Bupren® ic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUPREN® IS (BUPREN IS)

Composition:

Active substance: buprenorphine;

1 tablet contains buprenorphine hydrochloride (calculated as buprenorphine) 0.2 mg (0.0002 g) or 0.4 mg (0.0004 g);

Excipients: lactose monohydrate, mannitol (E 421), potato starch, citric acid monohydrate, sodium citrate, povidone, sodium starch glycolate (type A), polyethylene glycol (macrogol), talc, calcium stearate; Ponceau 4R (E 124) – for the 0.2 mg dosage.

Pharmaceutical form. Sublingual tablets.

Main physicochemical properties: tablets are pale pink (0.2 mg dosage) or white (0.4 mg dosage) in color, flat cylindrical in shape, with a bevel; the company trademark is imprinted on one surface of the tablet, and a line on the other surface.

Pharmacotherapeutic group.

Analgesics. Opioids. Orvinol derivatives. Buprenorphine.

ATC code: N02AE01.

Pharmacological properties.

Pharmacodynamics.

Buprenorphine is a centrally-acting opioid analgesic. By its mechanism of action, it belongs to the group of partial agonists/antagonists of opioid receptors (μ- and κ-receptors). The binding to μ-receptors is so strong that buprenorphine inhibits the action of other agonists. At the same time, buprenorphine's own activity at μ-receptors is very low, and no activity at κ-receptors has been demonstrated. Buprenorphine activates the antinociceptive system, thereby disrupting interneuronal transmission of pain impulses at various levels of the central nervous system (CNS) and altering the emotional perception of pain. The duration of analgesic effect is longer than that of morphine. Buprenorphine suppresses the respiratory center to a lesser extent than morphine. With prolonged use, the risk of developing drug dependence is significantly lower with buprenorphine than with morphine. The partial agonist activity of buprenorphine reduces its suppressive effects on cardiac and respiratory functions, thereby increasing the safety of its use.

Pharmacokinetics.

Following oral administration, buprenorphine undergoes presystemic metabolism in the small intestine and liver via N-dealkylation and glucuronidation. Therefore, oral administration of the drug is not advisable. After sublingual administration, absorption is very slow, with bioavailability ranging from 35 to 55%. Buprenorphine is evenly distributed in body tissues and penetrates the blood-brain barrier. Onset of action after sublingual administration occurs within 30 minutes, and peak plasma concentration is reached within 90 minutes. Plasma protein binding reaches 96%. The dose–concentration relationship remains linear within the dose range of 2 mg to 16 mg. Following absorption, a rapid distribution phase occurs, with a half-life ranging from 2 to 5 hours.

Buprenorphine is primarily metabolized in the liver via 14-N-dealkylation to 14-N-dealkylbuprenorphine (nor-buprenorphine), mediated by CYP3A4, as well as by glucuronidation of the parent compound and the dealkylated metabolite. Norbuprenorphine is a μ-agonist with weak intrinsic activity.

Elimination of buprenorphine follows a bi- or triexponential pattern. The elimination phase lasts from 20 to 25 hours, due to reabsorption of buprenorphine in the intestine following hydrolysis of conjugated metabolites, as well as the high lipophilicity of the buprenorphine molecule. Approximately 80% of buprenorphine is eliminated primarily via feces as a result of biliary excretion of glucuronidated metabolites; the remainder is excreted in urine.

Clinical characteristics.

Indications.

Acute and chronic high-intensity pain syndrome (in oncology patients, after surgical procedures, in myocardial infarction, burns, renal colic).

Contraindications.

Hypersensitivity to buprenorphine and other components of the medicinal product, respiratory dysfunction, cardiac failure, hepatic and renal insufficiency, head injuries, acute alcohol intoxication, opioid dependence.

Interaction with other medicinal products and other forms of interaction.

Alcohol

Ethanol enhances the sedative effect of buprenorphine. Buprenorphine should not be taken together with alcoholic beverages or medicinal products containing ethanol.

Concomitant use of medicinal products that must be considered

Benzodiazepines

Concomitant use of buprenorphine with benzodiazepines is associated with risk of fatal outcome due to respiratory depression associated with CNS function impairment. Dose should be individually titrated and patient’s condition carefully monitored. The risk of drug abuse should be taken into account.

