Buprexon-zn

Ukraine

Brand name Buprexon-zn

Form tablets, sublingual

Active substance / Dosage

buprenorphine · 8 mg

naloxone · 2 mg

Prescription type prescription only

ATC code

N07BC51

Registration number UA/13443/01/02

Manufacturer LLC "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu"

Table of Contents

INSTRUCTION for medical use of the medicinal product BUPREXON-ZN (BUPREXON-ZN) Composition: buprenorphine, naloxone; active substances: 1 tablet contains buprenorphine hydrochloride equivalent to buprenorphine 2.0 mg and naloxone hydrochloride dihydrate equivalent to naloxone 0.5 mg, or buprenorphine hydrochloride equivalent to buprenorphine 8.0 mg and naloxone hydrochloride dihydrate equivalent to naloxone 2.0 mg; excipients: celactose 80 (a mixture of lactose monohydrate and powdered cellulose (75:25)), corn starch, crospovidone, anhydrous citric acid, mannite (E 421), aspartame (E 951), magnesium stearate. Medicinal form. Sublingual tablets. Basic physicochemical properties: white or almost white tablets with a flat surface and a bevel. Pharmacotherapeutic group. Medicinal products for opioid dependence treatment. Buprenorphine, combinations. ATC code N07BC51. Pharmacological properties. Pharmacodynamics. Buprenorphine hydrochloride is a centrally acting analgesic. It stimulates opioid κ-receptors, which explains its high analgesic activity, and simultaneously blocks μ-receptors responsible for the development of euphoria. In terms of analgesic effect, buprenorphine is 2–2.5 times weaker than morphine. Unlike other centrally acting narcotic analgesics, the drug does not cause euphoria, thus being less dangerous as a substance to which dependence may develop. Naloxone blocks the effects of opioids such as morphine, codeine, and heroin. If buprenorphine and naloxone are administered by injection, naloxone blocks the effects of buprenorphine, leading to the development of withdrawal symptoms in individuals with narcotic dependence. When administered sublingually in usual doses, the effect of naloxone is minimal due to its almost complete metabolism during first-pass metabolism. Pharmacokinetics. After sublingual administration, buprenorphine absorption occurs very slowly, with maximum plasma levels observed after 90 minutes. After oral administration, the presence of naloxone in plasma is barely detectable. Buprenorphine and naloxone are evenly distributed in body tissues and penetrate the blood-brain barrier. Buprenorphine is approximately 96% bound to blood proteins, primarily to α- and β-globulins. Naloxone is approximately 45% bound to blood proteins, primarily to albumins. The active components of the fixed combination are metabolized in the liver and are primarily excreted via bile, although a small amount of the administered dose is excreted by the kidneys. Buprenorphine is metabolized via N-dealkylation to norbuprenorphine and via glucuronidation. N-dealkylation is mediated by the cytochrome P450 enzyme system. Norbuprenorphine is an active metabolite that is further subjected to glucuronidation. Naloxone undergoes glucuronidation to naloxone-3-glucuronide, as well as N-dealkylation and reduction of the 6-oxo group. Buprenorphine has an average serum half-life of 37 hours. For naloxone, the average serum half-life is 1 hour. Clinical characteristics. Indications. Treatment of opioid dependence in combination with medical, social, and psychological support provided by specialists. Contraindications.
Interaction with other medicinal products and other types of interactions. Buprexon-ZN should not be taken together with alcoholic beverages or medicinal products containing alcohol. Alcohol enhances the sedative effect of buprenorphine. The drug should be used with caution when administered concurrently with:
No significant interaction has been observed so far with cocaine, the substance most commonly used by dependent patients in combination with opioids. Suspected interactions between intravenous administration of buprenorphine and phenprocoumon leading to purpura have been reported. Buprenorphine should be used with caution when administered concurrently with serotonergic medicinal products such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as this increases the risk of developing serotonin syndrome – a potentially life-threatening condition (see section "Special precautions"). Interaction of buprenorphine with ketoconazole (a strong CYP3A4 inhibitor) leads to an increase in Cmax and AUC of buprenorphine (approximately by 70% and 50%, respectively) and to a lesser extent in its metabolite norbuprenorphine. In this case, the patient's condition should be carefully monitored, and the dose of Buprexon-ZN may need to be reduced when co-administered with potent CYP3A4 inhibitors (e.g., protease inhibitors or azole antifungals). Further dose titration of buprenorphine should be based on clinical indications. The use of other CYP3A4 inhibitors (such as gestodene, troleandomycin, HIV protease inhibitors, ritonavir, indinavir, and saquinavir) may also increase buprenorphine concentration; therefore, at the beginning of treatment, the feasibility of reducing the buprenorphine dose should be considered. CYP3A4 inducers: concurrent use of CYP3A4 inducers with buprenorphine may reduce plasma buprenorphine concentrations. When used concurrently with enzyme inducers (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin), careful monitoring of patients receiving buprenorphine treatment is recommended. The use of these drugs may enhance buprenorphine metabolism; therefore, the buprenorphine dose should be adjusted in patients who report reduced efficacy of buprenorphine or increased craving for drugs. Achieving adequate analgesia may be complicated by the administration of an opioid agonist to patients receiving buprenorphine/naloxone, thus posing a risk of overdose, especially when attempting to overcome the adverse agonistic effects of buprenorphine or when buprenorphine plasma concentration decreases. Naltrexone and nalmefene – opioid receptor antagonists – block the pharmacological effects of buprenorphine. Concurrent use of Buprexon-ZN with naltrexone or nalmefene should be avoided due to the potentially dangerous interaction that may provoke a sudden onset of prolonged and intense opioid withdrawal syndrome. Special precautions. Incorrect use, abuse, and drug-dependent behavior Buprenorphine has the potential for incorrect use or abuse, similar to other opioids, whether legal or illegal. Some risks of incorrect use and abuse include overdose, transmission of viral or localized systemic infections transmitted through blood when injecting, respiratory depression, and liver damage. Abuse of buprenorphine by someone other than the intended patient creates an additional risk for new drug-dependent individuals who use buprenorphine as the primary drug of abuse, which may occur if the medicinal product is distributed for illegal use directly by the intended patient or if it is not protected from theft. Suboptimal therapy with buprenorphine/naloxone may lead to incorrect use by the patient, resulting in overdose or relapse. A patient receiving an insufficient dose of buprenorphine/naloxone may continue to respond to uncontrolled withdrawal symptoms by self-medicating with opioids, consuming alcohol, or taking other sedative and hypnotic drugs, especially benzodiazepines. To minimize the risk of incorrect use, abuse, and drug-dependent behavior, appropriate preventive measures should be taken when prescribing and dispensing buprenorphine, such as avoiding prescribing multiple doses at the beginning of treatment and conducting control visits with clinical monitoring appropriate to the patient's needs. The combination of buprenorphine with naloxone in the drug