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BUSIETE 10 MICROGRAMS/HOUR TRANSDERMAL PATCH

Active substance(s): BUPRENORPHINE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Busiete 10 micrograms/hour Transdermal Patch

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each transdermal patch contains 10 mg of buprenorphine in a 12.5 cm² area
releasing a nominal 10 micrograms of buprenorphine per hour over a period of 7
days.
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 “10 µg/h” in blue colour.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of non-malignant pain of moderate intensity when an opioid is
necessary for obtaining adequate analgesia.
Busiete is not suitable for the treatment of acute pain.
Busieteis indicated in adults.

4.2

Posology and method of administration
Posology
Patients aged 18 years and over:
The lowest Busiete dose (Busiete 5 microgram/hour Transdermal Patch)
should be used as the initial dose. Consideration should be given to the
previous opioid history of the patient (see section 4.5) as well as to the current
general condition and medical status of the patient.
Titration:
During initiation of treatment with Busiete, short-acting supplemental
analgesics may be required (see section 4.5) as needed until analgesic efficacy
with Busiete is attained.
The dose of Busiete may be titrated upwards as indicated after 3 days, when
the maximum effect of a given dose is established. Subsequent dose increases
may then be titrated based on the need for supplemental pain relief and the
patient's analgesic response to the patch.
To increase the dose, a larger patch should replace the patch that is currently
being worn, or a combination of patches should be applied in different places
to achieve the desired dose. It is recommended that no more than two patches
are applied at the same time, up to a maximum total dose of 40
microgram/hour buprenorphine. A new patch should not be applied to the
same skin site for the subsequent 3-4 weeks (see section 5.2). Patients should
be carefully and regularly monitored to assess the optimum dose and duration
of treatment.
Busiete should be administered every 7th day.
Conversion from opioids:
Busiete can be used as an alternative to treatment with other opioids. Such
patients should be started on the lowest available dose (Busiete 5
microgram/hour Transdermal Patch) and continue taking short-acting
supplemental analgesics (see section 4.5) during titration, as required.
Duration of administration:
Busiete should under no circumstances be administered for longer than
absolutely necessary. If long-term pain treatment with Busiete 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:

After removal of the patch, 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 Busiete is to be followed
by other opioids. As a general rule, a subsequent opioid should not be
administered within 24 hours after removal of the patch. At present, only
limited information is available on the starting dose of other opioids
administered after discontinuation of the transdermal patch (see section 4.5).
Special populations
Elderly
No dosage adjustment of Busiete is required in elderly patients.
Renal impairment
No special dose adjustment of Busiete is necessary in patients with renal
impairment.
Hepatic impairment
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 hepatic insufficiency should be carefully monitored during
treatment with Busiete.
Patients with severe hepatic impairment may accumulate buprenorphine
during Busiete treatment. Consideration of alternate therapy should be
considered, and Busiete should be used with caution, if at all, in such patients.
Patients treated with CYP3A4 inhibors
Since CYP3A4 inhibitors may increase concentrations of buprenorphine
(see section 4.5), patients already treated with CYP3A4 inhibitors should
have their dose of Busiete carefully titrated since a reduced dosage might
be sufficient in these patients.
Paediatric population
The safety and efficacy of Busiete in children and ado-lescents below 18 years
of age has not been established. No data are available.

Method of administration
Busiete is for transdermal use.
The patch must not be divided or cut into pieces.
The patch should not be used if the seal is broken.

Patch application:
Busiete should be applied to non-irritated, intact skin of the upper outer arm,
upper chest, upper back or the side of the chest, but not to any parts of the skin
with large scars. Busiete should be applied to a relatively hairless or nearly
hairless skin site. If none are available, the hair at the site should be cut with
scissors, not shaven.
If the application site must be cleaned, it should be done with clean water only.
Soaps, alcohol, oils, lotions or abrasive devices must not be used. The skin
must be dry before the patch is applied. Busiete should be applied
immediately after removal from the sealed sachet. Following removal of the
protective layer, the transdermal patch should be pressed firmly in place with
the palm of the hand for approximately 30 seconds, making sure the contact is
complete, especially around the edges. If the edges of the patch begin to peel
off, the edges may be taped down with suitable skin tape, to ensure a 7 day
period. The patch should be worn continuously for 7 days. Bathing,
showering, or swimming should not affect the patch. If a patch falls off, a new
one should be applied and worn for 7 days.

