4.2 Posology and method of administration

Treatment goals and Discontinuation

Before initiating treatment with BuTrans, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with BuTrans, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

Duration of treatment

BuTrans should not be used longer than necessary.

4.4    Special warnings and precautions for use

Tolerance and Opioid use disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as BuTrans. Repeated use of BuTrans can lead to OUD. A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of BuTrans may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with BuTrans and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.

Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered. If opioid discontinuation is to occur see section 4.4 Long-term treatment effects and tolerance.

4.5    Interaction with other medicinal products and other forms of interaction

The concomitant use of BuTrans with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death (see section 4.4).

Concomitant administration of buprenorphine with anticholinergics or medications with anticholinergic activity (e.g. tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may results in increased anticholinergic adverse effects.

4.8 Undesirable effects

Drug dependence

Repeated use of BuTrans can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

10.    DATE OF REVISION OF THE TEXT

 2.       What you need to know before you use BuTrans patches

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using BuTrans patches:

Tolerance, dependence, and addiction

This medicine contains buprenorphine which is an opioid medicine. Repeated use of opioids can result in the drug being less effective (you become accustomed to it, known as tolerance). Repeated use of BuTrans can also lead to dependence, abuse, and addiction, which may result in life-threatening overdose. The risk of these side effects can increase with a higher dose and longer duration of use.

Dependence or addiction can make you feel that you are no longer in control of how much medicine you need to take or how often you need to take it.

The risk of becoming dependent or addicted varies from person to person. You may have a greater risk of becoming dependent on or addicted to BuTrans if:

• You or anyone in your family have ever abused or been dependent on alcohol, prescription medicines or illegal drugs (“addiction”).
• You are a smoker.
• You are treated with antidepressants.
• You have ever had problems with your mood (depression, anxiety or a personality disorder) or have been treated by a psychiatrist for other mental illnesses.

If you notice any of the following signs whilst taking BuTrans, it could be a sign that you have become dependent or addicted,

• You need to take the medicine for longer than advised by your doctor.
• You need to take more than the recommended dose.
• You might feel that you need to carry on taking your medicine, even when it doesn’t help to relieve your pain.
• You are using the medicine for reasons other than prescribed, for instance, ‘to stay calm’ or ‘help you sleep’.
• You have made repeated, unsuccessful attempts to quit or control the use of the medicine.
• When you stop taking the medicine you feel unwell, and you feel better once taking the medicine again (‘withdrawal effects’).

The use of these medicines together with BuTrans patches can lead to serotonin syndrome, a potentially life-threatening condition if (see “Other medicines and BuTrans patches”);

• You suffer from seizures, fits or convulsions.
• You suffer from a breathing related sleep disorder (sleep apnoea).
• You have a severe headache or feel sick due to a head injury or increased pressure in your skull (for instance due to brain disease). This is because the patches may make symptoms worse or hide the extent of a head injury.
• You are feeling light-headed or faint.
• You have severe liver problems.
• You have a high temperature, as this may lead to larger quantities of the active ingredient being absorbed into the blood than normal.
• You suffer from constipation.

If you notice any of these signs, speak to your doctor to discuss the best treatment pathway for you, including when it is appropriate to stop and how to stop safely (see section 3, If you stop taking BuTrans).

Other medicines and BuTrans patches

• BuTranspatches may make some people feel drowsy, sick or faint or make them breathe more slowly or weakly. These side effects may be made worse if other medicines that produce the same effects are taken at the same time. These include certain medicines to treat pain, depression, anxiety, psychiatric or mental disorders (antipsychotics or neuroleptics), medicines to help you sleep, medicines to treat high blood pressure such as clonidine, other opioids (which may be found in painkillers or certain cough mixtures e.g. morphine, dextropropoxyphene, codeine, dextromethorphan, noscapine), antihistamines which make you drowsy, or anaesthetics such as halothane.
• Gabapentin or pregabalin to treat epilepsy or pain due to nerve problems (neuropathic pain).
• Medicines to treat depression.
• Medicines used to treat allergies, travel sickness or nausea (antihistamines or antiemetics).
• Muscle relaxants.
• Medicines to treat Parkinson’s disease.