Other CNS depressants

Other opioid derivatives (analgesics, antitussives), certain antidepressants, antihistamines (H1-receptor blockers), barbiturates, non-benzodiazepine anxiolytics, neuroleptics, clonidine, and similar medicinal products, when used concomitantly with buprenorphine, may enhance CNS depression.

Serotonergic medicinal products

Buprenorphine should be used cautiously in combination with serotonergic medicinal products such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, due to increased risk of serotonin syndrome, a potentially life-threatening condition (see section "Special precautions for use").

Monoamine oxidase inhibitors (MAOIs)

Based on experience with morphine, a possible potentiation of opioid effects when used in combination with MAO inhibitors is known.

To date, no significant interaction between buprenorphine and cocaine has been identified.

Buprenorphine is metabolized by CYP3A4.

CYP3A4 inhibitors

Interaction studies between buprenorphine and ketoconazole (a potent CYP3A4 inhibitor) showed an increase in buprenorphine Cmax and AUC (area under the concentration-time curve) by approximately 70% and 50%, respectively, and to a lesser extent in norbuprenorphine. When buprenorphine and ketoconazole are used concomitantly, the patient should be closely monitored, and the buprenorphine dose should be halved at the start of ketoconazole treatment. Further dose titration of buprenorphine should be based on clinical response. Thus, concomitant use of buprenorphine with potent CYP3A4 inhibitors [such as gestodene, troleandomycin, azole antifungals (ketoconazole, itraconazole), HIV protease inhibitors (ritonavir, indinavir, saquinavir)] may lead to increased plasma concentrations of buprenorphine and norbuprenorphine. Therefore, at the initiation of treatment with CYP3A4 inhibitors, consideration should be given to reducing the buprenorphine dose.

CYP3A4 inducers

Interaction between buprenorphine and CYP3A4 inducers has not been studied; therefore, careful monitoring is recommended for patients receiving buprenorphine concomitantly with CYP3A4 inducers (phenobarbital, carbamazepine, phenytoin, or rifampicin). Use of these medicinal products may enhance buprenorphine metabolism; therefore, in patients reporting reduced efficacy of buprenorphine, the buprenorphine dose should be increased.

Special precautions for use.

The prescribing physician must inform patients about the proper use of the medicinal product.

Diversion

Diversion refers to the transfer of buprenorphine to the illicit market, both from patients themselves and from individuals who obtain the medicinal product through theft from a patient or from a pharmacy. Diversion may lead to the emergence of new individuals dependent on buprenorphine used as a primary drug, resulting in addiction, risk of overdose, transmission of blood-borne viral infections, respiratory depression, and liver injury.

Respiratory depression

Several fatal cases due to respiratory depression have been reported following misuse or inappropriate use of buprenorphine, or concomitant use of buprenorphine with CNS depressants (other opioids, benzodiazepines, ethanol).

Sleep-related breathing disorders

Opioids may cause sleep-related breathing disorders, including central sleep apnea and sleep-related hypoxemia. The risk of central sleep apnea is dose-dependent. Consideration should be given to reducing the total opioid dose in patients with central sleep apnea.

Hepatitis, hepatic reactions

Cases of acute liver injury have been reported both during clinical trials and in the post-marketing period. A range of abnormalities has been observed, from transient asymptomatic elevations in liver transaminases to hepatic failure. In many cases, underlying liver enzyme abnormalities, hepatitis B or C virus infection, or concomitant use of other potentially hepatotoxic medicinal products may have contributed to or exacerbated these events. These key factors should be considered before initiating buprenorphine therapy and throughout treatment. In case of suspected hepatic reaction of unknown origin, buprenorphine should be evaluated as a potential cause of liver necrosis or jaundice, and treatment should be discontinued if the patient's clinical condition allows. Liver function should be monitored regularly in all patients.

Serotonin syndrome

Concomitant use of buprenorphine with other serotonergic agents, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, may lead to 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 at the beginning of treatment and during dose escalation.

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

In case of suspected serotonin syndrome, dose reduction or discontinuation of therapy should be considered depending on the severity of symptoms.

Buprenorphine may cause drowsiness, which may be intensified by other centrally acting agents such as alcohol, tranquilizers, sedatives, and hypnotics.

Buprenorphine may cause orthostatic hypotension.

Animal studies and clinical experience have demonstrated that prolonged use of buprenorphine may lead to opioid dependence, although to a lesser extent than morphine. Discontinuation of the drug may result in withdrawal syndrome, sometimes delayed in onset. Therefore, during treatment, it is essential to consider all surrounding circumstances, maintain control, and adhere strictly to prescribed doses.