is intended to prevent incorrect use and abuse of buprenorphine. Incorrect intravenous or intranasal use of the drug is expected to be less likely than with buprenorphine alone, as naloxone in this medicinal product may accelerate withdrawal in individuals dependent on heroin, methadone, or other opioid agonists. Sleep-disordered breathing Opioids may cause sleep-disordered breathing, including central sleep apnea (CSA) and sleep hypoxemia. The use of opioids increases the risk of CSA and is dose-dependent. For patients with CSA, the possibility of reducing the total opioid dose should be considered. Dependence Buprenorphine is a partial agonist of opioid receptors; its continuous use leads to opioid-type dependence. Animal studies and available clinical experience confirm that buprenorphine can also cause drug dependence, although to a lesser extent than morphine. Therefore, during treatment, it is very important to consider all factors, maintain control, and adhere to prescribed doses. Abrupt discontinuation of treatment is not recommended, as it may lead to withdrawal syndrome, which may occur later. Respiratory depression Several fatal cases due to respiratory depression have been reported, especially when buprenorphine is used in combination with benzodiazepines or when it is used improperly. Fatal cases associated with the concurrent use of buprenorphine and other depressants such as alcohol or other opioids have also been reported. If buprenorphine is prescribed to certain individuals who are not opioid-dependent and do not have tolerance to opioid effects, potentially fatal respiratory depression may occur. This drug should be used with caution in patients with asthma or respiratory insufficiency (e.g., chronic obstructive pulmonary disease, cor pulmonale, reduced respiratory reserve, hypoxia, hypercapnia, existing respiratory depression, kyphoscoliosis (spinal curvature leading to potential dyspnea)). Buprenorphine/naloxone may lead to serious (including fatal) respiratory depression in children and individuals without drug dependence in case of accidental or intentional ingestion. Patients should store the tablet blister pack in a safe place, never open the blister pack in advance, keep the tablets out of reach of children and other family members, and not take this medicinal product in the presence of children. In case of accidental ingestion or suspected ingestion of the drug, immediate medical attention should be sought. Serotonin syndrome Concurrent use of buprenorphine and other serotonergic agents such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants may lead to serotonin syndrome – a potentially life-threatening condition (see section "Interaction with other medicinal products and other types of interactions"). If concomitant therapy with other serotonergic agents is clinically justified, careful monitoring of the patient is recommended, especially at the beginning of treatment and during dose escalation. Symptoms of serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, the possibility of reducing the dose or discontinuing therapy should be considered depending on the severity of symptoms. Hepatitis, hepatic reactions Buprenorphine metabolism may be altered in patients with impaired liver function. Cases of acute liver injury have been reported. A spectrum of abnormalities has been identified, ranging from transient asymptomatic elevation of liver transaminases to liver failure. In many cases, the presence of liver enzyme abnormalities, hepatitis B or C virus infection, concurrent use of other potentially hepatotoxic drugs, and chronic intravenous drug use could have been the cause or an additional factor. These underlying factors should be considered before prescribing buprenorphine and throughout treatment. If a hepatic reaction of unknown origin is suspected, the role of buprenorphine in liver necrosis or jaundice should be evaluated, and treatment should be discontinued as soon as the patient's clinical condition allows. All patients should have regular liver function tests. Central nervous system depression This drug may cause drowsiness, which is enhanced by other centrally acting agents such as alcohol, benzodiazepines, tranquilizers, sedatives, and hypnotics. Risk associated with concurrent use of sedative medicinal products such as benzodiazepines or medicinal products with benzodiazepine-like effects Concurrent use of buprenorphine/naloxone and sedative drugs such as benzodiazepines or medicinal products with benzodiazepine-like effects may lead to sedation, respiratory depression, coma, and fatal outcome. Despite the indicated risks, concurrent prescription of these sedative medicinal products should be maintained for patients for whom alternative treatment options are not possible. If a decision is made to use buprenorphine/naloxone concurrently with sedative drugs, the lowest effective doses should be used, and the duration of treatment should be as short as possible. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, patients and caregivers should be informed about these symptoms (see section "Interaction with other medicinal products and other types of interactions"). Development of opioid withdrawal syndrome When initiating treatment with buprenorphine/naloxone, the physician should be aware of the partial agonist profile of buprenorphine and that it may accelerate withdrawal in patients with opioid dependence, especially if administered less than 6 hours after the last dose of heroin or short-acting opioids or less than 24 hours after the last dose of methadone. Patients should be under close supervision during the transition from buprenorphine or methadone to buprenorphine/naloxone, as withdrawal symptoms have been reported. To avoid accelerating withdrawal syndrome, buprenorphine/naloxone treatment should be initiated when clear objective signs of withdrawal are present (see section "Method of administration and dosage"). Withdrawal symptoms may also be related to suboptimal dosing. Hepatic insufficiency The effect of hepatic insufficiency on the pharmacokinetics of buprenorphine and naloxone was evaluated based on post-marketing surveillance data. Both buprenorphine and naloxone are extensively metabolized in the liver, and plasma levels of buprenorphine and naloxone were found to be higher in patients with moderate and severe hepatic insufficiency compared to healthy subjects. Patients should be monitored for signs and symptoms of accelerated opioid withdrawal, toxicity, or overdose caused by elevated levels of naloxone and/or buprenorphine. Baseline liver function tests and documentation of viral hepatitis status are recommended before starting therapy. Patients with positive viral hepatitis test results who are taking concomitant medications and/or have impaired liver function are at higher risk of liver injury. Regular monitoring of liver function is recommended in such patients. Buprenorphine/naloxone should be used with caution in patients with moderate hepatic insufficiency. Renal insufficiency Since 30% of the administered dose is excreted by the kidneys, renal elimination may take longer. Buprenorphine metabolites accumulate in patients with renal insufficiency. The drug should be prescribed with caution to patients with severe renal insufficiency (creatinine clearance < 30 ml/min) (see section "Method of administration and dosage"). Use in children aged 16 to 18 years Due to the lack of data in children aged 16 to 18 years, the drug should be used with particular caution. QT interval prolongation Careful studies have demonstrated QT interval prolongation (less than or equal to 15 ms). This QT-prolonging effect does not appear to be mediated by hERG potassium channels. Based on these two findings, buprenorphine