Soloro

Moderate to severe cancer pain and severe pain which does not respond to non-opioid analgesics.

Soloro is not suitable for the treatment of acute pain.

Substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment.

Posology

Patients over 18 years of age

The Soloro dosage should be adapted to the condition of the individual patient (pain intensity, suffering, individual reaction).).

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 Soloro must be adapted to the requirements of the individual patient and checked at regular intervals.

After application of the first Soloro 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 medication (with the exception of transdermal opioids) should be given in the same dose during the first 12 hours after switching to Soloro and appropriate rescue medication on demand in the following 12 hours.

Dose titration and maintenance therapy

Soloro 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 Soloro strength the amount of total opioids administered in addition to the previous transdermal patch should be taken into consideration, i.e. the total amount of opioids required, and the dosage adjusted accordingly. Patients requiring a supplementary analgesic (e.g. for breakthrough pain) during maintenance therapy may take for example one to 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.

Paediatric population

As Soloro has not been studied in patients under 18 years of age, the use of the medicinal product in patients below this age is not recommended.

Elderly patients

No dosage adjustment of Soloro is required for elderly patients.

Patients with renal insufficiency

Since the pharmacokinetics of buprenorphine is not altered during the course of renal failure, its use in patients with renal insufficiency, including dialysis patients, is possible.

Patients with hepatic insufficiency

Buprenorphine is metabolised in the liver. The intensity and duration of its action may be affected in patients with impaired liver function. Therefore patients with liver insufficiency should be carefully monitored during treatment with Soloro.

Method of application

Soloro 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 Soloro should be avoided.

The skin must be completely dry before application. Soloro 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. However, it should not be exposed to excessive heat (e.g. sauna, infrared-radiation).

Soloro should be worn continuously for up to 4 days. After removal of the previous transdermal patch a new Soloro 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.

Duration of administration

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

After removal of Soloro 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 Soloro is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours after removal of Soloro. For the time being only limited information is available on the starting dose of other opioids administered after discontinuation of Soloro.

Posology

Treatment with Soloro sublingual tablets is intended for use in adults and children aged 16 years or over who have agreed to be treated for opioid dependence.

Precautions to be taken before dosing

Prior to treatment induction, physicians should be aware of the partial agonist profile of buprenorphine to the opiate receptors, which may precipitate a withdrawal syndrome in opioid-dependent patients and consideration should be given to the types of opioid dependence (i.e. long- or short-acting opioid), the time since last opioid use and the degree of opioid dependence. To avoid precipitating withdrawal, induction with Soloro should be undertaken when objective and clear signs of withdrawal are evident e.g. a score higher than 12 on the Clinical Opioid Withdrawal Scale (COWS).

- For patients dependent on heroin or short-acting opioids: the first dose of buprenorphine should be started when objective signs of withdrawal appear, but not less than 6 hours after the patient last used opioids.

- For patients receiving methadone: before beginning Soloro therapy, the dose of methadone should be reduced to a maximum of 30mg/day. Soloro may precipitate symptoms of withdrawal in patients dependent on methadone. The first dose of buprenorphine should be started only when objective signs of withdrawal appear and generally not less than 24 hours after the patient last used methadone because of the long half-life of methadone.

Baseline liver function tests and documentation of viral hepatitis status is recommended prior to commencing therapy.

Induction:

The initial dose is from 0.8mg to 4mg, administered as a single daily dose.

Dosage adjustment and maintenance:

The dose of Soloro should be increased progressively according to the clinical effect of the individual patient and should not exceed a maximum single daily dose of 32mg. The dosage is titrated according to reassessment of the clinical and psychological status of the patient.

Dosage reduction and termination of treatment:

After a satisfactory period of stabilisation has been achieved, the dosage may be reduced gradually to a lower maintenance dose; when deemed appropriate, treatment may be discontinued in some patients. The availability of the sublingual tablet in doses of 0.4mg, 2mg and 8mg, respectively, allows for a downward titration of dosage. Patients should be monitored following termination of buprenorphine treatment because of the potential for relapse.