Athletes should be informed that the use of buprenorphine leads to a positive result in anti-doping tests.

Safety measures during use

Special caution is required when using buprenorphine in patients with CNS depression, and in patients with the following concomitant conditions:

• Bronchial asthma (cases of buprenorphine-induced respiratory depression have been reported);
• Increased intracranial pressure;
• Arterial hypotension;
• Prostate hypertrophy;
• Urethral stricture/stenosis;
• Hypothyroidism, myxedema;
• Adrenal insufficiency;
• Toxic psychosis;
• Alcoholism.

Elderly patients, as well as patients with impaired hepatic or renal function, in whom elimination of buprenorphine may be slowed, leading to accumulation and increased sedative effects, should be given lower doses.

Buprenorphine should be administered with particular caution in patients receiving monoamine oxidase inhibitors (MAOIs) or other CNS depressants, in elderly and debilitated patients, and in those receiving concomitant respiratory depressants. Careful dose selection is necessary for patients taking CYP3A4 inhibitors. Since CYP3A4 inhibitors increase buprenorphine plasma concentrations, a reduction in buprenorphine dose may be required.

Dental problems

Reports of dental problems, including serious ones, have been received from patients using transmucosal formulations of buprenorphine. Specifically, cases of caries (including severe), tooth decay, dental abscesses/infections, tooth erosion, loss of dental fillings, tooth fractures, and tooth loss have been reported (see section "Adverse reactions"). Many such cases occurred in patients with no prior history of dental problems. Tooth extractions have frequently been required to treat resulting dental damage. Patients using sublingual buprenorphine tablets should be instructed that, after complete dissolution of the tablet in the oral cavity, they should take a large sip of water, gently swish it around the teeth and gums, and swallow; brushing should be avoided for at least 1 hour afterward to prevent mechanical damage to teeth that may occur from brushing. Patients should also be advised to undergo regular dental examinations throughout the entire duration of buprenorphine treatment, including at the initial stage of therapy. In case of any dental problems arising during sublingual use of buprenorphine, patients should seek prompt dental care.

QTc interval prolongation

Comprehensive studies on the effects of buprenorphine on cardiac function have demonstrated QT interval prolongation of up to ≤15 ms on electrocardiogram (ECG). This effect is most likely not mediated via hERG channels. Based on available data, buprenorphine is unlikely to have a proarrhythmic effect when used as monotherapy in patients without risk factors. The risk associated with concomitant use of buprenorphine and other medicinal products that prolong the QT interval is unknown. This information should be taken into account when assessing the benefit-risk ratio of buprenorphine before prescribing it to patients with risk factors such as hypokalemia, severe hypomagnesemia, bradycardia, recent atrial fibrillation, use of digitalis preparations, documented QT prolongation, or asymptomatic long QT syndrome.

Due to the lactose content, the medicinal product should not be taken by patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

The 0.2 mg dosage form contains a dye that may cause allergic reactions.

Use during pregnancy or breastfeeding.

There are currently insufficient clinical data to assess the safety of buprenorphine use during pregnancy; therefore, its use during pregnancy is not recommended.

Buprenorphine passes into breast milk and, at high doses, may suppress lactation. Breastfeeding is not recommended for women taking buprenorphine.

Ability to influence reaction speed when driving or operating machinery.

Patients, particularly drivers and machine operators, should be especially cautious about the risk of drowsiness associated with this medicinal product. This risk is increased when the product is used concomitantly with alcohol or other CNS depressant medicinal products.

Method of Administration and Dosage

The medicinal product is intended for use in adults and adolescents aged 16 years and older.

Administer sublingually. The tablet should not be swallowed or chewed. The tablet must be held under the tongue until completely dissolved.

For the treatment of pain syndrome, the medicinal product should be administered at a dose of 0.2–0.4 mg every 6–8 hours. Buprenorphine doses should be individually adjusted depending on the intensity of pain and individual patient sensitivity. If necessary, the dose may be increased. The maximum daily dose is 1.6 mg. The duration of treatment depends on the patient's condition, as well as the nature and duration of the pain syndrome.

Children

Due to limited data on the use of buprenorphine in children under 16 years of age, administration of the medicinal product in this patient population is not recommended.