4.3

Contraindications
-

4.4

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.

Special warnings and precautions for use
Buprenorphine should be used with particular caution in patients with acute
alcohol intoxication, head injury, shock, a reduced level of consciousness of
uncertain origin, intracranial lesions or increased intracranial pressure, or in
patients with severe hepatic impairment (see section 4.2).
Buprenorphine may lower the seizure threshold in patients with a histo-ry
of seizure disorder.
Significant respiratory depression has been associated with buprenorphine,
particularly by the intravenous route. A number of overdose deaths have
occurred when addicts have intravenously abused buprenorphine, usually

with benzodiazepines concomitantly. Additional overdose deaths due to
ethanol and benzodiazepines in combination with buprenorphine have been
reported.
Buprenorphine is not recommended for analgesia in the immediate postoperative period or in other situations characterised by a narrow therapeutic
index or a rapidly varying analgesic requirement.
Controlled human and animal studies indicate that buprenorphine has a
lower dependence liability than pure agonist analgesics. In humans limited
euphorigenic effects have been observed with buprenorphine. This may
result in some abuse of the medicinal product and caution should be
exercised when prescribing to patients known to have, or suspected of
having, a history of drug abuse or alcohol abuse or serious mental illness.
Chronic use of buprenorphine can result in the development of physical
dependence. Withdrawal (abstinence syndrome), when it occurs, is
generally mild, begins after 2 days and may last up to 2 weeks. Withdrawal
symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia,
tremor and gastrointestinal disorders.
Athletes should be aware that this medicine may cause a positive reaction
to sports doping control tests.
Patients with fever or exposed to external heat:
While wearing the patch, patients should be advised to avoid exposing the
application site to external heat sources, such as heating pads, electric
blankets, heat lamps, sauna, hot tubs, and heated water beds, etc., as an
increase in absorption of buprenorphine may occur. When treating febrile
patients, one should be aware that fever may also increase absorption resulting
in increased plasma concentrations of buprenorphine and thereby increased
risk of opioid reactions.

4.5

Interaction with other medicinal products and other forms of interaction
Buprenorphine must not be used concomitantly with MAOIs or in patients
who have received MAOIs within the previous two weeks (see section 4.3).
Effect of other active substances on the pharmacokinetics of
buprenorphine:
Buprenorphine is primarily metabolised by glucuronidation and to a lesser
extent (about 30%) by CYP3A4 .
Concomitant treatment with CYP3A4 inhibitors may lead to elevated
plasma concentrations with intensified efficacy of buprenorphine.

Studies with the CYP3A4 inhibitor ketoconazole did not produce clinically
relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine
exposure following buprenorphine with ketoconazole as compared to
buprenorphine alone.
The interaction between buprenorphine and CYP3A4 enzyme inducers has
not been studied.
Co-administration of buprenorphine and enzyme inducers (e.g.
phenobarbital, carbamazepine, phenytoin and rifampicin) could lead to
increased clearance which might result in reduced efficacy.
Reductions in hepatic blood flow induced by some general anaesthetics
(e.g. halothane) and other medicinal products may result in a decreased rate
of hepatic elimination of buprenorphine.
Pharmacodynamic interactions:
Buprenorphine should be used cautiously with:
Other central nervous system depressants: other opioid derivatives
(analgesics and antitussives containing e.g. morphine, dextropropoxyphene,
codeine, dextromethorphan or noscapine). Certain antidepressants, sedative
H1-receptor antagonists, alcohol, anxiolytics, neuroleptics, clonidine and
related substances. These combinations increase the CNS depressant
activity. Benzodiazepines: This combination can potentiate respiratory
depression of central origin (see section 4.4).
At typical analgesic doses buprenorphine is described to function as a pure
mu receptor agonist. In buprenorphine clinical studies subjects receiving
full mu agonist opioids (up to 90 mg oral morphine or oral morphine
equivalents per day) were transferred to buprenorphine. There were no
reports of abstinence syndrome or opioid withdrawal during conversion
from entry opioid to buprenorphine (see section 4.4).
4.6

Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of 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 neonate even after a short period of
administration. Long-term administration of buprenorphine during the last
three months of pregnancy may cause a withdrawal syndrome in the neonate.
Therefore buprenorphine should not be used during pregnancy and in women
of childbearing potential who are not using effective contraception.

