Buprenorphine hydrochloride

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUPRENORPHINE HYDROCHLORIDUM (BUPRENORPHINI HYDROCHLORIDUM)

Composition:

Active substance: buprenorphine;

1 ml of solution contains buprenorphine hydrochloride equivalent to 0.3 mg of buprenorphine;

Excipients: anhydrous glucose, hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Opioids. Orvinol derivatives. ATC code N02AE01.

Pharmacological properties.

Pharmacodynamics.

Buprenorphine hydrochloride is a centrally-acting analgesic. It stimulates the kappa subtype of opioid receptors, which accounts for its high analgesic activity, and simultaneously blocks mu-receptors responsible for the development of euphoria. Unlike other narcotic analgesics, it does not cause euphoria and therefore has a lower potential for abuse.

Pharmacokinetics.

It is evenly distributed in tissues and penetrates the blood-brain barrier. The elimination half-life after intramuscular and intravenous administration is 3–6 hours. It is metabolized in the liver and excreted with bile; a small amount is excreted by the kidneys.

Clinical characteristics.

Indications.

Moderate to severe pain following surgical procedures, in oncology patients, in myocardial infarction, renal colic, and burns.

Contraindications.

Individual intolerance or hypersensitivity to buprenorphine, severe respiratory or hepatic insufficiency, physical dependence.

Interaction with other medicinal products and other forms of interaction.

Mutually enhances the main and adverse effects, as well as the toxicity of monoamine oxidase inhibitors (MAOIs) and agents that depress the central nervous system (CNS), such as tranquilizers and neuroleptics.

Concomitant use of the following psychotropic agents and substances is not recommended:

Alcohol.

Alcohol enhances the sedative effect of buprenorphine. Reduced alertness (attention) increases the risk when driving vehicles or operating machinery. Consumption of alcoholic beverages and use of medicinal products containing alcohol should be avoided.

Medicinal products for concomitant use that should be taken into account:

Benzodiazepine tranquilizers.

Concomitant use with benzodiazepines is associated with a risk of fatal outcome due to respiratory insufficiency related to impairment of central nervous system function.

Other central nervous system depressants.

Other opioid derivatives (analgesics, antitussives), certain antidepressants, antihistamines (H1-receptor blockers), barbiturates, tranquilizers, and clonidine may enhance CNS depression when used simultaneously with buprenorphine.

MAO inhibitors.

An enhanced effect of opioids may occur when used concomitantly with buprenorphine.

CYP3A4 inhibitors.

Studies on the interaction between buprenorphine and ketoconazole (a potent CYP3A4 inhibitor) showed an increase in Cmax and AUC values of buprenorphine (by 70% and 50%, respectively), and to a lesser extent, norbuprenorphine. Therefore, patients receiving buprenorphine should be closely monitored when concurrently taking CYP3A4 inhibitors such as protease inhibitors (ritonavir, nelfinavir, indinavir), azole antifungal agents (ketoconazole, itraconazole). In such cases, dose reduction of buprenorphine may be justified.

CYP3A4 inducers.

The interaction between buprenorphine and CYP3A4 inducers has not been studied; therefore, careful monitoring of patients receiving concomitant CYP3A4 inducers (phenobarbital, carbamazepine, phenytoin, or rifampicin) is recommended. To date, no significant interaction between buprenorphine and cocaine has been identified.

The use of other CYP3A4 inhibitors (such as gestodene, troleandomycin, HIV protease inhibitors—ritonavir, indinavir, and saquinavir) may also increase buprenorphine concentrations; therefore, a proportional reduction in the buprenorphine dose should be considered at the start of treatment with these agents.

The use of these agents may enhance the metabolism of buprenorphine; therefore, in patients reporting reduced efficacy of buprenorphine or increased drug craving, the buprenorphine dose should be increased.

Buprenorphine should be used with caution when administered concomitantly with serotonergic medicinal products, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, due to an increased risk of serotonin syndrome—a potentially life-threatening condition (see section "Special precautions for use").

Special precautions for use.

Dependence.

Buprenorphine is a partial opioid receptor agonist, and its prolonged use may lead to opioid-type dependence. Discontinuation of treatment may result in withdrawal syndrome.

Respiratory depression.

There have been reports of fatal cases due to respiratory depression, particularly when buprenorphine was used concomitantly with benzodiazepines or when used inappropriately.

Serotonin syndrome.

Concomitant use of buprenorphine with other serotonergic agents, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, may result in serotonin syndrome—a potentially life-threatening condition (see section "Interaction with other medicinal products and other forms of interaction").

If concomitant treatment with other serotonergic agents is clinically justified, careful monitoring of the patient is recommended, particularly during initiation of therapy and dose escalation.

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

If serotonin syndrome is suspected, consideration should be given to reducing the dose or discontinuing therapy depending on the severity of symptoms.

Hepatitis, hepatic reactions.