is unlikely to cause arrhythmia when used alone in patients without risk factors. The risk of combining buprenorphine with other medicinal products that prolong the QT interval is unknown. These observations should be considered when making clinical decisions about prescribing buprenorphine hydrochloride-containing medicinal products to patients with such risk factors as hypokalemia, bradycardia, recent conversion of atrial fibrillation, congestive heart failure, digoxin therapy, baseline QT interval prolongation, subclinical long QT syndrome, or severe hypomagnesemia. Dental adverse reactions Cases of dental caries, sometimes severe (e.g., tooth fracture or loss), have been reported after the use of sublingual formulations of medicinal products containing buprenorphine. Cases of caries, including deep caries, tooth decay, dental abscesses/infections, tooth erosion, loss of fillings, and in some cases, complete tooth loss, have been reported. Treatment included tooth extraction, root canals, dental surgery, and restorative procedures (e.g., fillings, crowns, implants, dentures). Numerous cases have been reported in individuals with no prior history of dental problems. Patients should be referred to dentists and advised to undergo regular dental examinations during buprenorphine hydrochloride treatment. It is necessary to educate patients to seek dental care and methods to support or improve oral health during treatment with medicinal products containing sublingual buprenorphine formulations. Patients should wait at least 1 hour after taking buprenorphine hydrochloride before brushing their teeth. CYP3A4 inhibitors Medicinal products that inhibit the CYP3A4 enzyme may lead to increased buprenorphine concentrations. For patients already taking CYP3A4 inhibitors, a reduction in the buprenorphine/naloxone dose may be necessary. Class effects Opioids may cause orthostatic hypotension in ambulatory patients. Opioids may increase cerebrospinal fluid pressure, which may cause seizures; therefore, opioids should be used with caution in patients with head injuries, intracranial lesions, under other conditions where intracranial pressure may be elevated, or in patients with a history of seizures. Opioids should be used with caution in patients with arterial hypotension, prostate hypertrophy, or urethral stenosis. Buprenorphine is capable of alleviating pain symptoms in certain pathologies. Opioid-induced miosis, changes in level of consciousness, or changes in pain perception as a symptom of disease may interfere with patient assessment or mask the diagnosis or clinical course of a concomitant disease. Opioids should be used with caution in patients with myxedema, hypothyroidism, or adrenal cortex insufficiency (e.g., Addison's disease). It has been shown that opioids increase intrahepatic ductal pressure; therefore, they should be used with caution in patients with biliary tract dysfunction. Opioids should be prescribed with caution to elderly or debilitated patients. Based on experience with morphine use, concurrent use of monoamine oxidase inhibitors (MAOIs) may lead to enhanced opioid effects (see section "Interaction with other medicinal products and other types of interactions"). Athletes should be informed that buprenorphine is included in the list of doping substances (stimulants). Excipients If a patient has established intolerance to certain sugars, they should consult a physician before taking this medicinal product. Aspartame is a derivative of phenylalanine, which poses a risk to patients with phenylketonuria. Use during pregnancy or breastfeeding. Pregnancy There are no adequate data on the use of Buprexon-ZN in pregnant women. The potential risk to humans is unknown. At the end of pregnancy, buprenorphine may cause respiratory depression in the newborn even after a short period of administration. Prolonged use of buprenorphine during the last three months of pregnancy may cause withdrawal syndrome in the newborn (e.g., arterial hypertension, neonatal tremors, neonatal agitation, myoclonus, or seizures). The syndrome usually manifests within several hours to several days after birth. Due to the long half-life of buprenorphine, newborns require monitoring for several days to prevent respiratory depression or withdrawal syndrome in newborns. The use of the drug during pregnancy should be evaluated by a physician. Buprexon-ZN should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Breastfeeding It is unknown whether naloxone, buprenorphine, and its metabolites are present in breast milk; therefore, breastfeeding should be discontinued during treatment. Fertility Animal studies have demonstrated reduced fertility in females when high doses were used. Doses more than 2.4 times higher than the maximum human doses had no negative effect on fertility in female test animals. Ability to influence reaction speed when driving or operating machinery. Medicinal products containing buprenorphine and naloxone may cause drowsiness, dizziness, and cognitive disturbances, especially when taken concurrently with alcohol or CNS depressants. Patients should be aware of the possibility of the drug affecting reaction speed when driving or operating machinery. Method of administration and dosage. Buprexon-ZN is prescribed by a physician experienced in the treatment of opioid dependence, as a total therapeutic dose for opioid-dependent patients, only after a medical examination and based on the recommendation of a treatment center, individually, depending on the patient's condition. The drug is administered sublingually: the tablet should be placed under the tongue and allowed to dissolve completely. The patient must be warned that sublingual dissolution of the tablet is the only safe route of administration for the buprenorphine and naloxone combination. This medicinal product is intended only for the treatment of opioid dependence. Treatment should be prescribed by a physician who ensures the proper use of the medicinal product by dependent patients. Preventive measures to be taken before therapy Before starting treatment, the type of opioid dependence (i.e., long-acting or short-acting opioids), the time since the last opioid use, and the degree of opioid dependence should be considered. To avoid accelerating withdrawal, treatment with the drug should be initiated when clear objective signs of withdrawal are present.
The risk of misuse and the dose adaptation process require prescribing the drug for short periods at the beginning of therapy and, if possible, controlled administration, which also promotes adherence to the treatment regimen. Discontinuation of the drug may be accompanied by withdrawal syndrome, sometimes delayed. Initial therapy The recommended initial dose for adults and children aged 16 years is 2 mg/0.5 mg of the drug sublingually. An additional 2 mg/0.5 mg of the drug may be prescribed on the first day of treatment depending on the specific clinical situation. For patients without clinical signs of opioid withdrawal syndrome, the first dose of Buprexon-ZN may be prescribed no earlier than 6 hours after the last use of narcotic substances. For patients receiving methadone, the methadone dose should be reduced to a maximum of 30 mg/day before starting Buprexon-ZN therapy. The long half-life of methadone should be considered when starting Buprexon-ZN therapy. The first doses should be taken only when withdrawal signs appear, but no less than 24 hours after the last methadone dose by the patient. Buprenorphine may accelerate withdrawal symptoms in patients dependent on methadone. Maintenance therapy The recommended daily dose of the fixed combination should not exceed 16 mg (buprenorphine content). Permissible daily dose ranges are determined by the physician