Special populations

Elderly

The safety and efficacy of buprenorphine in elderly patients over 65 years of age has not been established.

Hepatic impairment

Patients who are positive for viral hepatitis, on concomitant medicinal products and / or have existing liver dysfunction are at risk of greater liver injury. Patients should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. Buprenorphine should be used with caution in patients with hepatic insufficiency. Buprenorphine is contraindicated in patients with severe hepatic insufficiency.

Renal impairment

Modification of the buprenorphine dose is not generally required for patients with renal impairment. Caution is recommended when dosing patients with severe renal impairment, which may require dose adjustment (creatinine clearance < 30 ml/min).

Paediatric population

Soloro is contraindicated in children under the age of 16.

Method of administration

Administration is sublingual. Physicians must advise patients that the sublingual route is the only effective and safe route of administration for this drug. The tablet should be kept under the tongue until dissolved, which usually occurs within 5 to 10 minutes.

- 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

- patients suffering from myasthenia gravis

- patients suffering from delirium tremens.

- pregnancy

Hypersensitivity to buprenorphine or any other component of the tablet

Children less than 16 years of age

Severe respiratory insufficiency

Severe hepatic insufficiency

Acute alcoholism or delirium tremens

Breast feeding

Soloro 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 Soloro, withdrawal reactions have not been observed. However, after long-term use of Soloro withdrawal symptoms, similar to those occurring during opiate withdrawal, cannot be entirely excluded. 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 Soloro treatment.

Athletes should be aware that this medicine may cause a positive reaction to sports doping control tests.

Paediatric population

As Soloro has not been studied in patients under 18 years of age, the use of the medicinal product in patients below this age is not recommended.

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 Soloro treatment. Therefore on treatment with Soloro, attention should be paid to the increased possibility of opioid reactions in febrile patients or those with increased skin temperature due to other causes.

Soloro sublingual tablets are recommended only for the treatment of opioid drug dependence. It is also recommended that treatment is prescribed by a physician who ensures comprehensive management of the opioid-dependent patient(s).

Misuse, abuse and diversion

Buprenorphine can be misused or abused in a manner similar to other opioids, legal or illicit. Some risks of misuse and abuse include overdose, spread of blood borne viral or localised infections, respiratory depression and hepatic injury. Buprenorphine misuse by someone other than the intended patient poses the additional risk of new drug dependent individuals using buprenorphine as the primary drug of abuse, and may occur if the medicine is distributed for illicit use directly by the intended patient or if the medicine is not safeguarded against theft.

Sub-optimal treatment with buprenorphine may prompt medication misuse by the patient, leading to overdose or treatment dropout. A patient who is under-dosed with buprenorphine may continue responding to uncontrolled withdrawal symptoms by self-medicating with opioids, alcohol or other sedative-hypnotics such as benzodiazepines.

To minimise the risk of misuse, abuse and diversion, physicians should take appropriate precautions when prescribing and dispensing buprenorphine, such as to avoid prescribing multiple refills early in treatment and to conduct patient follow-up visits with clinical monitoring that is appropriate to the patient's level of stability.

Respiratory depression

A number of cases of death due to respiratory depression have been reported, particularly when buprenorphine was used in combination with benzodiazepines or when buprenorphine was not used according to prescribing information. Deaths have also been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol or other opioids. If buprenorphine is administered to some non-opioid dependent individuals who are not tolerant to the effects of opioids, potentially fatal respiratory depression may occur.

Soloro should be used with care in patients with respiratory insufficiency (e.g. chronic obstructive pulmonary disease, asthma, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression or kyphoscoliosis).

Buprenorphine may cause severe, possibly fatal, respiratory depression in children and non-dependent persons who accidentally or deliberately ingest it. Protect children and non-dependent persons against exposure.

CNS depression

Buprenorphine may cause drowsiness particularly when used with alcohol or central nervous system depressants (such as benzodiazepines, tranquillisers, sedatives or hypnotics).