Overdose

With sublingual administration, overdose is unlikely. In case of overdose, symptoms may include nausea, vomiting, drowsiness, dizziness, hallucinations, respiratory depression (possible only with significant exceeding of therapeutic doses), and urticaria.

Treatment: In case of overdose, general supportive measures should be applied, including careful monitoring of respiratory and cardiac function. The main symptom requiring intensive therapy is respiratory depression, which may lead to respiratory arrest and fatal outcome. Airway patency must be ensured, and assisted or controlled ventilation should be provided. The patient should be transferred to an intensive care unit. Administration of an opioid antagonist (e.g., naloxone) is recommended, although its effectiveness in reversing buprenorphine-induced respiratory depression may be limited compared to its effects on full agonists. When determining the duration of overdose management, it should be taken into account that buprenorphine has a prolonged duration of action.

Adverse Reactions

The occurrence of adverse reactions depends on the patient's tolerance threshold, which is higher in opioid-dependent patients than in those without opioid dependence.

Immune system disorders: hypersensitivity reactions, including skin and mucous membrane rashes, urticaria, pruritus, anaphylactic shock, angioneurotic edema (Quincke's edema), respiratory distress, dyspnea, bronchospasm.

Psychiatric disorders: anxiety, nervousness, hallucinations, confusion.

Nervous system disorders: insomnia, somnolence, headache, dizziness, syncope.

Eye disorders: lacrimation.

Cardiovascular system disorders: ECG changes (QT interval prolongation), syncope, arterial hypotension (including orthostatic hypotension), bradycardia, tachycardia.

Respiratory system disorders: rhinorrhea, respiratory depression.

Gastrointestinal disorders: dry mouth, constipation, diarrhea, nausea, vomiting, abdominal pain.

Hepatobiliary disorders: under appropriate conditions of use, in isolated cases – increased levels of liver transaminases and jaundice, usually with benign clinical course, liver necrosis, hepatitis.

Renal and urinary disorders: urinary retention, impaired kidney function.

Skin and subcutaneous tissue disorders: increased sweating.

Local reactions: dental destruction (including caries, tooth fractures, tooth loss).

General disorders: pallor, asthenia, withdrawal syndrome, back pain, increased sensitivity to cold, chills.

Reporting of suspected adverse reactions

Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are kindly requested to report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at https://aisf.dec.gov.ua to monitor the benefit-risk balance of this medicinal product.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Limited liability company "INTERKHIM".

Manufacturer's address and place of business.

40-A, 21st km, Starokyivska Road, Odesa, Ukraine, 65025.

INSTRUCTION

for medical use of the medicinal product

BUPREN® IS

(BUPREN IS)

Composition:

Active substance: buprenorphine;

1 tablet contains buprenorphine hydrochloride (equivalent to buprenorphine) 0.4 mg (0.0004 g), 2 mg (0.002 g), or 8 mg (0.008 g);

Excipients: lactose monohydrate, mannitol (E 421), potato starch, citric acid monohydrate, sodium citrate, povidone, sodium starch glycolate (type A), polyethylene glycol (macrogol), talc, calcium stearate.

Pharmaceutical form. Sublingual tablets.

Main physicochemical properties: white, flat cylindrical tablets with bevelled edges; a company trademark is imprinted on one side of the tablet, and a line on the other side.

Pharmacotherapeutic group.

Medicinal products used in addictive disorders. Medicinal products used in opioid dependence. Buprenorphine.

ATC code N07BC01.

Pharmacological Properties

Pharmacodynamics

Buprenorphine is a centrally-acting opioid analgesic. Its mechanism of action classifies it as a partial agonist/antagonist of opioid receptors (μ- and κ-receptors). The binding to μ-receptors is so strong that buprenorphine blocks the effects of other agonists. At the same time, buprenorphine's intrinsic activity at μ-receptors is very low, while no activity at κ-receptors has been demonstrated. Buprenorphine's property as an opioid substitute is due to its slow dissociation from μ-receptors, allowing for a prolonged reduction in the need for narcotics in dependent patients. It activates the antinociceptive system, thereby interfering with interneuronal transmission of pain impulses at various levels of the central nervous system (CNS) and altering the emotional perception of pain. The duration of analgesic effect is longer than that of morphine. Buprenorphine depresses the respiratory center to a lesser extent than morphine. With prolonged use, the risk of developing drug dependence is significantly lower with buprenorphine than with morphine. The partial agonist activity of buprenorphine reduces its suppressive effects on cardiac and respiratory functions, thereby increasing the safety of its use.

