
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 5
days after the last administration of fentanyl.
4.7

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 Recivit and not to drive or operate machinery until they know
how they react.
This medicine can impair cognitive function and can affect a patient’s ability to drive
safely. This class of medicine is in the list of drugs included in regulations under 5a
of the Road Traffic Act 1988. When prescribing this medicine, patients should be
told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called ‘statutory defence’)
if:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in
the information provided with the medicine and
o It was not affecting your ability to drive safely

4.8

Undesirable effects

Typical opioid side effects are to be expected with Recivit. Frequently, these will
cease or decrease in intensity with continued use of the 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 and all patients should be closely monitored for
these.
The most frequently observed adverse reactions include: nausea, vomiting,
constipation, headache, somnolence/fatigue and dizziness.

The following adverse reactions have been reported with Recivit and/or other
fentanyl-containing compounds during clinical studies and post marketing
experience in real-world drug practice with concomitant opioid treatment.
Thus it is not possible to definitively separate the effects of fentanyl alone.
Adverse reactions are listed below as MedDRA preferred term 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, very rare <1/10,000), not known (cannot be estimated from the
available data):
MedDRA system
organ class
Metabolism and
nutrition
disorders
Psychiatric
disorders

Very
common

Nervous system
disorders

somnolence
, sedation,
dizziness

Common

Skin and
subcutaneous
tissue disorders
Renal and

Not known

anorexia

confusion, anxiety,
hallucinations,
abnormal thinking
loss of
consciousness,
vertigo, headache,
myoclonus, taste
perversion

Eye disorders
Vascular
disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Uncommon

abnormal dreams,
depersonalisation,
depression, emotional
lability, euphoria
coma, convulsion,
paraesthesia (including
hyperaesthesia/circumoral
paraesthesia), abnormal
gait/incoordination
abnormal vision (blurred,
double vision)

hypotension

insomnia

flushing and
hot flush
dyspnoea, respiratory
depression

nausea,
constipation

vomiting, dry mouth, ileus, flatulence, abdomen
abdominal pain,
enlarged, dental caries
dyspepsia,
pruritus, sweating

rash

urinary retention

diarrhoea,
tooth loss,
gingival
recession

MedDRA system
organ class
urinary
disorders
General
disorders and
administration
site conditions

Very
common

Common

Uncommon

Not known

asthenia

malaise

fatigue,
peripheral
oedema,
withdrawal
syndrome,
pyrexia

accidental injury (for
example, falls)

Injury,
poisoning and
procedural
complications

Opiate withdrawal symptoms, such as nausea, vomiting, diarrhoea, anxiety, chills,
tremor and sweating have been observed with transmucosal fentanyl.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
4.9

Overdose
The symptoms of fentanyl overdosage 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, coma, cardiorespiratory arrest, respiratory depression, respiratory
distress and respiratory failure, which have resulted in death.
Immediate management of opioid overdose includes removal of the Recivit 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 overdosage (accidental ingestion) in the opioid naïve 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 Summary of Product Characteristics 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.

If severe or persistent hypotension occurs, hypovolaemia should be considered, and
the condition should be managed with appropriate parenteral fluid therapy.

Muscle rigidity interfering with respiration has been reported with fentanyl
and other opioids. In this situation, endotracheal intubation, assisted
ventilation and administration of opioid antagonists as well as muscle
relaxants may be requested.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: phenylpiperidine derivatives.
ATC code: N02AB03.
Fentanyl is an opioid analgesic, interacting predominantly with the opioid μreceptor. 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 Recivit should be
individually titrated to achieve the desired effect (see section 4.2).
The efficacy and safety of Recivit have been assessed in a double blind
randomized, placebo-controlled, cross over study in 91 opioid-treated adult
cancer patients who experienced 1 to 4 episodes of breakthrough pain (BTP)
per day. The primary endpoint was the sum of pain intensity difference at
30 minutes (SPID30) after dosing which was statistically significant
compared to placebo (p< 0.0001).
Sum of pain intensity difference from 6 minutes after dosing and up to 60
minutes was also significant compared to placebo (respectively p=0.02 after 6
minutes and p<0.0001 after 60 minutes).
The secondary outcome measure mean pain intensity difference (PID) was
significantly higher for the BTP episodes treated with fentanyl than those treated with
placebo from 6 minutes after dosing and up to 60 minutes (respectively p=0.003 and
p<0.0001) (see figure below).
Also, the mean pain relief was significantly higher for the BTP episodes treated with
fentanyl than those treated with placebo from 6 minutes after dosing and up to 60
minutes. The difference in mean pain relief between active treatment and placebo was
0.1 (on a 5-point Numerical Rating Scale) at 6 minutes (p=0.002), 0.4 at 10 minutes,
0.5 at 15 minutes, 0.7 at 30 minutes and 0.7 at 60 minutes (p<0.0001).