Dependence

Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces dependence of the opioid type. Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce dependence, but at a lower level than a full agonist.

Abrupt discontinuation of treatment is not recommended as it may result in a withdrawal syndrome that may be delayed in onset.

Hepatitis and hepatic events

Cases of acute hepatic injury have been reported in opioid-dependent patients both in clinical trials and in post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of cytolytic hepatitis, hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy and death. In many cases, the presence of pre-existing liver enzyme abnormalities, genetic disease, infection with hepatitis B or hepatitis C virus, alcohol abuse, anorexia, concomitant use of other potentially hepatotoxic drugs and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing Soloro and during treatment. When a hepatic event is suspected further biological and etiological evaluation is required. Depending on the findings, Soloro may be discontinued cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use. If treatment is continued, hepatic function should be monitored closely.

All patients should have liver function tests performed at regular intervals.

Precipitation of opioid withdrawal syndrome

When initiating treatment with Soloro, it is important to be aware of the partial agonist profile of buprenorphine. Sublingually administered buprenorphine can precipitate withdrawal symptoms in opioid-dependent patients if administered before the agonist effects resulting from recent opioid use or misuse have subsided. To avoid precipitated withdrawal, induction should be undertaken when objective signs and symptoms of moderate withdrawal are evident.

Hepatic impairment

The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a post-marketing study. Buprenorphine is extensively metabolized in the liver, plasma levels were found to be higher for buprenorphine in patients with moderate and severe hepatic impairment. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of buprenorphine. Soloro sublingual tablets should be used with caution in patients with moderate hepatic impairment. In patients with severe hepatic insufficiency the use of buprenorphine is contraindicated.

Renal impairment

Renal elimination plays a relatively small role (approximately 30%) in the overall clearance of buprenorphine; therefore, no dose modification based on renal function is generally required. Metabolites of buprenorphine accumulate in patients with renal failure. Caution is recommended dosing patients with severe renal impairment (creatinine clearance < 30 ml/min).

Patients with lactose intolerance

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in adolescents

Due to lack of data in adolescents (age 16 - 18), patients in this age group should be more closely monitored during treatment.

General warnings related to the administration of opioids

Opioids may cause orthostatic hypotension in ambulatory patients.

Opioids may elevate cerebrospinal fluid pressure, which may cause seizures, so opioids should be used with caution in patients with head injury, intracranial lesions, other circumstances where cerebrospinal pressure may be increased, or history of seizure.

Opioids should be used with caution in patients with hypotension, prostatic hypertrophy or urethral stenosis.

Opioid-induced miosis, changes in the level of consciousness or changes in the perception of pain as a symptom of disease may interfere with patient evaluation or obscure the diagnosis or clinical course of concomitant disease.

Opioids should be used with caution in patients with myxoedema, hypothyroidism, or adrenal cortical insufficiency (e.g. Addison's disease).

Opioids have been shown to increase intracholedochal pressure, and should be used with caution in patients with dysfunction of the biliary tract.

Opioids should be administered with caution to elderly or debilitated patients.

Soloro has major influence on the ability to drive and use machines.

Even when used according to instructions, Soloro 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 dosage and when Soloro 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 Soloro and for at least 24 hours after the patch has been removed.

Patients stabilized on a specific dosage will not necessarily be restricted if the above mentioned symptoms are not present.

Additional information for UK only

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 you have this medicine in your body over a specified limit unless you have a defence (called the 'statutory defence').

- This defence applies when:

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.

- Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here:

https://www.gov.uk/drug-driving-law

Buprenorphine has moderate influence on the ability to use machines when administered to opioid dependent patients. Soloro may cause drowsiness, dizziness or impaired thinking, especially during treatment induction and dose adjustment. If taken together with alcohol or central nervous system depressants, the effect is likely to be more pronounced. Patients should be cautioned about operating hazardous machinery in case buprenorphine may affect their ability to engage in such activities.

