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RELEVTEC 52.5 MICROGRAM/HOUR TRANSDERMAL PATCH

Active substance(s): BUPRENORPHINE / BUPRENORPHINE / BUPRENORPHINE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Relevtec 52.5 microgram/hour transdermal patch

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each transdermal patch contains 30 mg of buprenorphine in a patch size of 37.5 cm2
releasing 52.5 micrograms of buprenorphine per hour.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Transdermal patch.
The product is composed of a drug containing transdermal patch integrated with an
oversized pale yellowish-brown cover patch without any active substance. The shape
of the transdermal patch is rectangular with rounded edges. The transdermal patch
contains the following imprint:
Buprenorphinum 52.5 µg/h

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Moderate to severe cancer pain and severe pain which does not respond to non-opioid
analgesics.
Relevtec 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: Relevtec 35 microgram/hour, Relevtec 52.5 microgram/hour
and Relevtec 70 microgram/hour.
Initial dose selection
Patients who have previously not received any analgesics should start with the lowest
transdermal patch strength (buprenorphine 35 microgram/hour). Patients previously
given a WHO step-I analgesic (non-opioid) or a step-II analgesic (weak opioid)
should also begin with buprenorphine 35 microgram/hour. 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 Relevtec and choosing
the initial transdermal patch strength, the nature of the previous medication,
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 (buprenorphine 35
microgram/hour). 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 Relevtec transdermal patches must be adapted to the
requirements of the individual patient and checked at regular intervals.
After application of the first buprenorphine 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(s) (with the exception of transdermal
opioids) should be given in the same dose during the first 12 hours after switching to
Relevtec and appropriate rescue medicinal product on demand in the following 12
hours.
Dose titration and maintenance therapy
The Relevtec transdermal patch 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 buprenorphine 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 dose adjusted
accordingly. Patients requiring a supplementary analgesic (e.g. for breakthrough pain)
during maintenance therapy may take for example one or two 0.2 mg buprenorphine
sublingual tablets 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
Relevtec should under no circumstances be administered for longer than absolutely
necessary. If long-term pain treatment with buprenorphine 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 Relevtec
After removal of the transdermal 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 Relevtec is to be followed by other
opioids. As a general rule, a subsequent opioid should not be administered within
24 hours after removal of Relevtec. For the time being only limited information is
available on the starting dose of other opioids administered after discontinuation of
buprenorphine transdermal patches.
Special populations
Elderly people
No dose adjustment of buprenorphine is required for elderly people.
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 buprenorphine
transdermal patches.
Paediatric population

As buprenorphine transdermal patches have not been studied in patients under 18
years of age, the use of Relevtec in patients below this age is not recommended.
Method of administration
Transdermal use.
The transdermal patch 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 the transdermal patch should be avoided.
The skin must be completely dry before application. The transdermal patch 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.
The transdermal patch should be worn continuously for up to 4 days. After removal
of the previous transdermal patch a new 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

4.4

Contraindications


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



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 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.
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 the transdermal patch, 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, infrared-radiation).
Athletes must be aware that this medicine may cause a positive reaction to sports
doping control tests.

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 CYP3A4 the efficacy of
buprenorphine may be intensified (inhibitors) or weakened (inducers).

4.6

Fertility, pregnancy and lactation
Pregnancy
There are limited amount of data from the use of buprenorphine transdermal patches
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 newborn infant even after a short period of administration. Longterm administration of buprenorphine during the last three months of pregnancy may
cause a withdrawal syndrome in the newborn infant.
Therefore, use of Relevtec is not recommended during pregnancy and in women of
childbearing potential who are not using effective contraception.
Breast-feeding
Buprenorphine is excreted in human milk. In rats, buprenorphine has been found to
inhibit lactation.
Relevtec should not be used during breast-feeding.
Fertility
No human data on the effect of buprenorphine on fertility are available. 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
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.
Buprenorphine transdermal patches have major influence on the ability to drive and
use machines.
Even when used according to instructions, buprenorphine transdermal patches 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 Relevtec and for at least
24 hours after the transdermal patch has been removed.
Patients stabilized on a specific dose will not necessarily be restricted if the above
mentioned symptoms are not present.

