REBRIKEL 5 UG/H TRANSDERMAL PATCH - summary of medicine characteristics

Rebrikel 5 ug/h transdermal patch

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each transdermal patch contains 5 mg of buprenorphine in a patch size of 6.25 cm2, 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.

Transdermal patch.

Rectangular beige coloured patch with rounded edges and imprinted with “Buprenorphin” and “5 gg/h” in blue colour.

4.1 Therapeutic indications

Treatment of non-malignant pain of moderate intensity when an opioid is necessary for obtaining adequate analgesia.

Rebrikel is not suitable for the treatment of acute pain.

Rebrikel is indicated in adults.

4.2 Posology and method of administration

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with buprenorphine in order to minimize the risk of addiction and drug withdrawal syndrome (see section 4.4).

Posology

Rebrikel should be administered every 7th day.

Patients aged 18 years and over

The lowest Rebrikel dose (Rebrikel 5 jig/h 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 and titration with Rebrikel, patients should use the usual recommended doses of short-acting supplemental analgesics (see section 4.5) as needed until analgesic efficacy with Rebrikel is attained.

The dose should not be increased before 3 days, when the maximum effect of a given dose is established. Subsequent dosage 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, regardless of the patch strength. 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.

Conversion from opioids

Rebrikel can be used as an alternative to treatment with other opioids. Such patients should be started on the lowest available dose (Rebrikel 5 jig/h transdermal patch) and continue taking short-acting supplemental analgesics (see section 4.5) during titration, as required.

Patients under 18 years of age

As Rebrikel has not been studied in patients under 18 years of age the use of Rebrikel in patients below this age is not recommended.

Elderly

No dosage adjustment of Rebrikel is required in elderly patients.

Renal impairment

No special dose adjustment of Rebrikel 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 Rebrikel.

Patients with severe hepatic impairment may accumulate buprenorphine during Rebrikel treatment. Consideration of alternate therapy should be considered, and Rebrikel should be used with caution, if at all, in such patients.

Method of administration

Route of administration

Transdermal patch. The patch must not be divided or cut into pieces.

Patch application

Rebrikel 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. Rebrikel 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. Rebrikel 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.

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.

Duration of administration

Rebrikel should under no circumstances be administered for longer than absolutely necessary. If long- term pain treatment with Rebrikel 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

Rebrikel 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).

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.

4.3 Contraindications

Rebrikel is contraindicated in:

patients with known hypersensitivity to the active substance buprenorphine or to any of the excipients (see 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.

4.4 Special warnings and precautions for use

Rebrikel should be used with particular caution in patients with convulsive disorders, 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 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.

Rebrikel 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.

Rebrikel should not be used at higher doses than recommended.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (eg., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

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 product and caution should be exercised when prescribing to patients known to have, or suspected of having, a history of drug abuse.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with buprenorphine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimize symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Withdrawal (abstinence syndrome), when it occurs, is generally mild, begins after 2 days and may last up to 2 weeks.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Serotonin syndrome

Concomitant administration of Rebrikel and other serotonergic agents, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dosedependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

4.5 Interaction with other medicinal products and other forms of interaction

Rebrikel 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.

A drug interaction study with the CYP3A4 inhibitor ketoconazole did not produce clinically relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure following Rebrikel with ketoconazole as compared to Rebrikel alone.

The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied.

Co-administration of Rebrikel 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

Rebrikel should be used cautiously with:

Benzodiazepines: This combination can potentiate respiratory depression of central origin, with risk of death in case of overdose (see section 4.4).

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.

Buprenorphine is a partial mu-receptor agonist but it is described to functions as a pure mu receptor agonist at typical analgesic doses. These doses produce buprenorphine exposures comparable to or greater than those produced by Rebrikel 5, 10 and 20 jig/h transdermal patches. In Rebrikel clinical studies subjects receiving full mu agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to Rebrikel. There were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to Rebrikel (see section 4.4).

Serotonergic medicinal products, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially lifethreatening condition, is increased (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in pregnant women, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate ad an antidote for the child should be readily available.

There are no or limited amounts of data from the use of Rebrikel 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.

Rebrikel should not be used during pregnancy and in women of childbearing potential who are not using effective contraception.

Breastfeeding

Administration to nursing women is not recommended as buprenorphine may be secreted in breast milk and may cause respiratory depression in the infant.

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 Rebrikel 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

Rebrikel has a major influence on the ability to drive and use machines. Even when used according to instructions, Rebrikel 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.

In patients who are affected, such as during treatment initiation or titration to a higher dose, these patients should not drive or use machines, nor for at least 24 hours after the patch has been removed.

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.

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/…-driving-law

4.8 Undesirable effects

Serious adverse reactions that may be associated with Rebrikel 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:

Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

*

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

1Includes application site erythema, application site oedema, application site pruritus, application site rash.

A specific opioid antagonist such as naloxone may reverse the effects of buprenorphine. The dose of naloxone may be in the range 5 to 12 mg intravenously.

The onset of the naloxone effect may be delayed by 30 minutes or more. Maintenance of adequate ventilation is more important than treatment with naloxone.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, opioids; ATC code: N02 AE01 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 five 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. Rebrikel 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 Rebrikel, buprenorphine concentrations decline, decreasing approximately 50% in 12 hours (range 10–24 h).

Absorption

Following Rebrikel application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for Rebrikel 10 ug/h 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

Rebrikel 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 Rebrikel 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 Rebrikel 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 Rebrikel 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 postoperative patients, the total elimination of buprenorphine was shown to be approximately 55 l/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 Rebrikel 20 iig/li transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.

5.3 Preclinical safety data

In single- and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs and minipigs, Rebrikel caused minimal or no adverse systemic events, whereas skin irritation was observed in all species examined. No teratogenic effects were observed in rats or rabbits. However, perinatal mortality was reported in the literature for rats treated with buprenorphine.

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.

Toxicological data available did not indicate a sensitising potential of the additives of the transdermal patches.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Adhesive matrix (containing buprenorphine):

(Oleyl oleate, Povidone K90,

Levulinic Acid

Poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl)acrylate-co-vinylacetate] (5:15:75:5))

Adhesive matrix (without buprenorphine):

Poly[(2-ethylhexyl)acrylate-co-glycidylmethacrylat-co-(2-hydroxyethyl)a­crylate-co-vinylacetate] (68:0,15:5:27).

Separating foil between the adhesive matrices with and without buprenorphine:

Poly(Ethylene­terephthalate)- foil.

Backing layer:

Polyester

Release liner (on the front covering the adhesive matrix containing buprenorphine) (to be removed before applying the patch):

Poly(Ethylene­terephthalate) – foil, 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: 1, 2, 3, 4, 5, 8, 10, 12 individually sealed transdermal patches.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

The patch should not be used if the seal is broken.

Disposal after use:

When changing the patch, the used patch should be removed, the adhesive layer folded inwards on itself,and the patch disposed of safely and out of sight and reach of children.