Pharmacokinetics

Following oral administration, buprenorphine undergoes presystemic metabolism in the small intestine and liver via N-dealkylation and glucuronidation. Therefore, oral administration of the drug is not advisable. After sublingual administration, absorption is very slow, with bioavailability ranging from 35% to 55%. Buprenorphine is evenly distributed in body tissues and penetrates the blood-brain barrier. The onset of action after sublingual administration occurs within 30 minutes, and peak plasma concentration is reached within 90 minutes. Plasma protein binding reaches 96%. The dose–concentration relationship remains linear within the dose range of 2 mg to 16 mg. Following absorption, buprenorphine enters a rapid distribution phase, with a half-life ranging from 2 to 5 hours.

Buprenorphine is primarily metabolized in the liver via 14-N-dealkylation to 14-N-desalkylbuprenorphine (nor-buprenorphine) by CYP3A4, as well as through glucuronidation of the parent compound and the dealkylated metabolite. Nor-buprenorphine is a μ-agonist with weak intrinsic activity.

Elimination of buprenorphine follows bi- or triexponential kinetics. The elimination phase lasts from 20 to 25 hours, which is attributed to enterohepatic reabsorption of buprenorphine following hydrolysis of conjugated metabolites, as well as the high lipophilicity of the buprenorphine molecule. Approximately 80% of buprenorphine is eliminated predominantly in feces via biliary excretion of glucuronidated metabolites; the remainder is excreted in urine.

Clinical characteristics.

Indications.

Opioid substitution therapy within the framework of medical, social, and psychological support.

Contraindications.

Hypersensitivity to buprenorphine or to other components of the medicinal product, severe respiratory insufficiency, severe hepatic insufficiency, acute alcohol intoxication, delirium.

Interaction with other medicinal products and other forms of interaction.

Alcohol

Ethanol enhances the sedative effect of buprenorphine. Buprenorphine should not be taken together with alcoholic beverages or medicinal products containing ethanol.

Concomitant use of medicinal products that should be considered

Benzodiazepines

Concomitant use of buprenorphine with benzodiazepines is associated with a risk of fatal outcome due to respiratory depression related to central nervous system (CNS) impairment. Dose titration should be individualized and the patient’s condition should be carefully monitored. The risk of medicinal product abuse should be taken into account.

Other CNS depressants

Other opioid derivatives (analgesics, antitussives), certain antidepressants, antihistamines (H1-receptor blockers), barbiturates, non-benzodiazepine anxiolytics, neuroleptics, clonidine, and similar medicinal products may enhance CNS depression when used concomitantly with buprenorphine.

Serotonergic medicinal products

Buprenorphine should be used cautiously in combination with serotonergic medicinal products such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, due to an increased risk of developing serotonin syndrome, a potentially life-threatening condition (see section "Special precautions for use").

Monoamine oxidase inhibitors (MAOIs)

Based on experience with morphine, a possible enhancement of opioid effects when used in combination with MAO inhibitors is known.

To date, no significant interaction between buprenorphine and cocaine has been identified.

Buprenorphine is metabolized by CYP3A4.

Inhibitors of CYP3A4

Interaction studies between buprenorphine and ketoconazole (a potent CYP3A4 inhibitor) showed an increase in buprenorphine Cmax and AUC (area under the concentration-time curve) by approximately 70% and 50%, respectively, and to a lesser extent in norbuprenorphine. When buprenorphine and ketoconazole are used concomitantly, the patient’s condition should be closely monitored, and the buprenorphine dose should be halved at the start of ketoconazole treatment. Further dose titration of buprenorphine should be based on clinical response. Thus, the use of buprenorphine in combination with potent CYP3A4 inhibitors [such as gestodene, troleandomycin, azole antifungals (ketoconazole, itraconazole), HIV protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir)] may lead to increased plasma concentrations of buprenorphine and norbuprenorphine. Continuous monitoring of patients receiving such combinations is required. Therefore, at the initiation of treatment with CYP3A4 inhibitors, the need to reduce the buprenorphine dose should be considered.

