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BUPEAZE 70 MICROGRAMS/H TRANSDERMAL PATCHES

Active substance(s): BUPRENORPHINE / BUPRENORPHINE / BUPRENORPHINE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Bupeaze 70 micrograms/h Transdermal Patches

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each transdermal patch contains 40 mg buprenorphine.
Area containing the active substance: 50 cm2
Nominal release rate: 70 micrograms of buprenorphine per hour (over a period of 96
hours).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Transdermal patch
Rectangular beige coloured patch with rounded edges and imprinted with
“Buprenorphin” and “70 μg/h ” in blue colour.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Moderate to severe cancer pain and severe pain which does not respond to non-opioid
analgesics.
Bupeaze is not suitable for the treatment of acute pain.

4.2

Posology and method of administration
Posology
Patients over 18 years of age
The dose should be adapted to the condition of the individual patient (pain intensity,
suffering, individual reaction). The lowest possible dose providing adequate pain
relief should be given. Three transdermal patch strengths are available to provide
such adaptive treatment: Bupeaze 35 micrograms/h, Bupeaze 52.5 micrograms/h and
Bupeaze 70 micrograms/h.
Initial dose selection: patients who have previously not received any analgesics
should start with the lowest transdermal patch strength (Bupeaze 35 micrograms/h).
Patients previously given a WHO step-I analgesic (non-opioid) or a step-II analgesic
(weak opioid) should also begin with Bupeaze 35 micrograms/h. According to the

WHO recommendations, the administration of a non-opioid analgesic can be
continued, depending on the patient's overall medical condition.
When switching from a step-III analgesic (strong opioid) to Bupeaze and choosing
the initial transdermal patch strength, the nature of the previous medicinal product,
administration and the mean daily dose should be taken into account in order to avoid
the recurrence of pain. In general it is advisable to titrate the dose individually,
starting with the lowest transdermal patch strength (Bupeaze 35 micrograms/h).
Clinical experience has shown that patients who were previously treated with higher
daily doses of a strong opioid (in the dimension of approximately 120 mg oral
morphine) may start the therapy with the next higher transdermal patch strength (see
also section 5.1).
To allow for individual dose adaptation in an adequate time period sufficient
supplementary immediate release analgesics should be made available during dose
titration.
The necessary strength of Bupeaze must be adapted to the requirements of the
individual patient and checked at regular intervals.
After application of the first Bupeaze transdermal patch the buprenorphine serum
concentrations rise slowly both in patients who have been treated previously with
analgesics and in those who have not. Therefore initially, there is unlikely to be a
rapid onset of effect. Consequently, a first evaluation of the analgesic effect should
only be made after 24 hours.
The previous analgesic medicinal product (with the exception of transdermal opioids)
should be given in the same dose during the first 12 hours after switching to Bupeaze
and appropriate rescue medicinal products on demand in the following 12 hours.
Dose titration and maintenance therapy
Bupeaze should be replaced after 96 hours (4 days) at the latest. For convenience of
use, the transdermal patch can be changed twice a week at regular intervals, e.g.
always on Monday morning and Thursday evening. The dose should be titrated
individually until analgesic efficacy is attained. If analgesia is insufficient at the end
of the initial application period, the dose may be increased, either by applying more
than one transdermal patch of the same strength or by switching to the next
transdermal patch strength. At the same time no more than two transdermal patches
regardless of the strength should be applied.
Before application of the next Bupeaze strength the amount of total opioids
administered in addition to the previous transdermal patch should be taken into
consideration, i.e. the total amount of opioids required, and the dosage adjusted
accordingly. Patients requiring a supplementary analgesic (e.g. for breakthrough pain)
during maintenance therapy may take for example 0.2 mg - 0.4 mg buprenorphine
sublingual every 24 hours in addition to the transdermal patch. If the regular addition
of 0.4 – 0.6 mg sublingual buprenorphine is necessary, the next strength should be
used.
Duration of administration
Bupeaze should under no circumstances be administered for longer than absolutely
necessary. If long-term pain treatment with Bupeaze is necessary in view of the
nature and severity of the illness, then careful and regular monitoring should be
carried out (if necessary with breaks in treatment) to establish whether and to what
extent further treatment is necessary.
Discontinuation of Bupeaze
After removal of Bupeaze buprenorphine serum concentrations decrease gradually
and thus the analgesic effect is maintained for a certain amount of time. This should