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

The following adverse reactions were reported after administration of Soloro in clinical studies and from postmarketing surveillance.

The frequencies are given as follows:

Very common (>1/10)

Common (>1/100, <1/10)

Uncommon (>1/1,000, <1/100)

Rare (>1/10,000, <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)

* see section c)

c) In some cases delayed allergic reactions occurred with marked signs of inflammation. In such cases treatment with Soloro should be terminated.

Buprenorphine has a low risk of dependence. After discontinuation of Soloro, 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 Soloro 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

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Summary of safety profile

The most commonly reported adverse drug reactions were those related to withdrawal symptoms (e.g. insomnia, headache, nausea and hyperhidrosis) and pain.

Tabulated list of adverse reactions

Table 1 summarises:

- adverse reactions reported from pivotal clinical studies. The frequency of possible side effects listed below is defined using the following convention: Very common (>1/10), common (>1/100 to <1/10).

- the most commonly reported adverse drug reactions during post-marketing surveillance. Events occurring in at least 1% of reports by healthcare professionals and considered expected are included. Frequency of events not reported in pivotal studies cannot be estimated and is given as not known.

Description of selected adverse reactions

The following is a summary of other post-marketing adverse event reports that are considered serious or otherwise noteworthy:

- In cases of intravenous misuse, local reactions, sometimes septic (abscess, cellulitis), and potentially serious acute hepatitis and other infections such as pneumonia, endocarditis have been reported.

- In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with naloxone.

- The most common signs and symptoms of hypersensitivity include rashes, urticaria, and pruritus. Cases of bronchospasm, angioedema, and anaphylactic shock have been reported.

- Transaminase increase, hepatitis, acute hepatitis, cytolytic hepatitis, jaundice, hepatorenal syndrome, hepatic encephalopathy, and hepatic necrosis have occurred.

- Neonatal drug withdrawal syndrome has been reported among newborns of women who have received buprenorphine during pregnancy. The syndrome may be milder than that seen with a full µ-opioid agonist and may be delayed in onset. The nature of the syndrome may vary depending upon the mother's drug use history.

- Hallucination, orthostatic hypotension, urinary retention and vertigo have been reported.

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.

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 Soloro 70 micrograms/h transdermal patch is about six times less than after the intravenous administration of the therapeutic dose of 0.3 mg buprenorphine.

Symptoms

In principal, on overdose with buprenorphine, symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These are: respiratory depression, sedation, somnolence, nausea, vomiting, cardiovascular collapse, and marked miosis.

Treatment

General emergency measures apply. Keep the airway open (aspiration!), maintain respiration and circulation 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.

Symptoms

Respiratory depression, as a result of central nervous system depression, is the primary symptom requiring intervention in the case of overdose because it may lead to respiratory arrest and death. Preliminary symptoms of overdose may also include somnolence, amblyopia, miosis, hypotension, nausea, vomiting and / or speech disorders.

Treatment

General supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. Symptomatic treatment of respiratory depression, following standard intensive care measures, should be instituted. A patent airway and assisted or controlled ventilation must be assured. The patient should be transferred to an environment within which full resuscitation facilities are available. Use of an opioid antagonist (i.e., naloxone) is recommended, despite the modest effect it may have in reversing the respiratory symptoms of buprenorphine compared with its effects on full agonist opioid agents.

The long duration of action of buprenorphine should be taken into consideration when determining length of treatment needed to reverse the effects of an overdose. Naloxone can be cleared more rapidly than buprenorphine, allowing for a return of previously controlled buprenorphine overdose symptoms.

Pharmacotherapeutic group: Opioids, Oripavine derivatives. ATC code: N02AE01.

Buprenorphine is a strong opioid with agonistic activity at the mu-opioid receptor and antagonistic activity at the kappa-opioid receptor. Buprenorphine appears to have the general characteristics of morphine, but has its own specific pharmacology and clinical attributes.

In addition, numerous factors, e.g. indication and clinical setting, route of administration and the interindividual variability, have an impact on analgesia and therefore have to be considered when comparing analgesics.