Inducers of CYP3A4

The interaction between buprenorphine and CYP3A4 inducers has not been studied; therefore, careful monitoring is recommended for patients who are taking CYP3A4 inducers (phenobarbital, carbamazepine, phenytoin, or rifampicin) concomitantly with buprenorphine. The use of these medicinal products may enhance the metabolism of buprenorphine; therefore, in patients reporting reduced effectiveness of buprenorphine or increased drug craving, the buprenorphine dose should be increased.

Special precautions for use.

This medicinal product is intended for the treatment of opioid dependence. Treatment must be prescribed by a physician who ensures the proper use of the medication in patients with dependence. The prescribing physician must inform patients about the correct use of the medicinal product. The physician should consider the risk of misuse of the medicinal product (including intravenous administration), particularly at the beginning of treatment. Due to the risk of misuse and for dose titration, the medicinal product should be initially prescribed for short periods and, whenever possible, administered under supervision, which also promotes treatment adherence.

Diversion

Diversion refers to the transfer of buprenorphine to the illegal market, either from patients or from individuals who obtain the medicinal product through theft from patients or pharmacies. Diversion may lead to the emergence of new dependent individuals who use buprenorphine as a primary drug, resulting in addiction, risk of overdose, transmission of blood-borne viral infections, respiratory depression, and liver injury.

Acceleration of withdrawal

At the beginning of buprenorphine treatment, physicians should consider the partial agonist profile of buprenorphine, which may precipitate withdrawal symptoms in opioid-dependent patients, particularly if buprenorphine is administered less than 6 hours after the last dose of heroin or other short-acting opioids, or less than 24 hours after the last dose of methadone. Withdrawal symptoms may also occur with suboptimal dosing.

The risk of overdose or treatment relapse is higher in patients who continue self-medicating withdrawal symptoms with opioids, alcohol, or other sedatives and hypnotics during buprenorphine treatment, especially benzodiazepines.

Dependence

Buprenorphine is a partial opioid receptor agonist, and its continuous use leads to opioid-type dependence. Discontinuation of treatment may result in withdrawal syndrome, sometimes delayed in onset.

Respiratory depression

There have been reports of fatal cases due to respiratory depression resulting from improper use of buprenorphine or concomitant use of buprenorphine with CNS depressants (other opioids, benzodiazepines, ethanol).

Sleep-related breathing disorders

Opioids may cause sleep-related breathing disorders, including central sleep apnea and nocturnal hypoxemia. The risk of central sleep apnea is dose-dependent. Consideration should be given to reducing the total opioid dose in patients with central sleep apnea.

Hepatitis, hepatic reactions

Cases of acute liver injury have been reported both during clinical trials and in the post-marketing period. A range of hepatic abnormalities have been observed, from transient asymptomatic elevations in liver transaminases to hepatic failure. In many cases, underlying factors such as pre-existing hepatic enzyme disorders, hepatitis B or C virus infection, concomitant use of other potentially hepatotoxic medicinal products, and chronic intravenous drug use may have contributed. These underlying factors should be considered before initiating buprenorphine treatment and throughout therapy. In case of suspected hepatic reaction of unknown origin, the possibility that buprenorphine is the cause of liver necrosis or jaundice should be evaluated, and treatment should be discontinued as soon as the patient's clinical condition allows. Liver function should be monitored regularly in all patients.

Serotonin syndrome

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

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

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

In case of suspected serotonin syndrome, dose reduction or discontinuation of therapy should be considered depending on the severity of symptoms.

Buprenorphine may cause drowsiness, which is enhanced by other centrally acting agents such as alcohol, tranquilizers, sedatives, and hypnotics.

Buprenorphine may mask pain, which is a symptom of underlying disease.

Buprenorphine may cause orthostatic hypotension.

Animal studies and clinical experience have demonstrated that chronic use of buprenorphine may lead to opioid dependence, although to a lesser extent than morphine. Therefore, during treatment, it is very important to consider all concomitant conditions, maintain monitoring, and adhere strictly to prescribed doses.

Athletes should be informed that the use of buprenorphine leads to a positive result in anti-doping tests.

Safety precautions for use

The use of buprenorphine requires special caution in cases of CNS depression and in patients with concomitant conditions such as:

• bronchial asthma or respiratory insufficiency (cases of buprenorphine-induced respiratory depression have been reported) (see section "Contraindications");
• renal insufficiency (20% of the administered dose is excreted by the kidneys; therefore, renal elimination of buprenorphine may be slowed in renal impairment);
• hepatic insufficiency (hepatic metabolism of buprenorphine may be altered in this case) (see section "Contraindications");
• head trauma;
• increased intracranial pressure;
• arterial hypotension;
• prostate hypertrophy;
• urethral stenosis/stricture;
• hypothyroidism, myxedema;
• adrenal insufficiency;
• toxic psychosis;
• alcoholism.