be considered when therapy with Bupeaze is to be followed by other opioids. As a
general rule, a subsequent opioid should not be administered within 24 hours after
removal of Bupeaze. For the time being only limited information is available on the
starting dose of other opioids administered after discontinuation of Bupeaze.
Elderly patients
No dosage adjustment of Bupeaze is required for elderly patients.
Patients with renal insufficiency
Since the pharmacokinetics of buprenorphine is not altered during the course of renal
failure, its use in patients with renal insufficiency, including dialysis patients, is
possible.
Patients with hepatic insufficiency
Buprenorphine is metabolised in the liver. The intensity and duration of its action
may be affected in patients with impaired liver function. Therefore patients with liver
insufficiency should be carefully monitored during treatment with Bupeaze.
Paediatric population
As Bupeaze has not been studied in patients under 18 years of age, the use of the
medicinal product in patients below this age is not recommended.
Method of administration
Bupeaze should be applied to non-irritated, clean skin on a non-hairy flat surface, but
not to any parts of the skin with large scars. Preferable sites on the upper body are:
upper back or below the collar-bone on the chest. Any remaining hairs should be cut
off with a pair of scissors (not shaved). If the site of application requires cleansing,
this should be done with water. Soap or any other cleansing agents should not be
used. Skin preparations that might affect adhesion of the transdermal patch to the area
selected for application of Bupeaze should be avoided.
The skin must be completely dry before application. Bupeaze is to be applied
immediately after removal from the sachet. Following removal of the release liner,
the transdermal patch should be pressed firmly in place with the palm of the hand for
approximately 30 seconds. The transdermal patch will not be affected when bathing,
showering or swimming.
Bupeaze should be worn continuously for up to 4 days. After removal of the previous
transdermal patch a new Bupeaze transdermal patch should be applied to a different
skin site. At least one week should elapse before a new transdermal patch is applied
to the same area of skin.

4.3

Contraindications
-

hypersensitivity to the active substance or to any of the excipients listed in section
6.1

-

opioid-dependent patients and for narcotic withdrawal treatment

-

conditions in which the respiratory centre and function are severely impaired or
may become so

-

patients who are receiving MAO inhibitors or have taken them within the last two
weeks (see section 4.5)

-

patients suffering from myasthenia gravis

-

patients suffering from delirium tremens.

-

pregnancy (see section 4.6)

4.4

Special warnings and precautions for use
Buprenorphine must only be used with particular caution in acute alcohol
intoxication, convulsive disorders, in patients with head injury, shock, a reduced level
of consciousness of uncertain origin, increased intracranial pressure without the
possibility of ventilation.
Buprenorphine occasionally causes respiratory depression. Therefore care should be
taken when treating patients with impaired respiratory function or patients receiving
medicinal products which can cause respiratory depression.
Buprenorphine has a substantially lower dependence liability than pure opioid
agonists. In healthy volunteer and patient studies with buprenorphine, withdrawal
reactions have not been observed. However, after long-term use of buprenorphine
withdrawal symptoms, similar to those occurring during opiate withdrawal, cannot be
entirely excluded (see section 4.8). These symptoms are: agitation, anxiety,
nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders.
In patients abusing opioids, substitution with buprenorphine may prevent withdrawal
symptoms. This has resulted in some abuse of buprenorphine and caution should be
exercised when prescribing it to patients suspected of having drug abuse problems.
Buprenorphine is metabolised in the liver. The intensity and duration of effect may be
altered in patients with liver function disorders. Therefore such patients should be
carefully monitored during buprenorphine treatment.
Athletes should be aware that this medicine may cause a positive reaction to sports
doping control tests.
Patients with fever / external heat
Fever and the presence of heat may increase the permeability of the skin.
Theoretically in such situations buprenorphine serum concentrations may be raised
during buprenorphine treatment. Therefore on treatment with buprenorphine,
attention should be paid to the increased possibility of opioid reactions in febrile
patients or those with increased skin temperature due to other causes.
The transdermal patch should not be exposed to excessive heat (e.g. sauna, infraredradiation).