individually, depending on the patient's somatic condition, severity, and clinical course of the disease (recommended doses are from 4 to 16 mg). During further treatment, the Buprexon-ZN dose must be adjusted (increased or decreased) to the optimal therapeutic level that ensures effective control of the main clinical manifestations of opioid withdrawal syndrome. The daily dose of the fixed combination should be increased or decreased gradually, changing it by 2–4 mg per day (depending on the patient's individual condition). Dose reduction and discontinuation of therapy The decision to discontinue Buprexon-ZN after maintenance therapy or short-term stabilization of the patient's condition should be justified as part of a comprehensive treatment plan for the drug-dependent patient. Gradual or abrupt discontinuation of the fixed combination is permitted. According to the results of some uncontrolled clinical studies of drugs similar to Buprexon-ZN, gradual dose reduction should be preferred at the end of treatment. After treatment, patients require monitoring due to the risk of relapse. Special patient groups Elderly patients The safety and efficacy of the buprenorphine/naloxone combination for patients aged 65 years and older have not been established. Patients with hepatic insufficiency Patients who are carriers of hepatitis virus and/or have liver dysfunction are at risk of accelerated liver damage. Regular monitoring of liver function is recommended. The effect of hepatic insufficiency on the pharmacokinetics of buprenorphine and naloxone is unknown. Since the active substances are extensively metabolized, plasma levels are expected to be higher in patients with moderate and severe hepatic insufficiency. Pharmacokinetics may be altered in patients with impaired liver function; lower initial doses and careful dose titration are recommended for patients with mild and moderate hepatic insufficiency. Patients with renal insufficiency Dosing should be prescribed with caution for patients with severe renal insufficiency (creatinine clearance < 30 ml/min). Children. Buprexon-ZN, like similar combination medicinal products containing buprenorphine and naloxone, is not recommended for the treatment of patients under 16 years of age due to insufficient clinical data on safety and efficacy of use. Overdose. Symptoms. With sublingual administration of the fixed combination, overdose is unlikely. In case of accidental oral overdose, possible symptoms include nausea, vomiting and/or speech disturbances, drowsiness, amblyopia, miosis, arterial hypotension. Respiratory depression due to CNS depression is the main symptom requiring intervention in case of overdose, as it may lead to respiratory arrest and fatal outcome. Treatment. First aid includes immediate gastric lavage. General resuscitation measures should be taken, including careful monitoring of respiratory and cardiac activity. Symptomatic treatment of respiratory depression and standard intensive care measures should be performed. Airway patency and assisted or controlled ventilation should be ensured. The patient should be transferred to an environment where full resuscitation facilities are available. If the patient vomits, measures should be taken to prevent aspiration of vomitus. The use of an opioid antagonist (i.e., naloxone) is recommended, despite the moderate effect it may have in reversing respiratory symptoms caused by buprenorphine compared to its effect on full opioid agonists. It should be considered that naloxone is eliminated from the body faster than buprenorphine; therefore, repeated naloxone infusions are necessary due to the risk of recurrence of overdose symptoms. Initial naloxone doses may reach 2 mg (not more than 10 mg) and should be repeated every 2–3 minutes until a satisfactory effect is achieved. If necessary, use respiratory analeptics. Adverse reactions. Reports of adverse reactions were mostly related to withdrawal syndrome (abdominal pain, diarrhea, muscle pain, anxiety, increased sweating). The adverse effect of Buprexon-ZN analogs is considered dose-dependent. Typical adverse reactions: Nervous system disorders: headache, migraine, dizziness, arterial hypertension, paresthesia, drowsiness, amnesia, seizure, hyperkinesia, speech disorder, tremor, hepatic encephalopathy, syncope. Cardiovascular system disorders: arterial hypertension, vasodilation, angina pectoris, bradycardia, myocardial infarction, palpitations, tachycardia, arterial hypotension, palpitation, orthostatic hypotension. Respiratory system disorders: cough, respiratory depression, dyspnea, yawning, asthma, bronchospasm. Gastrointestinal disorders: constipation, nausea, abdominal pain, diarrhea, dyspepsia, flatulence, vomiting, mouth ulcers, discoloration of the tongue, dental caries (including caries, tooth fracture, and tooth loss). Eye disorders: amblyopia, lacrimal apparatus disorders, conjunctivitis, miosis. Infections and infestations: influenza, pharyngitis, rhinitis, urinary tract infections, vaginal infections. Blood and lymphatic system disorders: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocytopenia. Immune system disorders: hypersensitivity (e.g., rash, urticaria, pruritus, bronchospasm), angioneurotic edema, anaphylactic shock. Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hyperlipidemia, hypoglycemia. Psychiatric disorders: insomnia, anxiety, depression, decreased libido, restlessness, pathological thinking, abnormal dreams, agitation, apathy, depersonalization, drug dependence, euphoria, hostility, hallucinations. Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, rash, urticaria, acne, alopecia, exfoliative dermatitis, dry skin, angioderma. Musculoskeletal and connective tissue disorders: back pain, arthralgia, muscle spasms, muscle pain, arthritis. Ear and labyrinth disorders: vertigo. Kidney and urinary system disorders: abnormal urine findings, albuminuria, urinary disorders, hematuria, nephrolithiasis, urinary retention. Reproductive system disorders: erectile dysfunction, amenorrhea, ejaculation disorders, menorrhagia, metrorrhagia. General disorders: drug withdrawal syndrome, asthenia, chest pain, chills, fever, malaise, pain, peripheral edema, hypothermia, increased sweating. Investigations: abnormal liver function tests, decreased body weight, elevated blood creatinine. Hepatobiliary disorders: elevated liver transaminase levels and jaundice, usually with a favorable clinical course, liver necrosis, hepatitis, hepatorenal syndrome. Injuries, poisonings, and procedural complications: injury, heat stroke. In cases of drug abuse with intravenous administration, local reactions have been recorded, sometimes septic (abscess, cellulitis), and potentially serious acute hepatitis and other infectious diseases such as pneumonia, endocarditis. In patients with pronounced drug dependence, initial administration of buprenorphine/naloxone may promote the development of drug withdrawal syndrome. Neonatal withdrawal syndrome has been observed in newborns when women received buprenorphine during pregnancy. The nature of the syndrome may vary depending on the type of narcotic drugs used. Unconsciousness was not detected. Reporting of adverse reactions. Reporting of adverse reactions after drug registration is of great importance. This allows monitoring of the benefit-risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua. Shelf life. 3 years. Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Store out of reach of children. Packaging. 10 tablets per blister, 1 or 5 blisters per box. Prescription category. Prescription only. Manufacturer. Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu". Manufacturer's location and address of business activity. Ukraine, 61002, Kharkiv region, Kharkiv, Kuikivska Street, 41.