3.       How to use BuTrans patches

Before starting treatment and regularly during treatment, your doctor will discuss with you what you may expect from using BuTrans, when and how long you need to take it, when to contact your doctor, and when you need to stop it (see also, If you stop taking BuTrans).

5.       How to store BuTrans patches

Store this medicine in a safe and secure place, where other people cannot access it. It can cause serious harm and be fatal to people who may take this medicine by accident, or intentionally when it has not been prescribed for them.

Section 4.2: Updated information on titration process, information about hyperalgesia, patch application and the use of hot water bottles.

Section 4.4: Reformatting into a bulleted list, addition of constipation. Addition of warning statements regarding signs of respiratory depression, tolerance, opioid use disorder, withdrawal, skin reactions and sleep apnoea.

Section 4.8: Addition of hyperalgesia and drug tolerance. Additional information about application site reactions.

Section 5.1: Clarification of action of buprenorphine at different opioid receptors.

Section 2:  Wording changes to improve clarity, addition of constipation, smoking, mental illnesses. Additional information about application site reactions and hyperalgesia.

Section 4: Addition of hyperalgesia and drug tolerance.

Section 4.4: re-wording of section on sleep-related breathing disorders

Section 4.8: addition of dermatitis contact and skin discolouration

Section 2 what you need to know… :  re-wording of section on sleep-related breathing disorders

Section 4 possible side effects: addition of dermatitis contact and skin discolouration

Addition of warnings regarding sleep apnoea

Addition of warnings regarding sleep apnoea

Section 4.2 - Addition of clarification that no dose adjustment is required for patients with mild to moderate hepatic impairment.

Section 4.4 - Addition of warnings regarding dependence and withdrawal syndrome. Addition of warnings regarding the potential for buprenorphine to impact the hypothalamic-pituitary-adrenal or -gonadal axes.

Section 4.5 - Addition of examples of sedative medicines.

Section 4.6 - Clarification regarding use during pregnancy and breast feeding.

Section 4.8 - Minor administrative changes.

Section 4.9 - Clarification of statement regarding apnoea.

Section 5.1 - Deletion of section on the endocrine system (relocated to section 4.4). Addition of statements regarding immunological effects and risk of respiratory depression.

Section 2 - Addition of warnings regarding hormone production. Addition of warnings regarding concomitant use of benzodiazepines. Addition of clarification on use during pregnancy and breast feeding.

Section 3 - Addition of instructions regarding use of two patches where necessary. Replacement of instructions for tearing the pouch with instructions for cutting with scissors.

Section 4 - Correction of side effect frequencies. Addition of mood swings as a possible side effect.

Addition of warnings regarding serotonin syndrome following PRAC recommendation.

Addition of warnings regarding serotonin syndrome following PRAC recommendation.

Addition of warnings in relation to concomitant use with benzodiazepines.

Updates to descriptions of frequencies of side effects.

Addition of warnings in relation to concomitant use with benzodiazepines.

Addition of details of child resistant packaging

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

Benzodiazepines: This combination can potentiate respiratory depression of central origin(see section 4.4).

Section 4.6

The following has been changed (text in red has been added)

Prolonged use Long term administration  of buprenorphine during the last three months of pregnancy can result in neonatal opioid may cause a withdrawal syndrome. in the neonate.

Section 4.8

 (Psychiartic disorders) Affect lability has been changed from liability. Libido decreased has been changed from Decreased Libido.

(Nervous system disorders)  Seizures has been added. Abnormal co-ordination has been changed to Co-ordination abnormal.

Renal and urinary disorders - Urinary incontinence has been added.  Urinary hesitation has been added. Micturtion disorder has been removed.

General disorders and administration site conditions - Drug withdrawal syndrome neonatal has been added.