Buprenorphine should be used with particular caution in patients receiving monoamine oxidase inhibitors (MAOIs) and other CNS depressants, in elderly and debilitated patients, and when co-administered with respiratory depressants. Dose regimens of buprenorphine should be carefully selected in patients taking CYP3A4 inhibitors. Since CYP3A4 inhibitors increase buprenorphine plasma concentrations, a reduction in buprenorphine dose may be necessary.

Dental problems

Reports of dental problems, including serious cases, have been received in patients using transmucosal formulations of buprenorphine. Cases of caries (including severe), tooth decay, dental abscesses/infections, tooth erosion, loss of dental fillings, tooth fractures, and tooth loss have been reported (see section "Adverse reactions"). Many such cases occurred in patients with no prior history of dental problems. Dental extractions were frequently required to treat the resulting damage. Patients using sublingual buprenorphine tablets should be advised that, after complete dissolution of the tablet in the oral cavity, they should take a large sip of water, gently swish it around the teeth and gums, and swallow the water. They should avoid brushing their teeth for at least 1 hour afterward to prevent mechanical damage to teeth that may result from brushing. Patients should also be informed of the need for regular dental check-ups throughout the entire period of buprenorphine treatment, including at the beginning of therapy. In case of any dental problems during sublingual use of buprenorphine, patients should seek dental care as soon as possible.

QTc interval prolongation

Comprehensive studies on the effect of buprenorphine on cardiac function have demonstrated QT interval prolongation of up to 15 ms on electrocardiogram (ECG). This effect is unlikely to be mediated via hERG channels. Based on available data, it is unlikely that buprenorphine has a proarrhythmic effect when used as monotherapy in patients without risk factors. The risk associated with concomitant use of buprenorphine and other medicinal products that prolong the QT interval is unknown. This information should be taken into account when assessing the benefit-risk ratio of buprenorphine before prescribing it to patients with risk factors such as hypokalemia, severe hypomagnesemia, bradycardia, recent atrial fibrillation, congestive heart failure, use of digitalis preparations, documented QT interval prolongation, or asymptomatic long QT syndrome.

Due to the presence of lactose, this medicinal product should not be used in patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Due to insufficient data on the effects of buprenorphine in pregnant women, its use during pregnancy is not recommended. Buprenorphine may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Buprenorphine passes into animal milk. At high doses, buprenorphine reduces milk production. Breastfeeding is not recommended for women taking buprenorphine.

Ability to affect reaction speed when driving or operating machinery.

Particular attention should be paid by drivers and machine operators to the risk of drowsiness associated with the use of this medicinal product. This risk is increased when the medicinal product is used concomitantly with alcohol or other CNS depressants.

Method of Administration and Dosage

Treatment must be conducted under the supervision of a specialist in opioid addiction management. The treatment outcome depends not only on pharmacological therapy but also on medical, psychological, and socio-educational interventions aimed at the patient's gradual reintegration. Sublingual buprenorphine tablets are intended for use in adults and children aged 16 years and older who have consented to treatment for drug addiction.

The physician must clearly specify the exact single dose and treatment regimen on the prescription.

Administer sublingually. The patient must be informed that sublingual administration is the only effective and safe route for this medicinal product. The tablet must be placed under the tongue and held there until completely dissolved. The tablet must not be swallowed or chewed.

The availability of sublingual tablets with different strengths (0.4 mg, 2 mg, and 8 mg) allows for appropriate dose titration.

At the beginning of buprenorphine treatment, the physician must consider the possibility of precipitated withdrawal syndrome in opioid-dependent patients due to buprenorphine’s partial agonist activity at opioid μ-receptors.

Initiation of Therapy

The recommended initial dose of buprenorphine is 0.8 mg to 4 mg as a single daily dose. An additional dose of buprenorphine (2 mg to 4 mg) may be administered once daily, depending on the individual patient’s needs.

Opioid-dependent patients not experiencing withdrawal symptoms

At the start of treatment, the first dose of buprenorphine should be administered upon the onset of withdrawal symptoms, but not earlier than 6 hours after the last use of opioids (e.g., heroin, short-acting opioids).