Breastfeeding
Buprenorphine is excreted in human milk. Studies in rats have shown
that buprenorphine may inhibit lactation. Available
pharmacodynamic/toxicological data in animals has shown excretion
of buprenorphine in milk (see section 5.3). Therefore the use of
buprenorphine during lactation should be avoided.
Fertility
No human data on the effect of buprenorphine on fertility are available. In a
fertility and early embryonic development study, no effects on reproductive
parameters were observed in male or female rats (see section 5.3).

4.7

Effects on ability to drive and use machines
Buprenorphine has a 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 in
the beginning of treatment and in conjunction with other centrally acting
substances including alcohol, tranquillisers, sedatives and hypnotics. An
individual recommendation should be given by the physician. A general
restriction is not necessary in cases where a stable dose is used.
Patients who are affected and experience undesirable effects (e.g. dizziness,
drowsiness, blurred vision) during treatment initiation or titration to a higher dose
should not drive or use machines, for at least 24 hours after the patch has been
removed.

4.8

Undesirable effects
Serious adverse reactions that may be associated with buprenorphine
therapy in clinical use are similar to those observed with other opioid
analgesics, including respiratory depression (especially when used with
other CNS depressants) and hypotension (see section 4.4).

System organ
class
MedDRA

Immune
system
disorders
Metabolism
and nutrition

The following undesirable effects have occurred:
Very
Common
Uncommon
Rare
common
(≥1/100 to
(≥1/1000 to
(≥1/10,000
(≥1/10)
<1/10)
<1/100)
to <1/1000)

Hypersensi
tivity
Anorexia

Anaphylactic
reaction
Dehydration

Very rare
Not known
(<1/10,000) (cannot be
estimated
from the
available data)
Anaphylactoid
reaction

disorders
Psychiatric
disorders

Nervous
system
disorders

Confusion,
Depression,
Insomnia,
Nervousness,
Anxiety

Headache,
Tremor
Dizziness,
Somnolence

Eye disorders

Ear and
labyrinth
disorders
Cardiac
disorders
Vascular
disorders

Psychotic
disorder

Drug
Depersonali
dependence, sation
Mood
swings

Balance
disorder,
Speech
disorder

Involuntary
muscle
contractions

Dyspnoea

Constipa
tion,
Nausea,
Vomiting

Abdominal
pain,
Diarrhoea,
Dyspepsia,

Palpitations,
Tachycardia
Hypotension,
Circulatory
collapse,
Hypertension,
Flushing
Cough,
Wheezing,
Hiccups

Flatulence

Convulsions

Visual
disturbance,
Eyelid
oedema,
Miosis

Tinnitus,
Vertigo

Respiratory,
thoracic and
mediastinal
disorders

Gastro
intestinal
disorders

Sleep disorder,
Restlessness,
Agitation,
Euphoric mood,
Affect liability,
Hallucinations,
Nightmares,
Decreased libido
Sedation,
Dysgeusia,
Dysarthria,
Hypoaesthesia,
Memory
impairment,
Migraine,
Syncope,
Abnormal coordination,
Disturbance in
attention,
Paraestheia
Dry eye,
Blurred vision

Ear pain

Angina
pectoris
Vasodilata
tion,
Orthostatic
hypotension
Respiratory
depression,
Respiratory
failure,
Asthma
aggravated,
Hyperventi
lation,
Rhinitis
Dysphagia,
Ileus

Diverticulitis

Dry mouth
Hepatobiliary
disorders
Skin and
subcutaneous
tissue
disorders

Biliary colic
Pruritus,
Erythema

Musculoskeletal
and connective

Rash,
Sweating,
Exanthema
Muscular
weakness

tissue
disorders
Renal and
urinary
disorders
Reproductive
system and
breast
disorders
General
disorders
and
administration
site conditions

Dry skin,
Urticaria,
Dermatitis
contact
Myalgia,
Muscle spasms

Face oedema

Pustules,
Vesicles

Urinary
retention,
Micturition
disorder

Application
site
reaction1

Investigations

Injury,
poisoning and
procedural
complications

Tiredness,
Asthenic
conditions,
Peripheral
oedema

Fatigue,
Pyrexia,
Rigors,
Oedema,
Drug
withdrawal
syndrome,
Application site
dermatitis*,
Chest pain
Alanine
aminotrans
ferase increased,
Weight
decreased
Accidental
injury,
Fall

Erectile
dysfunction,
Sexual
dysfunction
Influenza like
illness

* In some cases delayed local allergic reactions occurred with marked signs of
inflammation. In such cases treatment with buprenorphine should be terminated.
1

Includes application site erythema, application site oedema, application site
pruritus, application site rash.