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.
While opioids generally increase the tone of urinary tract smooth muscle, the net
effect tends to be variable, in some cases producing urinary urgency, in others,
difficulty in urination.

Opioids increase the tone and decrease the propulsive contractions of the
smooth muscle of the gastrointestinal tract leading to a prolongation in
gastrointestinal transit time, which may be responsible for the constipating
effect of fentanyl.
5.2

Pharmacokinetic properties
Fentanyl is highly lipophilic and can be absorbed very rapidly through the oral
mucosa and more slowly through the gastrointestinal tract. Orally
administered fentanyl undergoes pronounced hepatic and intestinal first pass
effects and the metabolites do not contribute to fentanyl’s therapeutic effects.
Recivit employs a technology that allows rapid release of fentanyl and enhances the
rate and extent of fentanyl absorbed through the oral mucosa. The absolute
bioavailability of Recivit has not been determined but is estimated to be about 70%.

Absorption

Mean maximal plasma concentrations range from 360 to 2070 pg/ml (after
administration of 133 to 800 µg of Recivit) and are reached within 50 and 90 minutes.

Distribution
Fentanyl is highly lipophilic and is well distributed beyond the vascular
system, with a large apparent volume of distribution. After sublingual
administration of Recivit, 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.
Biotransformation and elimination
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.
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.
The terminal elimination phase of fentanyl is the result of the redistribution
between plasma and a deep tissue compartment. Following the administration
of Recivit, the terminal elimination half-life is approximately 12 hours.
Linearity/non linearity
Dose proportionality from 133 micrograms to 800 micrograms has been
demonstrated.
Renal/hepatic impairment
Impaired hepatic or renal function could cause increased serum
concentrations. Elderly, cachectic or generally impaired patients may have a
lower fentanyl clearance, which could cause a longer terminal half-life for the
compound (see sections 4.2 and 4.4).
5.3

Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology, repeated dose toxicity, genotoxicity and
carcinogenicity.

Embryo-foetal developmental toxicity studies conducted in rats and rabbits
revealed no compound induced malformations or developmental variations
when administered during the period of organogenesis.
In a fertility and early embryonic development study in rats, a male-mediated
effect was observed at high doses (300 mcg/kg/day, s.c.) and is consistent with
the sedative effects of fentanyl in animal studies.
In studies on pre and postnatal development in rats the survival rate of
offspring was significantly reduced at doses causing severe maternal toxicity.
Further findings at maternally toxic doses in F1 pups were delayed physical
development, sensory functions, reflexes and behaviour. These effects could
either be indirect effects due to altered maternal care and/or decreased
lactation rate or a direct effect of fentanyl on the pups.
Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC
transgenic mice; two-year subcutaneous carcinogenicity study in rats) with
fentanyl did not reveal any findings indicative of oncogenic potential.
Evaluation of brain slides from the carcinogenicity study in rats revealed brain
lesions in animals administered high doses of fentanyl citrate. The relevance
of these findings to humans is unknown.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Calcium hydrogen phosphate anhydrous
Microcrystalline cellulose
Disodium phosphate anhydrous
Hypromellose
Macrogol
Magnesium stearate
Maltodextrin
Titanium dioxide (E171)
Triacetin
Printing ink [shellac, black iron oxide (E172)]

6.2

Incompatibilities
Not applicable.

6.3
4 years

Shelf life

6.4

Special precautions for storage
This medicinal product does not require any special temperature storage
conditions. Store in the original blister package, in order to protect from light.

6.5

Nature and contents of container
Peelable, child resistant blister:
-Polyamide-Aluminium-PVC / Aluminium foil blister, contained in a cardboard outer
carton.
-Polyamide-Aluminium-PVC / Aluminium-PET foil blister, contained in a cardboard
outer carton.
Pack sizes: 3, 4, 15 or 30 sublingual tablets.

Not all pack sizes may be marketed.
6.6

Special precautions for disposal
Sublingual tablets with remaining active substance must not be disposed of in
household waste.
Waste material should be disposed of safely. Patients/carers should be
encouraged to dispose any unused product in accordance with national and
local requirements.

7

MARKETING AUTHORISATION HOLDER
Grünenthal Ltd
Regus Lakeside House
1 Furzeground Way
Stockley Park East
Uxbridge
Middlesex UB11 1BD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 21727/0070

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
16/07/2015

10

DATE OF REVISION OF THE TEXT
09/03/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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