4.5

Interaction with other medicinal products and other forms of interaction
On administration of MAO inhibitors in the last 14 days prior to the administration of
the opioid pethidine life-threatening interactions have been observed affecting the
central nervous system and respiratory and cardiovascular function. The same
interactions between MAO inhibitors and buprenorphine cannot be ruled out (see
section 4.3).
When buprenorphine is applied together with other opioids, anaesthetics, hypnotics,
sedatives, antidepressants, neuroleptics, and in general, medicinal products that
depress respiration and the central nervous system, the CNS effects may be
intensified. This applies also to alcohol.
Administered together with inhibitors or inducers of CYP 3A4 the efficacy of
buprenorphine may be intensified (inhibitors) or weakened (inducers).

4.6

Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of buprenorphine in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential
risk for humans is unknown.
Towards the end of pregnancy high doses of buprenorphine may induce respiratory
depression in the new-born infant even after a short period of administration. Chronic
administration of buprenorphine during the last three months of pregnancy may cause
a withdrawal syndrome in the new-born infant.
Therefore administration of Bupeaze is contraindicated during pregnancy.
Breast-feeding
Buprenorphine is excreted in human milk. Studies in rats have shown that
buprenorphine can inhibit lactation.
Bupeaze should not be used during breast-feeding.
Fertility
An effect of buprenorphine on fertility in animals is not known (see section 5.3).

4.7

Effects on ability to drive and use machines
Buprenorphine has major influence on the ability to drive and use machines. Even
when used according to instructions, buprenorphine may affect the patient's reactions
to such an extent that road safety and the ability to operate machinery may be
impaired.
This applies particularly at the beginning of treatment, at any change of dose and
when buprenorphine is used in conjunction with other centrally acting substances
including alcohol, tranquillisers, sedatives and hypnotics.
Patients who are affected (e.g. feeling dizzy or drowsy or experience blurred or
double vision) should not drive or use machines while using buprenorphine and for at
least 24 hours after the patch has been removed.
Patients stabilised on a specific dose will not necessarily be restricted if the above
mentioned symptoms are not present.
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 the
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:
- The medicine has been prescribed to treat a medical or dental problem and
- You have taken it according to the instructions given by the prescriber and in

-

4.8

the information provided with the medicine and
It was not affecting your ability to drive safely.

Undesirable effects
The following adverse reactions were reported after administration of buprenorphine
in clinical studies and from postmarketing surveillance.
The frequencies are given as follows:
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)
The most commonly reported systemic adverse reactions were nausea and vomiting.
The most commonly reported local adverse reactions were erythema and pruritus.
Immune system disorders
Very rare
serious allergic reactions
Metabolism and nutrition disorders
Rare
appetite lost
Psychiatric disorders
Uncommon
confusion, sleep disorder, restlessness
Rare
psychotomimetic effects (e.g. hallucinations, anxiety,
nightmares), decreased libido
Very rare
dependence, mood swings
Nervous system disorders
Common
dizziness, headache
Uncommon
sedation, somnolence
Rare
concentration impaired, speech disorder, numbness,
dysequilibrium, paraesthesia (e.g. pricking or burning skin
sensation)
Very rare
muscle fasciculation, parageusia
Eye disorders
Rare
Very rare

visual disturbance, blurring of vision, eyelid oedema
miosis

Ear and labyrinth disorders
Very rare
ear pain
Vascular disorders
Uncommon

circulatory disorders (such as hypotension or, rarely, even
circulatory collapse)

