4.1. Therapeutic indications

Sublingual substitution treatment for opioid drug dependence in adults and adolescents aged 15 years or older, within the framework of a comprehensive, adequately monitored medical, social and psychological supervision.

The decision on the therapeutic indication should be limited to physicians at a special addiction treatment institution.

4.2. Posology and method of administration

As a partial opioid agonist / antagonist, buprenorphine is less potent than a full μ-receptor agonist such as e.g. methadone. Buprenorphine should therefore be used in particular for the first substitution therapy of opioid addicts with a shorter duration of the addiction and less solidified addictions.

Special precautions before initiating therapy

Before the start of treatment, the treating physician should be aware of the partial agonistic effect of the molecule on the μ receptor, which can trigger a withdrawal syndrome in opioid-dependent patients.

Prior to initiation of therapy, consideration should be given to the nature of opioid dependence (i.e. long or short acting opioid), the period since the last opioid use, and the degree of opioid dependence. In order to prevent an accelerated withdrawal, initiation with Buprenorphine should only be given if there are objective and clear signs of withdrawal (e.g. a score indicating mild to moderate withdrawal symptoms on the validated Clinical Opioid Withdrawal Scale (COWS) may be used as a guide):

- For patients dependent on heroin or short-acting opioids (i.v. use or non-retarded oral morphine), the first dose of Buprenorphine should be given at the first signs of withdrawal, but not earlier than 6 hours after the last opioid use.

- In patients on methadone, the dose of methadone must be reduced to a maximum of 30 mg/day prior to the start of Buprenorphine therapy. When initiating Buprenorphine therapy, the long half-life of methadone should be considered. The first dose of Buprenorphine should not be administered until withdrawal symptoms appear, but at the earliest 24 hours after the patient took the last dose of methadone (higher doses of methadone may require a longer wait). Buprenorphine may accelerate the onset of withdrawal symptoms in methadone-dependent patients. The recommended conversion ratio of methadone to buprenorphine is 5-6 : 1 and is especially valid for lower dose ranges up to about 60-80 mg methadone. Above, often no satisfactory conversion is possible, or very high doses are required.

- When switching from prolonged-release morphine to Buprenorphine, the rough conversion ratio is 25-30 : 1 after a waiting period of at least 24 hours.

Posology

The buprenorphine dose is adjusted according to the needs of the patient taking into account his withdrawal symptoms and must be adapted to the individual situation of each patient and his subjective feeling.

Induction therapy:

The initial dose is 2 mg to 4 mg buprenorphine daily as a single dose. Depending on the individual needs of the patient, this dose can be repeated (if necessary several times) so that a total dose of 4 to 8 mg (if necessary up to a maximum of 24 mg) is achieved on day 1. The daily dose administered on the second day is usually well below the dose of the first day (usually not more than 12 mg). From the 3rd day onwards, the dose is increased or decreased to the expected maintenance dose. Aim of the treatment is to stabilize the patient on day 2 or 3 with a dose that minimizes withdrawal symptoms and ensures that the patient maintains the therapy. This is generally the case for a single daily dose ranging from 12 to 16 mg.

Dose adjustment and maintenance:

The buprenorphine dose must be determined individually for each patient. The maintenance dose varies by patient and should be increased gradually until the minimum effective dose is found. This is usually 12 to 16 mg/day. It is recommended not to exceed a maximum daily dose of 24 mg, but the individual dose will be determined by the physician and will depend on the clinical status and condition of the patient.

Alternate dosing

Due to the pharmacokinetic properties of buprenorphine, the clinical effectiveness of Buprenorphine can last for 48 to 72 hours, depending on the dose. After a stable maintenance dose has been reached, the patient can alternately be administered double (for a 2-day interval) or triple (for a 3-day interval) daily dose of buprenorphine under supervision. The dose setting must be carried out under medical supervision. While setting the double or triple dose, the patient should be monitored for 3-4 hours for possible overdose symptoms. Before increasing the buprenorphine dose, the use of other central depressant substances (e.g. benzodiazepines) must be excluded.

Optimized doses are to be used individually. In individual cases, lower dosages may be sufficient.

In clinical studies, the efficacy and safety of buprenorphine for alternating doses of 8 to 34 mg/70 kg body weight were sublingually every other day for buprenorphine solution or, for alternating doses, for a 3-day interval in doses of 12 to 44 mg / 70 kg body weight of buprenorphine solution shown sublingually.

Signs of excessive effect of buprenorphine

A reduction in the dose of buprenorphine is recommended in cases where patients show signs and symptoms of excessive buprenorphine effect characterized by discomfort such as "feeling weird", poor concentration, drowsiness, and perhaps standing dizziness.

Buprenorphine withdrawal

If the prescribed buprenorphine dose is too low, withdrawal symptoms may occur during the 24-hour dosing interval (congestion of the nose, abdominal symptoms, diarrhoea, myalgia, anxiety). Doctors should be aware of the potential need to change the dose of Buprenorphine sublingual tablets when patients report withdrawal symptoms.

Duration of use

The duration of treatment depends on the agreed treatment goal.

Dose reduction and termination of treatment:

After a satisfactory period of stabilisation has been achieved, doses should be reduced gradually with the agreement of the patient and in some favourable cases until complete termination of treatment can be achieved. However, withdrawal should always be in agreement with the patient and should not be forced on the patient in order to avoid relapse.

The availability of other medicinal products with buprenorphine for substitution treatment in other pharmaceutical forms f of lower active substance content, allows gradual downward titration of dose. Alternatively, the dose may be taken every other day in order to achieve a further dose reduction at low doses. Patients should be monitored following termination of buprenorphine treatment because of the potential for relapse.

The rapid reduction of the buprenorphine dose can lead to withdrawal symptoms and the opioid tolerance decreases within a very short time. High opioid doses are only tolerated if they are taken over a longer period. The patient must therefore be informed about the opioid tolerance and the dangers of relapse including fatal overdose with appropriate clarity.

Special populations

Elderly (65 years and older)

There are no data on the safety and efficacy of buprenorphine in elderly patients over the age of 65 years. It may be necessary to take into account that patients of higher age and patients with poor physical condition may be more sensitive to opioids. The dose adjustment should be done accordingly with particular care and in accordance with occurring symptoms of withdrawal or overdose, respectively.

Patients with impaired renal function

Dose adjustment is generally not required in patients with renal insufficiency. Caution is recommended in patients with severe renal impairment (CLCR < 30 ml/min) (see sections 4.4 and 5.2).

Children and adolescents

The safety and efficacy of buprenorphine in children and adolescents below the age of 15 years have not been established. No data are available.

Adolescents aged 15 to 18 years should be monitored carefully.

Method of administration

Buprenorphine is for sublingual use.

Physicians must advise patients that the sublingual route is the only effective and safe route of administration for this medicinal product.

The tablets should be kept under the tongue until dissolved (usually within 5 to 10 minutes). If necessary, the oral mucosa should be moistened beforehand to facilitate the dissolution of the sublingual tablet. Patients should not swallow and should not eat or drink until the tablet has completely dissolved.

Treatment goals and discontinuation

Before initiating treatment with Buprenorphine, a treatment strategy including treatment duration and treatment goals, should be agreed together with the patient. 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 Buprenorphine, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal (see section 4.4).

4.3. Contraindications

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

• Severe respiratory insufficiency

• Severe hepatic insufficiency

• Acute alcoholism or delirium tremens

• Concomitant use of opioid antagonists (naltrexone, nalmefene) for treatment of alcohol or opioid dependence

4.4. Special warnings and precautions for use

Improper use and misuse

Buprenorphine, can be misused or used improperly. The risks of misuse or improper use include overdose, spread of haematogenous viral or local and systemic infections, respiratory depression, and liver damage. Unauthorized use of buprenorphine by persons who have not been prescribed the medicinal product also involves the risk of new drug addicts, who abuse buprenorphine as the major drug, if the medicinal product is or has been circulated directly by the patient for illicit use or if it is not adequately protected against theft.

Suboptimal treatment with buprenorphine may result in drug abuse by the patient, which may lead to overdose or treatment discontinuation. A patient receiving a too low dose of buprenorphine may continue to respond to uncontrolled withdrawal symptoms with self-treatment with opioids, alcohol or other sedatives/hypnotics, especially benzodiazepines.

To minimize the risk regarding improper use and misuse, physicians should take precautionary measures when prescribing and dispensing buprenorphine. Therefore, during early phase of therapy, prescribing several doses concurrently should be avoided and follow-up appointments for clinical monitoring should be scheduled adjusted to the patients need.

Precautions for use

In case of the following diseases while using Buprenorphine sublingual tablets, caution should be exercised and the dose of the medicinal product reduced if necessary:

Take-home prescription

In the case of a take-home prescription, the doctor must ensure that the risks of self- or third-party harm resulting from carrying along the substitution medicinal product are excluded as far as possible and that the patient uses the substitution medicinal product prescribed for him as intended. In the event of improper, abusive use by the patient, the take-home prescription must be stopped immediately. Abusive use exists if the patient uses substances such as e.g. benzodiazepines (see section 4.4) or injects buprenorphine i.v..

Respiratory depression

Some cases of death due to respiratory depression have been reported, particularly when buprenorphine was used in combination with benzodiazepines (see section 4.5) or when it was not used according to the product information. Furthermore, deaths related to concomitant use of buprenorphine and other centrally depressing substances, such as alcohol and other opioids, have been reported.

The medicinal product should be used with caution in patients with bronchial asthma or respiratory insufficiency (e.g. chronic obstructive pulmonary disease, cor pulmonale, restricted respiratory reserves, hypoxia, hypercapnia, pre-existing respiratory depression, or kyphoscoliosis (curvature of the spine with potentially resultant respiratory distress)).

Buprenorphine may cause severe or potentially fatal respiratory depression in children and non-dependent persons if accidentally or deliberately ingested. Patients should be reminded to keep the blister in a safe place, never open the blister in advance, keep the blister out of reach of children and other household members, and never take this medicine in front of children. In case of accidental ingestion or suspicion of ingestion, an emergency service should be notified immediately.

CNS depression

Buprenorphine may cause somnolence, especially when combined with alcohol or centrally depressing substances (such as tranquillizers, sedatives, or hypnotics) (see section 4.5).

Alcoholic beverages or medicinal products containing alcohol must not be taken during treatment with Buprenorphine. The simultaneous use of central depressants, other opioid derivatives (analgesics and antitussives), certain antidepressants, sedative H1 receptor antagonists, barbiturates, anxiolytics, neuroleptics, clonidine and related substances requires medical supervision.

Risk from concomitant use of sedative medicinal products such as benzodiazepines or related medicinal products

Concomitant use of Buprenorphine and sedative medicinal products such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma, and death. Because of these risks, concomitant prescribing with these sedative medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Buprenorphine concomitantly with sedative medicinal products, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

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 dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Tolerance and opioid use disorder (abuse and dependence)

Buprenorphine is a partial μ (mu) opioid receptor agonist. As shown in animal studies and during clinical experience, buprenorphine can lead to dependence, but at a lower level than in a full agonist-like substance, such as morphine.

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as Buprenorphine. Abuse or intentional misuse of Buprenorphine 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 Buprenorphine and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2).

Patients will require monitoring for signs of drug-seeking behavior (e.g. too early requests for refills). This includes the review of concomitant opioids and psychoactive drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Abrupt discontinuation of treatment is not recommended because withdrawal syndrome, possibly delayed, may occur.

Before initiation of buprenorphine treatment, the patient's dependence on opioids must have been confirmed by a positive result of urine screening for opiates.

During substitution therapy, regular urine screening (supervised collection of samples) should be done for opiates (also quantitative determination), barbiturates, methaqualone and benzodiazepines, and where appropriate also for cocaine and amphetamines as well as their metabolites. The patient should also be examined for needle marks.

Patients may have pain symptoms even during substitution treatment. Once the somatic correlate has been identified, the appropriate additional analgesic treatment should be administered at a special addiction treatment institution.

Hepatitis and hepatic events

In clinical trials and post-marketing adverse reaction reports, cases of acute liver injury have been reported in opioid-dependent patients. The spectrum of liver dysfunction ranges from transient asymptomatic increases in liver transaminases to reports of liver failure, liver necrosis, hepatorenal syndrome, and hepatic encephalopathy and death. In many cases, pre-existing mitochondrial disorders (genetic disease), liver enzyme abnormalities, viral infection with hepatitis B or hepatitis C, alcohol abuse, anorexia, concomitant use of other potentially hepatotoxic medicinal products, or persistent intravenous drug abuse have played a causal or reinforcing role. These factors must be taken into account before and during treatment with buprenorphine. When a hepatic event is suspected, further biological and etiological evaluation is needed. Depending on the results of investigations, Buprenorphine may be discontinued with caution in order to avoid development of a withdrawal syndrome or relapse into drug dependence. If treatment is to be continued, liver function must be monitored closely.

Liver function tests should be performed at regular intervals in all patients.

Hepatic impairment

During an observational study, the effect of hepatic impairment on the pharmacokinetics of buprenorphine has been studied. As buprenorphine is metabolised predominantly by the liver, higher plasma levels of buprenorphine have been investigated after a single dose in patients with moderate and severe hepatic impairment. Patients should be monitored regarding signs and symptoms of opioid withdrawal symptoms and toxicity or overdose caused by elevated buprenorphine concentration. In patients with moderate hepatic impairment, Buprenorphine should be used with caution (see section and 5.2). Buprenorphine is contraindicated in patients with severe hepatic impairment (see section 4.3).

Liver function and viral hepatitis status should be determined prior to initiating therapy. Patients with positive viral hepatitis, patients receiving concomitant medication (see section 4.5), and / or patients with hepatic impairment are at greater risk of liver damage. Regular monitoring of liver function is recommended (see section 4.4).

Triggering an opioid withdrawal syndrome

At the beginning of buprenorphine treatment, the partial agonistic profile of buprenorphine must be considered by the physician. Buprenorphine may cause the onset of withdrawal symptoms in opioid-dependent patients, especially if administered to the patient earlier than 6 hours after the last administration of heroin or another short-acting opioid or earlier than 24 hours after the last dose of methadone or administration of retarded morphine. Patients should be monitored closely for methadone conversion to buprenorphine as withdrawal symptoms have been reported. To prevent an accelerated withdrawal, the patient should have objective signs and symptoms of mild withdrawal prior to dose initiation (see section 4.2).

Withdrawal symptoms may also occur with suboptimal dosing.

Serotonin syndrome

Concomitant administration of Buprenorphine and other serotonergic medicinal products, 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 medicinal products 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.

Renal impairment

As 30% of the applied dose is eliminated renal, excretion via the kidney may be delayed. In patients with renal insufficiency, there is an accumulation of buprenorphine metabolites. Caution is advised in the treatment of patients with severe renal insufficiency (ClCr < 30 ml/min) (see sections 4.2 and 5.2).

CYP3A4 inhibitors

Medicinal product inhibiting CYP3A4 may lead to elevated buprenorphine concentrations. Therefore, reduction of buprenorphine dose may be necessary. Dose titration should be particularly careful in patients already on a treatment with CYP3A4 inhibitors. In these patients lower doses may prove adequate (see section 4.5).

General warnings for the use of opioids

In Ambulatory patients opioids can cause orthostatic hypotension.

Opioids may lead to increased cerebrospinal fluid pressure, which can cause seizures. Therefore, opioids should be used with caution in patients with head injuries, intracranial lesions, other conditions that may be associated with increased intracranial pressure or seizures in the medical history.

Caution should be exercised when administering opioids to patients with hypotension, prostatic hypertrophy or urethral stenosis.

Opioid-induced miosis, changes in the state of consciousness and changes in pain perception as a symptom of a disease can affect patient assessment and obscure the diagnosis or clinical course of concomitant disease.

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

Since opioids have been shown to increase the pressure in the bile duct, they should be used carefully in patients with biliary disorders.

Caution is advised when using opioids in elderly or debilitated patients.

On the basis of experience with morphine, the simultaneous use of MAO inhibitors with buprenorphine may lead to enhanced effects of opioids (see section 4.5).

Attempted suicide with opioids, especially in combination with tricyclic antidepressants, alcohol and other substances affecting the CNS, are part of the clinical picture of substance dependence. Individual evaluation and treatment planning, which may include inpatient care, should be considered in patients who, despite appropriate pharmacotherapeutic intervention, show uncontrolled drug use and persistent, high risk behaviour.

Studies in animals as well as clinical experience have demonstrated that buprenorphine has a dependence potential, but it is lower than with morphine. An existing dependence on opiates cannot be reversed by substitution therapy. Therefore, compliance with the recommendations for initiation of treatment, dose adjustments and monitoring of patients are very important (see section 4.2).

Doping Warning:

Athletes should be aware that this medicinal product may cause a positive reaction to “doping tests”.

Lactose

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

Sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per sublingual tablet, that is to say essentially 'sodium free'.

Children and adolescents (aged 15 to 18 years)

Adolescents aged 15 to 18 years should be monitored carefully during therapy.

No data is available in children under 15 years of age. Therefore Buprenorphine should not be administered to children under 15 years of age.

4.5. Interaction with other medicinal products and other forms of interaction

Combinations contraindicated

• Naltrexone and nalmefene are opioid antagonists that can block the pharmacological effects of buprenorphine. Concomitant use during treatment with buprenorphine should be avoided desperately due to a potential dangerous interaction, which may lead to the onset of persistent and severe opioid withdrawal symptoms.

Combinations not recommended

• Alcoholic drinks or medicinal products containing alcohol, as alcohol increases the sedative effect of buprenorphine (see sections 4.4 and 4.7).

Combinations to be used with caution

• Sedative medicinal products such as benzodiazepines or related medicinal products: Because of additive CNS depressant effect, the concomitant use of opioids with sedative medicinal products such as benzodiazepines or related medicinal products increases the risk of sedation, respiratory depression, coma and death. Therefore, the dose must be limited and, in cases of existing risk of abuse, combination must be avoided. Patients should be warned that the concomitant intake of not prescribed benzodiazepines and Buprenorphine is extremely dangerous. Furthermore, patients have to be informed that the intake of benzodiazepines together with Buprenorphine is only allowed after their doctor's instruction. The dose and duration of concomitant use should be limited (see section 4.4).

• Other central nervous system depressants, other opioid derivatives (e.g. methadone, analgesics and antitussives), certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances. These combinations increase central nervous system depression. Due to reduced attentiveness, driving cars and using machinery may be dangerous.

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

• Besides, it may be difficult to reach an adequate analgesia if patients receiving buprenorphine are given a full opioid agonist. There is a possibility of full agonist overdose, particularly if it is tried to overcome the partial agonistic effect of buprenorphine or if buprenorphine plasma levels decrease.

• CYP3A4 inhibitors: An interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased Cmax and AUC (area under the curve) of buprenorphine (approximately 50% and 70%, respectively) and, to a lesser extent, of norbuprenorphine. Patients receiving Buprenorphine should be monitored closely and may need dose reduction if strong CYP3A4 inhibitors (such as the protease inhibitors ritonavir, nelfinavir or indinavir, or azole-type antifungals, e.g. ketoconazole or itraconazole, macrolide antibiotics) are given concomitantly.

• CYP3A4 inducers: Concomitant administration of CYP3A4 inducers and buprenorphine can reduce buprenorphine plasma concentration and may therefore lead to suboptimal treatment of opioid dependence with buprenorphine. Close monitoring is recommended in patients receiving buprenorphine together with CYP3A4 inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin). Doses of buprenorphine or CYP3A4 inducer may be adapted accordingly.

• On the basis of experience with morphine, the simultaneous use of MAO inhibitors with buprenorphine may lead to enhanced effects of opioids.

• Phenprocoumon: A suspected interaction between buprenorphine injection and phenprocoumon, resulting in purpura, has been reported.

• Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (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 result in increased anticholinergic adverse effects.

Effects of buprenorphine on other medicinal products

Buprenorphine has been shown to be a CYP2D6 and CYP3A4 inhibitor in vitro. The risk of inhibition at therapeutic concentrations seems low, but cannot be excluded. When buprenorphine is combined with other medicinal products that are CYP2D6 or CYP3A4 substrates the plasma concentrations of these medicinal products may be increased and the risk of dose-dependent adverse reactions may occur.

Buprenorphine does not inhibit the enzyme CYP2C19 in vitro.

Interactions with CYP3A4 are of minor clinical relevance. The effect on other enzymes that metabolise medicinal products has not been investigated.

To date, no notable interaction has been observed with cocaine, the agent most frequently used by multi-drug abusers in association with opioids.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited data from the use of buprenorphine in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Buprenorphine should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.

Adequate substitution and prevention of withdrawal symptoms during pregnancy must be ensured in order to minimize damage to the foetus. Dose increase may be necessary due to enzyme induction during pregnancy if withdrawal symptoms develop.

When used at the end of pregnancy, buprenorphine may induce respiratory depression in the newborn infant even after a short period of administration. Long-term administration during the last three months of pregnancy may cause a withdrawal syndrome in the neonate (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus or convulsions). The syndrome is generally delayed from several hours to several days after birth.

Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered at the end of pregnancy to prevent the risk of respiratory depression or withdrawal syndromes in neonates.

Breast-feeding

Buprenorphine and its metabolites are excreted in human breast milk. In rats, buprenorphine has been found to inhibit lactation. Breast-feeding should be discontinued during treatment with Buprenorphine.

Fertility

There are no data on the effects of buprenorphine on human fertility.

4.7. Effects on ability to drive and use machines

When administered to opioid dependent patients, buprenorphine has minor to moderate influence on the ability to drive and use machines. Buprenorphine may cause drowsiness, dizziness or impaired thinking, particularly at beginning of treatment and dose adjustment. These effects may be enhanced when taken together with alcohol or central nervous system depressants (see sections 4.4 and 4.5).

Patients should be cautioned about operating hazardous machinery in case buprenorphine may affect their ability to engage in such activities.

4.8. Undesirable effects

Summary of the safety profile

The most common therapy-related adverse reactions reported during pivotal clinical studies were constipation and symptoms, generally related to withdrawal (i.e. insomnia, headache, nausea, hyperhidrosis, and pain). Certain reported cases regarding seizures, vomiting, diarrhoea, and elevated liver function values have been classified as serious.

Tabulated list of adverse reactions

Table 1 summarises adverse reactions reported during pivotal clinical studies (where 342 out of 472 patients (72.5%) reported adverse reactions) as well as post-marketing.

The evaluation of side effects is based on the following frequencies:

Very common

Common

Uncommon

Rare

Very rare

Not known

≥ 1/10

≥ 1/100, < 1/10

≥ 1/1 000, < 1/100

≥ 1/10 000, < 1/1 000

< 1/10 000

Frequency cannot be estimated from the available data

Table 1: Therapy-related adverse reactions observed in clinical trials and post-marketing surveillance studies

System organ class

Very common

Common

Uncommon

Not known

Infections and infestations

influenza

infection

pharyngitis

rhinitis

urinary tract infection

vaginal infection

Blood and lymphatic system disorders

anaemia

leucocytosis

leucopenia

lymphadenopathy

thrombocytopenia

Immune system disorders

hypersensitivity

anaphylactic shock

Metabolism and nutrition disorders

decreased appetite

hyperglycaemia

hyperlipidaemia

hypoglycaemia

Psychiatric disorders

insomnia

anxiety

depression

decreased libido

nervousness

abnormal thinking

abnormal dreaming

agitation

apathy

depersonalisation

euphoria

hostility

hallucinations

Nervous system disorders

headache

migraine

dizziness

hypertension

paraesthesia

somnolence

amnesia

hyperkinesia

seizure

impaired speech

tremor

syncope

Eye disorders

amblyopia

tears disturbance

conjunctivitis

miosis

Ear and labyrinth disorders

vertigo

Cardiac disorders

angina pectoris

bradycardia

myocardial infarction

palpitations

tachycardia

orthostatic hypotension

Vascular disorders

hypertension

vasodilatation

hypotension

Respiratory, thoracic and mediastinal disorders

cough

asthma

dyspnoea

yawning

bronchospasm

respiratory depression

Gastrointestinal disorders

constipation

nausea

abdominal pain

diarrhoea

dyspepsia

flatulence

vomiting

mouth ulceration

discoloration of the tongue

dental caries

Hepatobiliary disorders

hepatitis

acute hepatitis

jaundice

hepatic necrosis

hepatorenal syndrome

Skin and subcutaneous tissue disorders

hyperhidrosis

pruritus

rash

urticaria

acne

alopecia

dermatitis exfoliativa

dry skin

mass of the skin

angioedema

Musculoskeletal and connective tissue disorders

back pain

arthralgia

muscle spasms

myalgia

arthritis

Renal and urinary disorders

urinary aberration

albuminuria

dysuria

haematuria

nephrolithiasis

urinary retention

Reproductive system and breast disorders

erectile dysfunction

amenorrhoea

ejaculation disorder

menorrhagia

Intermenstrual bleeding

General disorders and administration site conditions

withdrawal syndrome

asthenia

chest pain

chills

pyrexia

malaise

pain

peripheral oedema

hypothermia

neonatal withdrawal syndrome (see section 4.6)

Investigations

liver function test abnormal

weight loss

blood creatinine increased

transaminases increased

Injury, Poisoning and procedural complications

injury

heatstroke

Description of selected adverse reactions that have been observed post marketing.

The following is a summary of other adverse event reports reported after market launch that are considered serious or are noteworthy for other reasons:

• In cases of intravenous drug abuse, local, sometimes septic reactions (abscess, cellulitis) and a potential serious acute hepatitis as well as other acute infections, such as pneumonia and endocarditis, have been described (see sections 4.4). However, these adverse reactions are caused more likely by the abuse than by the medicinal substance itself.

• In patients with marked drug dependence, initial administration of buprenorphine may produce a withdrawal effect similar to that associated with naloxone (see sections 4.2 and 4.4) if used before the agonistic effects caused by recent opioid use or abuse have subsided.

• The most common signs and symptoms of hypersensitivity include rashes, urticaria, and pruritus. Cases of bronchospasm, angioedema, and anaphylactic shock have been reported (see section 4.3).

• Transaminase increase, hepatitis, acute hepatitis, cytolytic hepatitis, jaundice, hepatorenal syndrome, hepatic encephalopathy, and hepatic necrosis have occurred (see section 4.4).

• 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 (see section 4.6).

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

Drug dependence

Repeated use of Buprenorphine 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).

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 national reporting system listed in Appendix V.

4.9. Overdose

Symptoms

Particularly in the case of non-tolerant people (especially children), threatening poisoning (intoxications) can be caused by lower doses than those customary in substitution therapy.

Signs and symptoms of excessive buprenorphine effects are characterized by symptoms such as "feeling strange", poor concentration, sleepiness and possibly dizziness when standing. The primary symptom of overdose that requires intervention is respiratory depression resulting from depression of the central nervous system, which could lead to apnoea and death. The first signs of an overdose may 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.

In case of vomiting, care must be taken that there is no aspiration of the vomit.

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.

If naloxone is used, the long duration of action of buprenorphine has to be taken into account when choosing duration of treatment and clinical monitoring, necessary for correction of overdoses effects. Naloxone is eliminated more rapidly than buprenorphine, which can lead to the reoccurrence of previously controlled symptoms of buprenorphine overdose. Therefore, prolonged infusion may be necessary. Where infusion is not possible, repeated use of naloxone may be needed. The initial naloxone doses may be up to 2 mg and repeated every 2 to 3 minutes until adequate response is obtained, with a starting dose of 10 mg not exceeding. Infusion rates should be adjusted according to the response of the patient.