INSTRUCTION for medical use of the medicinal product BUPREXON-ZN (BUPREXON-ZN) Composition: buprenorphine, naloxone; active substances: 1 tablet contains buprenorphine hydrochloride equivalent to buprenorphine 2.0 mg and naloxone hydrochloride dihydrate equivalent to naloxone 0.5 mg, or buprenorphine hydrochloride equivalent to buprenorphine 8.0 mg and naloxone hydrochloride dihydrate equivalent to naloxone 2.0 mg; excipients: celactose 80 (a mixture of lactose monohydrate and powdered cellulose (75:25)), corn starch, crospovidone, anhydrous citric acid, mannite (E 421), aspartame (E 951), magnesium stearate. Medicinal form. Sublingual tablets. Basic physicochemical properties: white or almost white tablets with a flat surface and a bevel. Pharmacotherapeutic group. Medicinal products for opioid dependence treatment. Buprenorphine, combinations. ATC code N07BC51. Pharmacological properties. Pharmacodynamics. Buprenorphine hydrochloride is a centrally acting analgesic. It stimulates opioid κ-receptors, which explains its high analgesic activity, and simultaneously blocks μ-receptors responsible for the development of euphoria. In terms of analgesic effect, buprenorphine is 2–2.5 times weaker than morphine. Unlike other centrally acting narcotic analgesics, the drug does not cause euphoria, thus being less dangerous as a substance to which dependence may develop. Naloxone blocks the effects of opioids such as morphine, codeine, and heroin. If buprenorphine and naloxone are administered by injection, naloxone blocks the effects of buprenorphine, leading to the development of withdrawal symptoms in individuals with narcotic dependence. When administered sublingually in usual doses, the effect of naloxone is minimal due to its almost complete metabolism during first-pass metabolism. Pharmacokinetics. After sublingual administration, buprenorphine absorption occurs very slowly, with maximum plasma levels observed after 90 minutes. After oral administration, the presence of naloxone in plasma is barely detectable. Buprenorphine and naloxone are evenly distributed in body tissues and penetrate the blood-brain barrier. Buprenorphine is approximately 96% bound to blood proteins, primarily to α- and β-globulins. Naloxone is approximately 45% bound to blood proteins, primarily to albumins. The active components of the fixed combination are metabolized in the liver and are primarily excreted via bile, although a small amount of the administered dose is excreted by the kidneys. Buprenorphine is metabolized via N-dealkylation to norbuprenorphine and via glucuronidation. N-dealkylation is mediated by the cytochrome P450 enzyme system. Norbuprenorphine is an active metabolite that is further subjected to glucuronidation. Naloxone undergoes glucuronidation to naloxone-3-glucuronide, as well as N-dealkylation and reduction of the 6-oxo group. Buprenorphine has an average serum half-life of 37 hours. For naloxone, the average serum half-life is 1 hour. Clinical characteristics. Indications. Treatment of opioid dependence in combination with medical, social, and psychological support provided by specialists. Contraindications.