Rare

hot flushes

Respiratory, thoracic and mediastinal disorders
Common
dyspnoea
Rare
respiratory depression
Very rare
hyperventilation, hiccups
Gastrointestinal disorders
Very common
nausea
Common
vomiting, constipation
Uncommon
dry mouth
Rare
pyrosis
Very rare
retching
Skin and subcutaneous tissue disorders
Very common
erythema, pruritus
Common
exanthema, diaphoresis
Uncommon
rash
Rare
urticaria
Very rare
pustules, vesicles
Renal and urinary disorders
Uncommon
urinary retention, micturition disorders
Reproductive system and breast disorders
Rare
decreased erection
General disorders and administration site conditions
Common
oedema, tiredness
Uncommon
weariness
Rare
withdrawal symptoms, administration site reactions
Very rare
thoracic pain
In some cases delayed allergic reactions occurred with marked signs of
inflammation. In such cases treatment with buprenorphine should be
terminated.
Buprenorphine has a low risk of dependence. After discontinuation of buprenorphine,
withdrawal symptoms are unlikely. This is due to the very slow dissociation of
buprenorphine from the opiate receptors and to the gradual decrease of buprenorphine
serum concentrations (usually over a period of 30 hours after removal of the last
transdermal patch). However, after long-term use of buprenorphine withdrawal
symptoms, similar to those occurring during opiate withdrawal, cannot be entirely
excluded.
These symptoms include: agitation, anxiety, nervousness, insomnia, hyperkinesia,
tremor and gastro-intestinal disorders.
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 Website: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Buprenorphine has a wide safety margin. Due to the rate-controlled delivery of small
amounts of buprenorphine into the blood circulation high or toxic buprenorphine
concentrations in the blood are unlikely. The maximum serum concentration of
buprenorphine after the application of the buprenorphine 70 micrograms/h
transdermal patch is about six times less than after the intravenous administration of
the therapeutic dose of 0.3 mg buprenorphine.
Symptoms
In principal, on overdose with buprenorphine, symptoms similar to those of other
centrally acting analgesics (opioids) are to be expected. These are: respiratory
depression, sedation, somnolence, nausea, vomiting, cardiovascular collapse, and
marked miosis.
Treatment
General emergency measures apply. The airway should be kept open (aspiration!),
Respiration and circulation should be maintained, depending on the symptoms.
Naloxone has a limited impact on the respiratory depressant effect of buprenorphine.
High doses are needed given either as repeated boluses or infusion (for example
starting with a bolus administration of 1-2 mg intravenously. Having attained an
adequate antagonistic effect, administration by infusion is recommended to maintain
constant naloxone plasma levels). Therefore, adequate ventilation should be
established.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Opioids, Oripavine derivatives
ATC code: N02AE01
Buprenorphine is a strong opioid with agonistic activity at the mu-opioid receptor and
antagonistic activity at the kappa-opioid receptor. Buprenorphine appears to have the
general characteristics of morphine, but has its own specific pharmacology and
clinical attributes.
In addition, numerous factors, e.g. indication and clinical setting, route of
administration and the interindividual variability, have an impact on analgesia and
therefore have to be considered when comparing analgesics.
In daily clinical practice different opioids are ranked by a relative potency, although
this is to be considered a simplification.
The relative potency of buprenorphine in different application forms and in different
clinical settings has been described in literature as follows:


Morphine p.o.: BUP i.m. as 1 : 67 - 150 (single dose; acute pain model)



Morphine p.o.: BUP s.l. as 1 : 60 - 100 (single dose, acute pain model; multiple
dose , chronic pain, cancer pain)



Morphine p.o.: BUP TTS as 1 : 75 - 115 (multiple dose, chronic pain)

Abbreviations:
p.o = oral; i.m. = intramuscular; s.l. = sublingual; TTS = transdermal; BUP =
buprenorphine
Adverse reactions are similar to those of other strong opioid analgesics.
Buprenorphine appears to have a lower dependence liability than morphine.

