Bupren® ic

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

Composition:

Active substance: buprenorphine;

One tablet contains buprenorphine hydrochloride (calculated as 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-colored, flat cylindrical tablets with a score line; the trade mark of the manufacturer 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. According to its mechanism of action, it belongs to the group of partial agonists/antagonists of opioid receptors (μ- and κ-receptors). Its binding to μ-receptors is so strong that buprenorphine blocks the effects of other agonists. At the same time, buprenorphine's own activity at μ-receptors is very low, while activity at κ-receptors is not observed. Buprenorphine's property as an opioid substitute is due to its slow reversible binding to μ-receptors, allowing a prolonged reduction in the need for narcotics in dependent patients. It activates the antinociceptive system and thereby disrupts interneuronal transmission of pain impulses at various levels of the central nervous system (CNS), 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 compared to 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 crosses the blood-brain barrier. Onset of action after sublingual administration occurs within 30 minutes, with maximum plasma concentration reached at 90 minutes. Plasma protein binding is up to 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 of 2 to 5 hours.

Buprenorphine is metabolized primarily in the liver via 14-N-dealkylation to 14-N-desalkylbuprenorphine (nor-buprenorphine) by CYP3A4, as well as via glucuronidation of the parent molecule 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 20 to 25 hours, due to enterohepatic reabsorption of buprenorphine after hydrolysis of conjugated metabolites, as well as the high lipophilicity of the buprenorphine molecule. Approximately 80% of buprenorphine is eliminated primarily in feces via biliary excretion of glucuronidated metabolites; the remainder is excreted in urine.

Clinical characteristics.

Indications.

Replacement therapy for opioid dependence within the framework of medical, social, and psychological support.

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

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

Benzo diazepines

Concomitant use of buprenorphine with benzodiazepines is associated with a risk of fatal outcome due to respiratory insufficiency related to central nervous system (CNS) dysfunction. 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 cause enhanced 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 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 is known when used in combination with MAO inhibitors.

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 Cmax and AUC (area under the concentration-time curve) of buprenorphine (approximately by 70% and 50%, respectively) and to a lesser extent of norbuprenorphine. When buprenorphine is used concomitantly with ketoconazole, the patient should be closely monitored, and the dose of buprenorphine should be halved at the start of ketoconazole therapy. Further dose titration of buprenorphine should be based on clinical response. Thus, co-administration of buprenorphine 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, when initiating treatment with CYP3A4 inhibitors, the need to reduce the buprenorphine dose should be considered.

CYP3A4 inducers

Interaction between buprenorphine and CYP3A4 inducers has not been studied; therefore, careful monitoring of patients who are taking CYP3A4 inducers (phenobarbital, carbamazepine, phenytoin, or rifampicin) concomitantly with buprenorphine is recommended. These medicinal products may enhance the metabolism of buprenorphine; therefore, in patients reporting reduced efficacy 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 appropriate use of the medicinal product in patients with dependence. The prescribing physician must inform patients about the proper use of the medication. The physician should consider the risk of misuse of the medicinal product (including intravenous administration), especially 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 adherence to the treatment regimen.

Diversion

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

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 when 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 relapse is higher in patients who continue to self-medicate opioid withdrawal symptoms with opioids, alcohol, or other sedatives and hypnotics during buprenorphine treatment, particularly benzodiazepines.

Dependence

Buprenorphine is a partial opioid receptor agonist, and its chronic 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 use of buprenorphine in combination 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 has been observed, from transient asymptomatic elevations in liver transaminases to hepatic failure. In many cases, underlying 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 and 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 patient monitoring is recommended, especially 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, consideration should be given to reducing the dose or discontinuing therapy 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 measures for use

Special caution is required when using buprenorphine in patients with CNS depression or those with concomitant conditions such as:

• bronchial asthma or respiratory insufficiency (cases of buprenorphine-induced respiratory depression have been reported) (see section "Contraindications");
• renal impairment (20% of the administered dose is excreted by the kidneys; therefore, renal elimination of buprenorphine may be slowed in renal impairment);
• hepatic impairment (hepatic metabolism of buprenorphine may be altered in this case) (see section "Contraindications");
• head trauma;
• increased intracranial pressure;
• arterial hypotension;
• prostatic hypertrophy;
• urethral stricture/stenosis;
• 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, elderly and debilitated patients, and those receiving concomitant medications that depress respiration. Dose regimens of buprenorphine should be carefully adjusted in patients taking CYP3A4 inhibitors. Since CYP3A4 inhibitors increase buprenorphine plasma concentrations, a reduction in buprenorphine dose may be necessary.

Dental problems

Reports have been received regarding the occurrence of dental problems, including serious ones, in 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. Dental extractions were frequently required to treat the resulting dental damage. Patients using sublingual buprenorphine tablets should be informed 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 then swallow the water; they should not brush their teeth for at least 1 hour to avoid mechanical damage to teeth that may result from brushing. Patients should also be advised to undergo regular dental examinations throughout the entire duration of buprenorphine treatment, including at the beginning of therapy. In case of any dental problems during sublingual use of buprenorphine, patients should seek immediate dental care.

QTc interval prolongation

Comprehensive studies on the effect of buprenorphine on cardiac function have demonstrated QT interval prolongation of ≤ 15 ms on electrocardiogram (ECG). This effect is most likely not mediated via hERG channels. Based on available data, it is unlikely that buprenorphine has proarrhythmic effects 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 use 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 problems 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 when the expected benefit to the mother outweighs the potential risk to the fetus.

Buprenorphine crosses 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 vehicles 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 depressant medicinal products.

Method of Administration and Dosage

Treatment must be conducted under the supervision of a specialist in opioid addiction management. Treatment outcomes depend 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 provided consent for treatment of drug addiction.

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

Administer sublingually. Patients must be informed that sublingual administration is the only effective and safe route for this medication. 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.

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 beginning of treatment, the first dose of buprenorphine should be administered when signs of withdrawal appear, 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 when withdrawal symptoms appear, 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 based on 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 according to the results of repeated clinical assessments and the effectiveness of the comprehensive treatment approach. Inadequate stabilization of the patient's condition while on a 16 mg daily dose of buprenorphine 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 proceed to complete discontinuation of substitution maintenance therapy. When stopping treatment, particular attention should be paid to the potential development 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 treatment 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

After implementing 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 effectiveness in reversing respiratory depression caused by buprenorphine may be limited compared to its effects on full agonists. When determining the duration of treatment for overdose, it should be considered 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 patients without opioid dependence.

Immune system side effects: 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 side effects: insomnia, somnolence, headache, dizziness, syncope.

Eye-related side effects: lacrimation.

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

Respiratory system side effects: rhinorrhea, respiratory depression.

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

Hepatobiliary system side effects: under appropriate conditions of use, in rare cases – elevated liver transaminase levels and jaundice, usually with benign clinical course, liver necrosis, hepatitis.

Urinary system side effects: urinary retention, renal function impairment.

Skin and subcutaneous tissue side effects: 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 trigger a paradoxical reaction leading to a withdrawal syndrome similar to that caused by naloxone.

Reporting suspected adverse reactions

Healthcare and pharmacy professionals, as well as patients or their legal representatives, are kindly requested to report all suspected adverse reactions and lack of drug efficacy 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 and sight of children.

Packaging:

10 tablets per blister; 1 blister per cardboard box.

Prescription category: Prescription only.

Manufacturer:

Limited liability company "INTERKHIM".

Manufacturer's address and place of business:

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