THORBUP 5 MICROGRAM/HOUR TRANSDERMAL PATCH
Active substance(s): BUPRENORPHINE
NAME OF THE MEDICINAL PRODUCT
ThorBup 5 microgram/hour transdermal patch
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each transdermal patch contains 5 mg of buprenorphine in a 6.25 cm² area releasing a
nominal 5 micrograms of buprenorphine per hour over a period of 7 days.
For the full list of excipients, see section 6.1.
Rectangular patch beige coloured with rounded edges and imprinted with
“Buprenorphin” and “5 μg/h” in blue colour.
Treatment of non-malignant pain of moderate intensity when an opioid is necessary
for obtaining adequate analgesia.
ThorBup 5 microgram/hour transdermal patch is not suitable for the treatment of
ThorBup 5 microgram/hour transdermal patch is indicated in adults.
Posology and method of administration
Patients aged 18 years and over:
The lowest ThorBup 5 microgram/hour transdermal patch dose (ThorBup 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.
During initiation of treatment with ThorBup 5 microgram/hour transdermal patch,
short-acting supplemental analgesics may be required (see section 4.5) as needed until
analgesic efficacy with ThorBup 5 microgram/hour transdermal patch is attained.
The dose of ThorBup 5 microgram/hour transdermal patch 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.
ThorBup 5 microgram/hour transdermal patch should be administered every 7th day.
Duration of administration
ThorBup 5 microgram/hour transdermal patch should under no circumstances be
administered for longer than absolutely necessary. If long-term pain treatment with
ThorBup 5 microgram/hour transdermal patch 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.
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 ThorBup 5 microgram/hour transdermal patch 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).
Conversion from opioids
ThorBup 5 microgram/hour transdermal patch can be used as an alternative to
treatment with other opioids. Such patients should be started on the lowest available
dose ThorBup 5 microgram/hour transdermal patch) and continue taking short-acting
supplemental analgesics (see section 4.5) during titration, as required.
No dosage adjustment of ThorBup 5 microgram/hour transdermal patch is required in
No special dose adjustment of ThorBup 5 microgram/hour transdermal patch is
necessary in patients with renal 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 ThorBup 5
microgram/hour transdermal patch.
Patients with severe hepatic impairment may accumulate buprenorphine during
ThorBup 5 microgram/hour transdermal patch treatment. Consideration of alternate
therapy should be considered, and ThorBup 5 microgram/hour transdermal patch
should be used with caution, if at all, in such patients.
The safety and efficacy of ThorBup 5 microgram/hour transdermal patch in children
and adolescents below 18 years of age has not been established. No data are
Method of administration
ThorBup 5 microgram/hour transdermal patch 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.
ThorBup 5 microgram/hour transdermal patch 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. ThorBup 5 microgram/hour transdermal
patch 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. ThorBup 5 microgram/hour transdermal patch 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 of wear. 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.
hypersensitivity to the active substance or to any of the excipients listed in
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 history of seizure
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.
Since CYP3A4 inhibitors may increase concentrations of buprenorphine (see section
4.5), patients already treated with CYP3A4 inhibitors should have their dose of
ThorBup 5 microgram/hour transdermal patchcarefully titrated since a reduced
dosage might be sufficient in these patients.
Buprenorphine is not recommended for analgesia in the immediate post-operative
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.
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
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.
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).
Fertility, pregnancy and lactation
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.
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.
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).
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
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).
The following undesirable effects have occurred:
* In some cases delayed local allergic reactions occurred with marked signs of
inflammation. In such cases treatment with buprenorphine should be terminated.
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.
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 assisted or 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.
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.
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).
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.
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
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-Oglucuronide, 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.
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 development 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.
A standard battery of genotoxicity tests indicated that buprenorphine is nongenotoxic.
In long-term studies in rats and mice there was no evidence of any carcinogenic
potential relevant for humans.
List of excipients
Adhesive matrix (containing buprenorphine):
Adhesive matrix (without buprenorphine):
Separating foil between adhesive matrices with and without buprenorphine:
poly(ethylene terephthalate) film
Backing foil: polyester
Release liner: poly(ethylene terephthalate) film, siliconised
blue printing ink
Special precautions for storage
Do not store above 25°C.
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) (=Surlyn). One sachet contains
one transdermal patch.
Packs containing 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 18, 20 or 24 individually sealed
Not all pack sizes may be marketed.
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.
MARKETING AUTHORISATION HOLDER
Thornton & Ross Ltd
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT