The adverse reactions most frequently reported for buprenorphine are headache, nausea, hyperhidrosis, insomnia, drug withdrawal syndrome and pain.
- Hypersensitivity to the active substance or to any of the excipients
- Severe respiratory insufficiency
- Severe hepatic impairment
- Acute alcoholism or delirium tremens
Special warnings and precautions for use
Care must be taken to avoid inadvertent injection of Buvidal®. The dose must not be administered intravascularly (intravenously), intramuscularly or intradermally.
To minimise the risk of misuse, abuse and diversion, appropriate precautions should be taken when prescribing and dispensing buprenorphine.
Healthcare professionals should administer Buvidal directly to the patient.
Take-home use or self-administration of the product by patients is not allowed. Any attempts to remove the depot should be monitored throughout treatment.
The prolonged-release properties of the product should be considered during treatment including initiation and termination.
In particular, patients with concomitant medicinal products and/or co-morbidities, should be monitored for signs and symptoms of toxicity, overdose or withdrawal caused by increased or decreased levels of buprenorphine.
A number of cases of death due to respiratory depression have been reported for patients being treated with buprenorphine, particularly when 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, gabapentinoids (such as pregabalin and gabapentin) or other opioids.
Buprenorphine 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-opioid dependent persons who accidentally or deliberately use it.
Buprenorphine may cause drowsiness particularly when taken together with alcohol or central nervous system depressants such as benzodiazepines, tranquilisers, sedatives, gabapentinoids or hypnotics.
Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration can produce opioid dependence.
Hepatitis and hepatic events
Baseline liver function tests and documentation of viral hepatitis status are recommended prior to starting therapy. Patients who are positive for viral hepatitis, on certain concomitant medicinal products and/or who have existing liver dysfunction are at greater risk of liver injury. Regular monitoring of the liver function is recommended.
Cases of acute hepatic injury have been reported in opioid-dependent patients both in clinical studies and in post-marketing adverse reaction reports with medicinal products containing buprenorphine.
When a hepatic event is suspected, further biological and aetiological evaluation is required. Depending on the findings, Buvidal may be discontinued. Monitoring beyond the weekly and monthly treatment period may be needed. If treatment is continued, hepatic function should be monitored closely.
Precipitation of opioid withdrawal syndrome
When initiating treatment with buprenorphine, it is important to be aware of the partial agonist profile of buprenorphine. Buprenorphine products have caused precipitated withdrawal symptoms in opioid-dependent patients when administered before the agonist effects resulting from recent opioid use or misuse have subsided.
To avoid precipitated withdrawal, induction must be undertaken when objective signs and symptoms of mild to moderate withdrawal are evident.
Discontinuation of treatment may result in a withdrawal syndrome that may be delayed in onset.
Buprenorphine is extensively metabolised in the liver.
Patients with moderate hepatic impairment should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of buprenorphine.
Buprenorphine should be used with caution in patients with moderate hepatic impairment. Hepatic function should be monitored regularly whilst on treatment.
The use of buprenorphine is contraindicated in patients with severe hepatic impairment.
Caution should be exercised when co-administering Buvidal with other medicinal products that prolong the QT interval and in patients with a history of long QT syndrome or other risk factors for QT prolongation.
Metabolites of buprenorphine accumulate in patients with renal failure.
Caution is recommended when dosing patients with severe renal impairment (creatinine clearance <30 ml/min).
Acute pain management
For management of acute pain during continued use of Buvidal, a combination of use of opioids with high mu-opioid receptor affinity (e.g. fentanyl), non-opioid analgesics and regional anaesthesia might be necessary.
Titration of oral or intravenous short-acting opioid pain medicinal products (immediate-release morphine, oxycodone or fentanyl) to the desired analgesic effect in patients treated with Buvidal might require higher doses. Patients should be monitored during treatment.
Use in children and adolescents
The safety and efficacy of buprenorphine in children below the age of 16 years have not been established.
Due to limited data in adolescents (aged 16 or 17 years), patients in this age group should be monitored closely during treatment.
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.
Opioids may cause orthostatic hypotension.
Opioids may elevate cerebrospinal fluid pressure, which may cause seizures. Therefore, 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.
Concomitant administration of Buvidal 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. 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.
The table below presents adverse reactions reported for buprenorphine, including Buvidal. The following terms and frequencies are applied: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100) and frequency not known (cannot be estimated from available data).
Adverse reactions listed by body system
|System Organ Class||Very common||Common||Uncommon||Not known|
|Infections and infestations||Infection
Injection site cellulitis
|Blood and lymphatic system disorders||Lymphadenopathy|
|Immune system disorders||Hypersensitivity|
|Metabolism and nutrition disorders||Decreased appetite|
|Nervous system disorders||
|Eye disorders||Lacrimal disorder
|Ear and labyrinth disorders||Vertigo|
|Respiratory, thoracic and mediastinal disorders||Cough
|Hepatobiliary disorders||Alanine aminotransferase increased
Aspartate aminotransferase increased
Hepatic enzymes increased
|Skin and subcutaneous tissue disorders||Rash
|Musculoskeletal and connective tissue disorders||Arthralgia
|Renal and urinary disorders||Urinary retention|
|Reproductive system and breast disorders||Dysmenorrhoea|
|General disorders and administration site conditions||Hyperhidrosis
Drug withdrawal syndrome
|Injection site pain
Injection site pruritus
Injection site erythema
Injection site swelling
Injection site reaction
Injection site induration
Injection site mass
Neonatal withdrawal syndrome
|Injection site inflammation
Injection site bruising
Injection site urticaria
|Investigations||Abnormal liver function tests|
|Injury, poisoning and procedural complications||Procedural dizziness|
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medical 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 their national reporting system.