5.2

Pharmacokinetic properties
General characteristics of the active substance
Buprenorphine has a plasma protein binding of about 96%.
Buprenorphine is metabolised in the liver to N-dealkylbuprenorphine (norbuprenorphine) and to glucuronide conjugated metabolites. 2/3 of the active substance is
eliminated unchanged in the faeces and 1/3 eliminated as conjugates of unchanged or
dealkylated buprenorphine via the urinary system. There is evidence of enterohepatic
recirculation.
Studies in non-pregnant and pregnant rats have shown that buprenorphine passes the
blood-brain and placental barriers. Concentrations in the brain (which contained only
unchanged buprenorphine) after parenteral administration were 2-3 times higher than
after oral administration. After intramuscular or oral administration buprenorphine
apparently accumulates in the foetal gastrointestinal lumen – presumably due to
biliary excretion, as enterohepatic circulation has not fully developed.
Characteristics of buprenorphine in healthy volunteers
After the application of buprenorphine, buprenorphine is absorbed through the skin.
The continuous delivery of buprenorphine into the systemic circulation is by
controlled release from the adhesive polymer-based matrix system.
After the initial application of buprenorphine the plasma concentrations of
buprenorphine gradually increase, and after 12-24 h the plasma concentrations reach
the minimum effective concentration of 100 pg/ml. From the studies performed with
the buprenorphine 35 micrograms/h in healthy volunteers, an average Cmax of 200 to
300 pg/ml and an average tmax of 60-80 h were determined. In one volunteer study,
buprenorphine 35 micrograms/h and buprenorphine 70 micrograms/h were applied in
a cross-over design. From this study, dose proportionality for the different strengths
was demonstrated.
After removal of buprenorphine the plasma concentrations of buprenorphine steadily
decrease and are eliminated with a half-life of approx. 30 hours (range 22 - 36). Due
to the continuous absorption of buprenorphine from the depot in the skin elimination
is slower than after intravenous administration.

5.3

Preclinical safety data
Standard toxicological studies have not provided evidence of any particular potential
risks for humans. In studies with repeated application of buprenorphine in rats a
reduced increase in body weight was observed.

Studies on fertility and general reproductive capacity in rats showed no detrimental
effects. Studies in rats and rabbits provided evidence for fetotoxicity and an increased
post-implantation loss.
Studies in rats showed an impaired intra-uterine growth, delays in the development of
certain neurological functions and high peri/post natal mortality in neonates after
treatment of the dams during gestation or lactation. There is evidence that
complications during delivery and reduced lactation contributed to these effects.
There was no evidence of embryotoxicity including teratogenicity in rats or rabbits.
In vitro and in vivo evaluations on the mutagenic potential of buprenorphine did not
indicate any clinically relevant effects.
In long-term studies in rats and mice there was no evidence of any carcinogenic
potential relevant for humans.
Toxicological data available did not indicate a sensitising potential of the excipients
used in the transdermal patches.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Adhesive matrix (containing buprenorphine): povidone K90, levulinic acid, oleyl
oleate, poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl)acrylate-co-vinylacetate]
(5:15:75:5)
Adhesive matrix (without buprenorphine): poly[(2-ethylhexyl)acrylate-coglycidylmethacrylate-co-(2-hydroxyethyl)acrylate-co-vinylacetate] (68:0,15:5:27)
Separating foil between adhesive matrices with and without buprenorphine:
polyethylene terephthalate film
Backing foil: polyester
Release liner (on the front covering the adhesive matrix containing buprenorphine):
polyethylene terephthalate film, siliconised
blue printing ink

6.2

Incompatibilities
Not applicable

6.3

Shelf life
2 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Each child-proof sachet is made of a composite layer material consisting of Paper/
PET/ PE/ Aluminium/ Surlyn. One sachet contains one transdermal patch.
Pack sizes:
Packs containing 3, 4, 5, 6, 8, 10, 12, 16, 18, 20 or 24 individually sealed transdermal
patches.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Used transdermal patches should be folded in half, with the adhesive side inwards,
placed in the original sachet and discarded safely, or whenever possible returned to
the pharmacy. Any used or unused transdermal patches should be disposed of in
accordance with local requirements or returned to the pharmacy.

7

MARKETING AUTHORISATION HOLDER
Dr. Reddy’s Laboratories (UK) Ltd.
6 Riverview Road
Beverley
East Yorkshire
HU17 0LD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 08553/0546

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30/12/2015

10

DATE OF REVISION OF THE TEXT
30/12/2015

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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