4.8

Undesirable effects
The following adverse reactions were reported after administration of buprenorphine
transdermal patches in clinical studies and from post marketing 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)
a)
The most commonly reported systemic adverse reactions were nausea and vomiting.
The most commonly reported local adverse reactions were erythema and pruritus.
b)

System Organ
Class

Very
common

Common

Uncommon Rare

Very rare

System Organ
Very
Class
common
Immune system
disorders

Common

Uncommon Rare

Serious
allergic
reactions*
Loss of appetite

Metabolism
and nutrition
disorders
Psychiatric
disorders

Confusion,
sleep
disorder,
restlessness

Dizziness,
headache

Nervous system
disorders

Sedation,
somnolence

Eye disorders

Psychotomimeti
c effects (e.g.
hallucinations,
anxiety,
nightmares),
libido decreased
Concentration
impaired,
speech disorder,
numbness,
dysequilibrium,
paraesthesia
(e.g. pricking or
burning skin
sensation)
Visual
disturbance,
vision blurred,
eyelid oedema

Dependence
,
mood
swings

Muscle
fasciculatio
n,
parageusia

Miosis

Ear pain

Ear and
labyrinth
disorders
Vascular
disorders

Respiratory,
thoracic and
mediastinal
disorders
Gastrointestina
l disorders
Skin and
subcutaneous
tissue disorders

Very rare

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

Nausea
Erythem
a,
pruritus

Vomiting,
constipation
Exanthema,
diaphoresis

Hot flushes

Respiratory
depression

Hyperventil
ation,
hiccups

Dry mouth

Pyrosis

Retching

Rash

Urticaria

Pustules,
vesicles

System Organ
Class
Renal and
urinary
disorders

Very
common

Reproductive
system and
breast
disorders
General
disorders and
administration
site conditions

Common

Uncommon Rare

Very rare

Urinary
retention,
micturition
disorders
Decreased
erection

Oedema,
tiredness

Weariness

Withdrawal
symptoms*,
administration
site reactions

Thoracic
pain

* see section c)
c)
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 at: 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/hour
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: Analgesics, opioids, oripavine derivatives, ATC code:
N02AE01
Mechanism of action
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.
Clinical efficacy and safety
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 pharmaceutical 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 transdermal patches in healthy volunteers
After the application of the buprenorphine transdermal patch, 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 transdermal patch, 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 transdermal patch in
healthy volunteers, an average Cmax of 200 to 300 pg/ml and an average tmax of 6080 h were determined. In one volunteer study, transdermal patches with
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 transdermal patch, the plasma concentrations of
buprenorphine steadily decrease and are eliminated with a half-life of approximately
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 shown evidence of any particular potential
risks for humans. In tests with repeated doses of buprenorphine in rats the increase in
body weight was reduced.
Studies on fertility and general reproductive capacity of rats showed no detrimental
effects. Studies in rats and rabbits revealed signs of fetotoxicity and increased postimplantation loss.
Studies in rats showed diminished intra-uterine growth, delays in the development of
certain neurological functions and high peri/postnatal mortality in the neonates after
treatment of the dams during gestation or lactation. There is evidence that
complicated 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 examinations 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
in the transdermal patches.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Release liner (to be removed before applying the patch):
Poly(ethylene terephthalate) foil, siliconized
Adhesive matrix (containing buprenorphine):
Levulinic acid
Oleyl oleate
Povidone K90

Poly[butylacrylate-co-(2-ethylhexyl)acrylate-co-methylmethacrylate-co-N-tertoctylacrylamid] (32:32:15:20)
Poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl)acrylate-co-vinylacetate]
(5:15:75:5)
Separating film (between the adhesive matrices with and without buprenorphine):
Poly(ethylene terephthalate) foil
Adhesive matrix (without buprenorphine):
Acrylate adhesive
Backing layer (printed):
Polyurethane backing foil
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 transdermal patch is individually packed in a child resistant sachet made of
PET/Al/PE.
Carton containing 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 16, 18, 19, 20, 21 or 24 transdermal
patches.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Used transdermal patches should be folded with the adhesive surfaces inwards. Any
unused medicinal product or waste material should be disposed of in accordance with
local requirements.

7

MARKETING AUTHORISATION HOLDER
Sandoz Limited
Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR,
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 04416/1456

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
16/06/2016

10

DATE OF REVISION OF THE TEXT
16/06/2016

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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