Buprenorphine has a low risk of physical dependence. After discontinuation
of buprenorphine, withdrawal symptoms are unlikely. This may be due to
the very slow dissociation of buprenorphine from the opioid receptors and
to the gradual decrease of buprenorphine plasma concentrations (usually
over a period of 30 hours after removal of the last patch). However, after
long-term use of buprenorphine, withdrawal symptoms similar to those

occurring during opioid withdrawal, cannot be entirely excluded. These
symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia,
tremor and gastrointestinal 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 at:
www.mhra.gov.uk/yellowcard.

4.9

Overdose
Symptoms: Symptoms similar to those of other centrally acting analgesics
are to be expected. These include respiratory depression, sedation,
drowsiness, nausea, vomiting, cardiovascular collapse and marked miosis.
Treatment: Any patches should be removed from the patient's skin. A
patent airway should be established and maintained , respiration should be
assissed and controlled as indicated and adequate body temperature and
fluid balance should be maintained. Oxygen, intravenous fluids,
vasopressors and other supportive measures should be employed as
indicated.
A specific opioid antagonist such as naloxone may reverse the effects of
buprenorphine, although naloxone may be less effective in reversing the
effects of buprenorphine than other µ-opioid agonists. Treatment with
continuous intravenous naloxone should begin with the usual doses but
high doses may be required.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics, opioids, oripavine derivatives;
ATC code: N02AE01
Buprenorphine is a partial agonist opioid, acting at the mu opioid receptor.
It also has antagonistic activity at the kappa opioid receptor.
Efficacy has been demonstrated in seven pivotal phase III studies of up to
12 weeks duration in patients with non-malignant pain of various
aetiologies. These included patients with moderate and severe OA and back
pain. Buprenorphine demonstrated clinically significant reductions in pain
scores (approximately 3 points on the BS-11 scale) and significantly greater

pain control compared with placebo.
A long term, open-label extension study (n=384) has also been performed
in patients with non-malignant pain. With chronic dosing, 63% of patients
were maintained in pain control for 6 months, 39% of patients for 12
months, 13% of patients for 18 months and 6% for 21 months.
Approximately 17% were stabilised on the 5 mg dose, 35% on the 10 mg
dose and 48% on the 20 mg dose.

5.2

Pharmacokinetic properties
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.
Each patch provides a steady delivery of buprenorphine for up to seven
days. Steady state is achieved during the first application. After removal of
buprenorphine, buprenorphine concentrations decline, decreasing
approximately 50% in 12 hours (range 10–24 h).
Absorption:
Following buprenorphine application, buprenorphine diffuses from the
patch through the skin. In clinical pharmacology studies, the median time
for “buprenorphine 10 microgram/hour” to deliver detectable
buprenorphine concentrations (25 picograms/ml) was approximately 17
hours. Analysis of residual buprenorphine in patches after 7-day use shows
15% of the original load delivered. A study of bioavailability, relative to
intravenous administration, confirms that this amount is systemically
absorbed. Buprenorphine concentrations remain relatively constant during
the 7-day patch application.
Application site:
A study in healthy subjects demonstrated that the pharmacokinetic profile
of buprenorphine delivered by buprenorphine is similar when applied to
upper outer arm, upper chest, upper back or the side of the chest
(midaxillary line, 5th intercostal space). The absorption varies to some
extent depending on the application site and the exposure is at the most
approximately 26 % higher when applied to the upper back compared to the
side of the chest.

In a study of healthy subjects receiving buprenorphine repeatedly to the
same site, an almost doubled exposure was seen with a 14 day rest period.
For this reason, rotation of application sites is recommended, and a new
patch should not be applied to the same skin site for 3-4 weeks.
In a study of healthy subjects, application of a heating pad directly on the
transdermal patch caused a transient 26 - 55% increase in blood
concentrations of buprenorphine. Concentrations returned to normal within
5 hours after the heat was removed. For this reason, applying direct heat
sources such as hot water bottles, heat pads or electric blankets directly to
the patch is not recommended. A heating pad applied to a buprenorphine
site immediately after patch removal did not alter absorption from the skin
depot.
Distribution:
Buprenorphine is approximately 96% bound to plasma proteins.
Studies of intravenous buprenorphine have shown a large volume of
distribution, implying extensive distribution of buprenorphine. In a study of
intravenous buprenorphine in healthy subjects, the volume of distribution at
steady state was 430 l, reflecting the large volume of distribution and
lipophilicity of the active substance.
Following intravenous administration, buprenorphine and its metabolites
are secreted into bile, and within several minutes, distributed into the
cerebrospinal fluid. Buprenorphine concentrations in the cerebrospinal fluid
appear to be approximately 15% to 25% of concurrent plasma
concentrations.
Biotransformation and elimination:
Buprenorphine metabolism in the skin following buprenorphine application
is negligible. Following transdermal application, buprenorphine is
eliminated via hepatic metabolism, with subsequent biliary excretion and
renal excretion of soluble metabolites. Hepatic metabolism, through
CYP3A4 and UGT1A1/1A3 enzymes, results in two primary metabolites,
norbuprenorphine and buprenorphine 3-O-glucuronide, respectively.
Norbuprenorphine is glucuronidated before elimination. Buprenorphine is
also eliminated in the faeces. In a study in post-operative patients, the total
elimination of buprenorphine was shown to be approximately 551/h.
Norbuprenorphine is the only known active metabolite of buprenorphine.
Effect of buprenorphine on the pharmacokinetics of other active
substances:
Based on in vitro studies in human microsomes and hepatocytes,
buprenorphine does not have the potential to inhibit metabolism catalysed
by the CYP450 enzymes CYP1A2, CYP2A6 and CYP3A4 at
concentrations obtained with use of buprenorphine 20μg/h transdermal
patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and

CYP2C19 has not been studied.

5.3

Preclinical safety data
Systemic toxicity and dermal toxicity
In single- and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs
and minipigs, buprenorphine caused minimal or no adverse systemic
events, whereas skin irritation was observed in all species examined.
Toxicological data available did not indicate a sensitising potential of the
additives of the transdermal patches.
Reproductive and developmental toxicity
No effect on fertility or general reproductive performance was observed in
rats treated with buprenorphine.
In embryofoetal developmental toxicity studies conducted in rats and
rabbits using buprenorphine, no embryofoetal toxicity effects were
observed. In a rat pre- and post-natal developmental toxicity study with
buprenorphine there was pup mortality, decreased pup body weight and
concomitant maternal reduced food consumption and clinical signs.
Genotoxicity
A standard battery of genotoxicity tests indicated that buprenorphine is
non-genotoxic.
Carcinogenicity
In long-term studies in rats and mice there was no evidence of any
carcinogenic potential relevant for humans.

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-covinylacetate] (5:15:75:5)
Adhesive matrix
(without
buprenorphine):
Poly[(2-ethylhexyl)acrylate-co-glycidylmethacrylat-co-(2hydroxyethyl)acrylate-co-vinylacetate] (68:0,15:5;27)
Separating foil between adhesive matrices with and without buprenorphine:
poly(ethylene therephthalate)

Backing foil: polyester
Release liner: poly(ethylene therephthalate), siliconised
blue printing ink
6.2

Incompatibilities
Not applicable

6.3

Shelf life
21 months

6.4

Special precautions for storage
Do not store above 25°C.

6.5

Nature and contents of container
Each child-proof sachet is made of a composite layer material consisting of
Paper/ PET/ PE/ Aluminium/ Poly(acrylic acid-co-ethylene). One sachet
contains one transdermal patch.
Pack sizes:
Packs containing 1, 2, 3, 4, 5, 8, 10 or 12 individually sealed transdermal
patches.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
When changing the patch, the used patch should be removed, the adhesive
layer folded inwards on itself, and the patch disposed of safely.

7

MARKETING AUTHORISATION HOLDER
TEVA UK Limited
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex BN22 9AG
UNITED KINGDOM

8

MARKETING AUTHORISATION NUMBER(S)
PL 00289/2023

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
13/10/2016

10

DATE OF REVISION OF THE TEXT
13/10/2016

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