Cases of acute liver injury have been reported both during clinical trials and in the post-marketing period. A spectrum of abnormalities has been observed, ranging from transient asymptomatic elevations in liver transaminases to hepatic failure. In many cases, underlying factors such as pre-existing liver enzyme abnormalities, hepatitis B or C virus infection, concomitant use of other potentially hepatotoxic drugs, or chronic intravenous drug use may have contributed. These underlying factors should be considered before initiating buprenorphine therapy and throughout treatment. If hepatic reaction of unknown origin is suspected, buprenorphine should be evaluated as a potential cause of liver necrosis or jaundice, and treatment should be discontinued as soon as the patient's clinical condition allows. All patients should undergo regular liver function tests.

This medicinal product may cause somnolence, which may be intensified by other centrally acting agents such as alcohol, tranquilizers, sedatives, and hypnotics.

This medicinal product may cause orthostatic hypotension.

Animal studies and clinical experience have demonstrated that buprenorphine may produce a low degree of dependence.

Buprenorphine is capable of alleviating pain symptoms in certain conditions. Animal studies and clinical experience confirm that buprenorphine may also lead to drug dependence, although to a lesser extent than morphine. Therefore, during treatment, it is essential to consider all concomitant conditions, maintain control, and adhere strictly to prescribed doses.

Contraindications for the use of this medicinal product include respiratory, hepatic, and renal insufficiency, and cranial trauma. Special caution is required when used concomitantly with monoamine oxidase inhibitors (MAOIs) and other central nervous system depressants, as well as in cases of myxedema or hypothyroidism, adrenal insufficiency, central nervous system depression, toxic psychosis, benign prostatic hyperplasia, urethral stricture, alcoholism, in elderly and debilitated patients, and when used concomitantly with respiratory depressants. The drug may be used for premedication in prolonged surgeries (over 4 hours); however, anesthetic control may be complicated, and post-anesthetic respiratory depression may occur, requiring prolonged intensive ventilation.

Use during pregnancy or breastfeeding.

Hydrochloride buprenorphine is contraindicated during pregnancy. Since buprenorphine hydrochloride and its metabolites pass into breast milk, breastfeeding should be discontinued during treatment with this medicinal product.

Ability to influence reaction speed when driving or operating machinery.

On the day of administration, patients should refrain from activities requiring high attention concentration and rapid reaction times.

Administration and Dosage

The medication should be administered intravenously slowly or intramuscularly. The dose for adults is 0.5–1 ml (0.15–0.3 mg); if necessary, injections may be repeated at intervals of 6–8 hours. The maximum daily dose for adults is 8 ml (2.4 mg). For children aged 12 years and older, the dose is 0.5–0.8 ml (0.15–0.25 mg). The maximum daily dose for children is 6.6 ml (2 mg).

Children. The medication may be used in children aged 12 years and older.

Overdose

Symptoms: respiratory center depression. In case of accidental overdose, standard symptomatic therapy should be applied, including careful monitoring of vital functions. The main symptom requiring intensive treatment is respiratory center depression, which may lead to respiratory arrest and fatal outcome. If vomiting occurs, measures should be taken to prevent aspiration of gastric contents into the airways.

Treatment: symptomatic therapy. Administer naloxone; if necessary, use respiratory analeptics. Intensive care measures should be initiated, and symptomatic treatment of respiratory insufficiency should be started. The upper airways must remain patent to allow for assisted or controlled ventilation. An opioid antagonist (naloxone) is recommended, as it gradually counteracts the respiratory effects of buprenorphine. If necessary, administer oxygen and respiratory analeptics. The patient should be managed in an intensive care unit while implementing the above measures.

When determining the duration of treatment for overdose, the prolonged duration of action of buprenorphine should be taken into account.

Adverse reactions.

Central nervous system: Rarely – hallucinogenic effect, dizziness, somnolence, insomnia, headache, asthenia, syncope, pallor, anxiety, restlessness, confusion.

Cardiovascular system: Orthostatic hypotension, bradycardia, tachycardia, arterial hypotension.

Hepatobiliary system: Under proper conditions of use, in isolated cases – increased liver transaminase levels and jaundice, usually with favorable clinical course; liver necrosis and hepatitis.

Respiratory system: Respiratory depression.

Gastrointestinal tract: Dry mouth, nausea, vomiting, constipation, asthenia, liver necrosis and hepatitis, acute hepatitis.

Immune system: Hypersensitivity reactions (e.g., rash, urticaria, pruritus, bronchospasm), Quincke's edema (angioneurotic edema), anaphylactic shock.

Urinary system: Urinary retention.

Other adverse events: Sweating, pallor, injection site reactions, rhinitis, chills, back pain, lacrimation.

In cases of improper intravenous administration, local reactions have been reported, sometimes septic, as well as potentially severe acute hepatitis.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility.

The drug should not be mixed with other medicinal products in the same container.

Packaging. 1 ml in a vial; 5 vials in a blister pack; 1, 2, or 20 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu".

Manufacturer's address.

41 Kulikovska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.