Hypersensitivity to buprenorphine, naloxone, or to any other component of the fixed combination.
Severe respiratory insufficiency.
Severe hepatic insufficiency.
Acute alcohol intoxication or alcohol delirium.
Concurrent administration of opioid antagonists (naltrexone, nalmefene) for the treatment of alcohol or opioid dependence.

Interaction with other medicinal products and other types of interactions. Buprexon-ZN should not be taken together with alcoholic beverages or medicinal products containing alcohol. Alcohol enhances the sedative effect of buprenorphine. The drug should be used with caution when administered concurrently with:

benzodiazepines, as this combination may enhance central respiratory depression, with a risk of fatal outcome; it is necessary to individually titrate the dose and carefully monitor the patient's condition; the risk of drug abuse should be considered;
other central nervous system (CNS) depressants; other opioid derivatives (methadone, analgesics, and antitussive agents); certain antidepressants, H1-receptor antagonists, barbiturates, other anxiolytic agents, neuroleptics, clonidine, and related substances; these combinations enhance CNS depression;
gabapentinoids (gabapentin and pregabalin), as this may lead to respiratory depression, hypotension, profound sedation, coma, or death;
monoamine oxidase inhibitors (MAOIs); as experience with morphine use indicates a possible enhancement of opioid effects.

No significant interaction has been observed so far with cocaine, the substance most commonly used by dependent patients in combination with opioids. Suspected interactions between intravenous administration of buprenorphine and phenprocoumon leading to purpura have been reported. Buprenorphine should be used with caution when administered concurrently with serotonergic medicinal products such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as this increases the risk of developing serotonin syndrome – a potentially life-threatening condition (see section "Special precautions"). Interaction of buprenorphine with ketoconazole (a strong CYP3A4 inhibitor) leads to an increase in Cmax and AUC of buprenorphine (approximately by 70% and 50%, respectively) and to a lesser extent in its metabolite norbuprenorphine. In this case, the patient's condition should be carefully monitored, and the dose of Buprexon-ZN may need to be reduced when co-administered with potent CYP3A4 inhibitors (e.g., protease inhibitors or azole antifungals). Further dose titration of buprenorphine should be based on clinical indications. The use of other CYP3A4 inhibitors (such as gestodene, troleandomycin, HIV protease inhibitors, ritonavir, indinavir, and saquinavir) may also increase buprenorphine concentration; therefore, at the beginning of treatment, the feasibility of reducing the buprenorphine dose should be considered. CYP3A4 inducers: concurrent use of CYP3A4 inducers with buprenorphine may reduce plasma buprenorphine concentrations. When used concurrently with enzyme inducers (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin), careful monitoring of patients receiving buprenorphine treatment is recommended. The use of these drugs may enhance buprenorphine metabolism; therefore, the buprenorphine dose should be adjusted in patients who report reduced efficacy of buprenorphine or increased craving for drugs. Achieving adequate analgesia may be complicated by the administration of an opioid agonist to patients receiving buprenorphine/naloxone, thus posing a risk of overdose, especially when attempting to overcome the adverse agonistic effects of buprenorphine or when buprenorphine plasma concentration decreases. Naltrexone and nalmefene – opioid receptor antagonists – block the pharmacological effects of buprenorphine. Concurrent use of Buprexon-ZN with naltrexone or nalmefene should be avoided due to the potentially dangerous interaction that may provoke a sudden onset of prolonged and intense opioid withdrawal syndrome. Special precautions. Incorrect use, abuse, and drug-dependent behavior Buprenorphine has the potential for incorrect use or abuse, similar to other opioids, whether legal or illegal. Some risks of incorrect use and abuse include overdose, transmission of viral or localized systemic infections transmitted through blood when injecting, respiratory depression, and liver damage. Abuse of buprenorphine by someone other than the intended patient creates an additional risk for new drug-dependent individuals who use buprenorphine as the primary drug of abuse, which may occur if the medicinal product is distributed for illegal use directly by the intended patient or if it is not protected from theft. Suboptimal therapy with buprenorphine/naloxone may lead to incorrect use by the patient, resulting in overdose or relapse. A patient receiving an insufficient dose of buprenorphine/naloxone may continue to respond to uncontrolled withdrawal symptoms by self-medicating with opioids, consuming alcohol, or taking other sedative and hypnotic drugs, especially benzodiazepines. To minimize the risk of incorrect use, abuse, and drug-dependent behavior, appropriate preventive measures should be taken when prescribing and dispensing buprenorphine, such as avoiding prescribing multiple doses at the beginning of treatment and conducting control visits with clinical monitoring appropriate to the patient's needs. The combination of buprenorphine with naloxone in the drug is intended to prevent incorrect use and abuse of buprenorphine. Incorrect intravenous or intranasal use of the drug is expected to be less likely than with buprenorphine alone, as naloxone in this medicinal product may accelerate withdrawal in individuals dependent on heroin, methadone, or other opioid agonists. Sleep-disordered breathing Opioids may cause sleep-disordered breathing, including central sleep apnea (CSA) and sleep hypoxemia. The use of opioids increases the risk of CSA and is dose-dependent. For patients with CSA, the possibility of reducing the total opioid dose should be considered. Dependence Buprenorphine is a partial agonist of opioid receptors; its continuous use leads to opioid-type dependence. Animal studies and available clinical experience confirm that buprenorphine can also cause drug dependence, although to a lesser extent than morphine. Therefore, during treatment, it is very important to consider all factors, maintain control, and adhere to prescribed doses. Abrupt discontinuation of treatment is not recommended, as it may lead to withdrawal syndrome, which may occur later. Respiratory depression Several fatal cases due to respiratory depression have been reported, especially when buprenorphine is used in combination with benzodiazepines or when it is used improperly. Fatal cases associated with the concurrent use of buprenorphine and other depressants such as alcohol or other opioids have also been reported. If buprenorphine is prescribed to certain individuals who are not opioid-dependent and do not have tolerance to opioid effects, potentially fatal respiratory depression may occur. This drug should be used with caution in patients with asthma or respiratory insufficiency (e.g., chronic obstructive pulmonary disease, cor pulmonale, reduced respiratory reserve, hypoxia, hypercapnia, existing respiratory depression, kyphoscoliosis (spinal curvature leading to potential dyspnea)). Buprenorphine/naloxone may lead to serious (including fatal) respiratory depression in children and individuals without drug dependence in case of accidental or intentional ingestion. Patients should store the tablet blister pack in a safe place, never open the blister pack in advance, keep the tablets out of reach of children and other family members, and not take this medicinal product in the presence of children. In case of accidental ingestion or suspected ingestion of the drug, immediate medical attention should be sought. Serotonin syndrome Concurrent use of buprenorphine and other serotonergic agents such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants may lead to serotonin syndrome – a potentially life-threatening condition (see section "Interaction with other medicinal products and other types of interactions"). If concomitant therapy with other serotonergic agents is clinically justified, careful monitoring of the patient is recommended, especially at the beginning of treatment and during dose escalation. Symptoms of serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, the possibility of reducing the dose or discontinuing therapy should be considered depending on the severity of symptoms. Hepatitis, hepatic reactions Buprenorphine metabolism may be altered in patients with impaired liver function. Cases of acute liver injury have been reported. A spectrum of abnormalities has been identified, ranging from transient asymptomatic elevation of liver transaminases to liver failure. In many cases, the presence of liver enzyme abnormalities, hepatitis B or C virus infection, concurrent use of other potentially hepatotoxic drugs, and chronic intravenous drug use could have been the cause or an additional factor. These underlying factors should be considered before prescribing buprenorphine and throughout treatment. If a hepatic reaction of unknown origin is suspected, the role of buprenorphine in liver necrosis or jaundice should be evaluated, and treatment should be discontinued as soon as the patient's clinical condition allows. All patients should have regular liver function tests. Central nervous system depression This drug may cause drowsiness, which is enhanced by other centrally acting agents such as alcohol, benzodiazepines, tranquilizers, sedatives, and hypnotics. Risk associated with concurrent use of sedative medicinal products such as benzodiazepines or medicinal products with benzodiazepine-like effects Concurrent use of buprenorphine/naloxone and sedative drugs such as benzodiazepines or medicinal products with benzodiazepine-like effects may lead to sedation, respiratory depression, coma, and fatal outcome. Despite the indicated risks, concurrent prescription of these sedative medicinal products should be maintained for patients for whom alternative treatment options are not possible. If a decision is made to use buprenorphine/naloxone concurrently with sedative drugs, the lowest effective doses should be used, and the duration of treatment should be as short as possible. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, patients and caregivers should be informed about these symptoms (see section "Interaction with other medicinal products and other types of interactions"). Development of opioid withdrawal syndrome When initiating treatment with buprenorphine/naloxone, the physician should be aware of the partial agonist profile of buprenorphine and that it may accelerate withdrawal in patients with opioid dependence, especially if administered less than 6 hours after the last dose of heroin or short-acting opioids or less than 24 hours after the last dose of methadone. Patients should be under close supervision during the transition from buprenorphine or methadone to buprenorphine/naloxone, as withdrawal symptoms have been reported. To avoid accelerating withdrawal syndrome, buprenorphine/naloxone treatment should be initiated when clear objective signs of withdrawal are present (see section "Method of administration and dosage"). Withdrawal symptoms may also be related to suboptimal dosing. Hepatic insufficiency The effect of hepatic insufficiency on the pharmacokinetics of buprenorphine and naloxone was evaluated based on post-marketing surveillance data. Both buprenorphine and naloxone are extensively metabolized in the liver, and plasma levels of buprenorphine and naloxone were found to be higher in patients with moderate and severe hepatic insufficiency compared to healthy subjects. Patients should be monitored for signs and symptoms of accelerated opioid withdrawal, toxicity, or overdose caused by elevated levels of naloxone and/or buprenorphine. Baseline liver function tests and documentation of viral hepatitis status are recommended before starting therapy. Patients with positive viral hepatitis test results who are taking concomitant medications and/or have impaired liver function are at higher risk of liver injury. Regular monitoring of liver function is recommended in such patients. Buprenorphine/naloxone should be used with caution in patients with moderate hepatic insufficiency. Renal insufficiency Since 30% of the administered dose is excreted by the kidneys, renal elimination may take longer. Buprenorphine metabolites accumulate in patients with renal insufficiency. The drug should be prescribed with caution to patients with severe renal insufficiency (creatinine clearance < 30 ml/min) (see section "Method of administration and dosage"). Use in children aged 16 to 18 years Due to the lack of data in children aged 16 to 18 years, the drug should be used with particular caution. QT interval prolongation Careful studies have demonstrated QT interval prolongation (less than or equal to 15 ms). This QT-prolonging effect does not appear to be mediated by hERG potassium channels. Based on these two findings, buprenorphine is unlikely to cause arrhythmia when used alone in patients without risk factors. The risk of combining buprenorphine with other medicinal products that prolong the QT interval is unknown. These observations should be considered when making clinical decisions about prescribing buprenorphine hydrochloride-containing medicinal products to patients with such risk factors as hypokalemia, bradycardia, recent conversion of atrial fibrillation, congestive heart failure, digoxin therapy, baseline QT interval prolongation, subclinical long QT syndrome, or severe hypomagnesemia. Dental adverse reactions Cases of dental caries, sometimes severe (e.g., tooth fracture or loss), have been reported after the use of sublingual formulations of medicinal products containing buprenorphine. Cases of caries, including deep caries, tooth decay, dental abscesses/infections, tooth erosion, loss of fillings, and in some cases, complete tooth loss, have been reported. Treatment included tooth extraction, root canals, dental surgery, and restorative procedures (e.g., fillings, crowns, implants, dentures). Numerous cases have been reported in individuals with no prior history of dental problems. Patients should be referred to dentists and advised to undergo regular dental examinations during buprenorphine hydrochloride treatment. It is necessary to educate patients to seek dental care and methods to support or improve oral health during treatment with medicinal products containing sublingual buprenorphine formulations. Patients should wait at least 1 hour after taking buprenorphine hydrochloride before brushing their teeth. CYP3A4 inhibitors Medicinal products that inhibit the CYP3A4 enzyme may lead to increased buprenorphine concentrations. For patients already taking CYP3A4 inhibitors, a reduction in the buprenorphine/naloxone dose may be necessary. Class effects Opioids may cause orthostatic hypotension in ambulatory patients. Opioids may increase cerebrospinal fluid pressure, which may cause seizures; therefore, opioids should be used with caution in patients with head injuries, intracranial lesions, under other conditions where intracranial pressure may be elevated, or in patients with a history of seizures. Opioids should be used with caution in patients with arterial hypotension, prostate hypertrophy, or urethral stenosis. Buprenorphine is capable of alleviating pain symptoms in certain pathologies. Opioid-induced miosis, changes in level of consciousness, or changes in pain perception as a symptom of disease may interfere with patient assessment or mask the diagnosis or clinical course of a concomitant disease. Opioids should be used with caution in patients with myxedema, hypothyroidism, or adrenal cortex insufficiency (e.g., Addison's disease). It has been shown that opioids increase intrahepatic ductal pressure; therefore, they should be used with caution in patients with biliary tract dysfunction. Opioids should be prescribed with caution to elderly or debilitated patients. Based on experience with morphine use, concurrent use of monoamine oxidase inhibitors (MAOIs) may lead to enhanced opioid effects (see section "Interaction with other medicinal products and other types of interactions"). Athletes should be informed that buprenorphine is included in the list of doping substances (stimulants). Excipients If a patient has established intolerance to certain sugars, they should consult a physician before taking this medicinal product. Aspartame is a derivative of phenylalanine, which poses a risk to patients with phenylketonuria. Use during pregnancy or breastfeeding. Pregnancy There are no adequate data on the use of Buprexon-ZN in pregnant women. The potential risk to humans is unknown. At the end of pregnancy, buprenorphine may cause respiratory depression in the newborn even after a short period of administration. Prolonged use of buprenorphine during the last three months of pregnancy may cause withdrawal syndrome in the newborn (e.g., arterial hypertension, neonatal tremors, neonatal agitation, myoclonus, or seizures). The syndrome usually manifests within several hours to several days after birth. Due to the long half-life of buprenorphine, newborns require monitoring for several days to prevent respiratory depression or withdrawal syndrome in newborns. The use of the drug during pregnancy should be evaluated by a physician. Buprexon-ZN should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Breastfeeding It is unknown whether naloxone, buprenorphine, and its metabolites are present in breast milk; therefore, breastfeeding should be discontinued during treatment. Fertility Animal studies have demonstrated reduced fertility in females when high doses were used. Doses more than 2.4 times higher than the maximum human doses had no negative effect on fertility in female test animals. Ability to influence reaction speed when driving or operating machinery. Medicinal products containing buprenorphine and naloxone may cause drowsiness, dizziness, and cognitive disturbances, especially when taken concurrently with alcohol or CNS depressants. Patients should be aware of the possibility of the drug affecting reaction speed when driving or operating machinery. Method of administration and dosage. Buprexon-ZN is prescribed by a physician experienced in the treatment of opioid dependence, as a total therapeutic dose for opioid-dependent patients, only after a medical examination and based on the recommendation of a treatment center, individually, depending on the patient's condition. The drug is administered sublingually: the tablet should be placed under the tongue and allowed to dissolve completely. The patient must be warned that sublingual dissolution of the tablet is the only safe route of administration for the buprenorphine and naloxone combination. This medicinal product is intended only for the treatment of opioid dependence. Treatment should be prescribed by a physician who ensures the proper use of the medicinal product by dependent patients. Preventive measures to be taken before therapy Before starting treatment, the type of opioid dependence (i.e., long-acting or short-acting opioids), the time since the last opioid use, and the degree of opioid dependence should be considered. To avoid accelerating withdrawal, treatment with the drug should be initiated when clear objective signs of withdrawal are present.