In daily clinical practice different opioids are ranked by a relative potency, although this is to be considered a simplification.

The relative potency of buprenorphine in different application forms and in different clinical settings has been described in literature as follows:

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

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

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

Abbreviations:

p.o = oral; i.m. = intramuscular; s.l. = sublingual; TTS = transdermal; BUP = buprenorphine

Adverse reactions are similar to those of other strong opioid analgesics. Buprenorphine appears to have a lower dependence liability than morphine.

Pharmacodynamic group

Drugs used in opioid dependence ATC-code: N07BC01

Mechanism of action

Buprenorphine is an opioid partial agonist/antagonist which attaches itself to the µ (mu) k (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible link with the µ receptors which, over a prolonged period, minimises the need of the opioid-dependent patient.

Clinical efficacy and safety

During clinical pharmacologic studies in opiate-dependent subjects, buprenorphine demonstrated a ceiling effect on a number of parameters, including positive mood, “good effect” and respiratory depression.

a) 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.

b) Characteristics of Soloro in healthy volunteers

After the application of Soloro, 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 Soloro 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 Soloro 35 micrograms/h in healthy volunteers, an average C_max of 200 to 300 pg/ml and an average t_max of 60-80 h were determined. In one volunteer study, Soloro 35 micrograms/h and Soloro 70 micrograms/h were applied in a cross-over design. From this study, dose proportionality for the different strengths was demonstrated.

After removal of Soloro the plasma concentrations of buprenorphine steadily decrease and are eliminated with a half-life of approx. 30 hours (range 22 - 36). Due to the continuous absorption of buprenorphine from the depot in the skin elimination is slower than after intravenous administration.

Absorption

When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjungation in the small intestine. The use of this medication by oral route is therefore inappropriate.

Peak plasma concentrations are achieved 90 minutes after sublingual administration and the maximal dose - concentration relationship is linear, between 2 mg and 16 mg.

Distribution

The absorption of buprenorphine is followed by a rapid distribution phase and a half - life of 2 to 5 hours.

Biotransformation and elimination

Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjungation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is µ (mu) agonist with weak intrinsic activity.

Elimination of buprenorphine is bi- or tri- exponential, with long terminal elimination phase of 20-25 hours, due in part to reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature of the molecule.

Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70%), the rest being eliminated in the urine.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a postmarketing study.

Table 2 summarizes the results from a clinical trial in which the exposure of buprenorphine was determined after administering a Suboxone 2.0/0.5mg (buprenorphine/naloxone) sublingual tablet in healthy subjects, and in subjects with varied degrees of hepatic impairment.

Overall, buprenorphine plasma exposure increased approximately 3-fold in patients with severely impaired hepatic function.

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/post natal 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 additives of the transdermal patches.

Acute toxicity of buprenorphine was determined in the mouse and rat following oral and parenteral administration. The median lethal doses (LD₅₀) in the mouse were 26, 94 and 261 mg/kg for intravenous, intraperitoneal and oral administration, respectively. The LD₅₀ values in a rat were 35, 243 and 600 mg/kg for intravenous, intraperitoneal and oral administration, respectively.

When beagles were dosed continuously subcutaneously for one month, rhesus monkeys orally for one month and rats and baboons intramuscularly for six months, buprenorphine showed remarkably low tissue and biochemical toxicities.

From teratology studies in rats and rabbits, it was concluded that buprenorphine is not embryotoxic or teratogenic, and it does not have any marked effects on weaning potential. There were no adverse effects of fertility of general reproductive function in rats, although at the highest intramuscular dose (5mg/kg/day) the mothers experienced some difficulty in parturition and there was a high neonatal mortality.

Minimal to moderate hyperplasia of the bile duct with associated peribiliary fibrosis occurred in dogs following 52 weeks of oral dosing of 75mg/kg/day.

Not applicable.

None known

Any unused product or waste material should be disposed of in accordance with local requirements.

Not applicable