Patients receiving methadone

Prior to initiating buprenorphine therapy, the methadone dose should be reduced (maximum allowable dose is 30 mg per day). Nevertheless, buprenorphine may precipitate withdrawal symptoms in methadone-dependent patients. In such patients, the first dose of buprenorphine should be administered upon the onset of withdrawal symptoms, but not earlier than 24 hours after the last methadone dose.

Dose Titration to Achieve a Maintenance Dose

A two-week course of buprenorphine is recommended, especially at the beginning of treatment.

The buprenorphine dose should be gradually increased according to the therapeutic effect observed in the patient. The average maintenance dose of buprenorphine is 8 mg per day. Most patients do not require doses exceeding 16 mg per day; however, clinical studies have demonstrated the efficacy and safety of sublingual buprenorphine administration at doses up to 24 mg per day.

Dose adjustments should be made based on repeated assessments of the patient’s clinical condition and the effectiveness of the comprehensive treatment approach. Inadequate stabilization of the patient’s condition while receiving 16 mg of buprenorphine per day may be associated with possible comorbid psychiatric disorders or incorrect medication use. These factors should be considered when determining further treatment strategies.

Dose Reduction and Discontinuation of Treatment

After achieving satisfactory clinical stabilization and with the patient’s consent, the daily maintenance dose of buprenorphine may be gradually reduced. Dose titration should be performed gradually, and in favorable individual cases, may lead to complete discontinuation of substitution maintenance therapy. When discontinuing treatment, particular attention must be paid to the possible occurrence of withdrawal symptoms or relapses.

Children

The safety and efficacy of buprenorphine in patients under 16 years of age have not been established.

Overdose

In case of overdose, general supportive measures should be applied, including careful monitoring of respiratory and cardiac function. The primary symptom requiring intensive therapy is respiratory depression, which may lead to respiratory arrest and fatal outcome. If vomiting occurs, measures should be taken to prevent aspiration of vomitus.

Treatment

Following standard emergency procedures, symptomatic treatment of respiratory depression should be initiated. Airway patency must be ensured, and assisted or controlled ventilation should be provided. The patient should be transferred to an intensive care unit. Administration of an opioid antagonist (e.g., naloxone) is recommended, although its efficacy in reversing buprenorphine-induced respiratory depression may be limited compared to its effect on full agonists. When determining the duration of treatment for overdose, it should be considered that buprenorphine has a prolonged duration of action.

Side effects

The occurrence of adverse reactions depends on the patient's tolerance threshold, which is higher in opioid-dependent patients than in those without opioid dependence.

Immune system disorders: hypersensitivity reactions, including skin and mucous membrane rashes, urticaria, pruritus, anaphylactic shock, angioneurotic edema (Quincke's edema), respiratory distress, dyspnea, bronchospasm.

Psychiatric disorders: anxiety, nervousness, hallucinations, confusion.

Nervous system disorders: insomnia, drowsiness, headache, dizziness, loss of consciousness.

Eye disorders: lacrimation.

Cardiovascular system disorders: ECG changes (prolongation of QT interval), syncope, arterial hypotension (including orthostatic hypotension), bradycardia, tachycardia.

Respiratory system disorders: rhinorrhea, respiratory depression.

Gastrointestinal disorders: dry mouth, constipation, diarrhea, nausea, vomiting, abdominal pain.

Hepatobiliary system disorders: under appropriate conditions of use, in isolated cases – increased levels of liver transaminases and jaundice, usually with benign clinical course, liver necrosis, hepatitis.

Renal and urinary system disorders: urinary retention, impaired kidney function.

Skin and subcutaneous tissue disorders: increased sweating.

Local reactions: dental destruction (including caries, tooth fractures, tooth loss).

General disorders: pallor, asthenia, withdrawal syndrome, back pain, increased sensitivity to cold, chills.

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

In patients with pronounced physical (somatic) opioid dependence, initial sublingual administrations of buprenorphine may cause a paradoxical reaction leading to withdrawal syndrome similar to that caused by naloxone.

Reporting suspected adverse reactions

Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are kindly requested to report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at https://aisf.dec.gov.ua to monitor the benefit-risk balance during the use of this medicinal product.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 1 blister per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Limited liability company "INTERCHEM".

Manufacturer's address and location of business activity.

40-A, 21st km, Starokyivska Road, Odesa, 65025, Ukraine.