For patients dependent on heroin or short-acting opioids, the first dose of buprenorphine/naloxone should be taken when withdrawal signs appear, but no later than 6 hours after the patient last used opioids.
For patients receiving methadone, the methadone dose should be reduced to a maximum of 30 mg/day before starting buprenorphine/naloxone therapy. The long half-life of methadone should be considered at the beginning of buprenorphine/naloxone therapy. The first dose of buprenorphine/naloxone should be taken only when withdrawal signs appear, but no later than 24 hours after the last methadone dose. Buprenorphine may provoke withdrawal symptoms in methadone-dependent patients.

The risk of misuse and the dose adaptation process require prescribing the drug for short periods at the beginning of therapy and, if possible, controlled administration, which also promotes adherence to the treatment regimen. Discontinuation of the drug may be accompanied by withdrawal syndrome, sometimes delayed. Initial therapy The recommended initial dose for adults and children aged 16 years is 2 mg/0.5 mg of the drug sublingually. An additional 2 mg/0.5 mg of the drug may be prescribed on the first day of treatment depending on the specific clinical situation. For patients without clinical signs of opioid withdrawal syndrome, the first dose of Buprexon-ZN may be prescribed no earlier than 6 hours after the last use of narcotic substances. For patients receiving methadone, the methadone dose should be reduced to a maximum of 30 mg/day before starting Buprexon-ZN therapy. The long half-life of methadone should be considered when starting Buprexon-ZN therapy. The first doses should be taken only when withdrawal signs appear, but no less than 24 hours after the last methadone dose by the patient. Buprenorphine may accelerate withdrawal symptoms in patients dependent on methadone. Maintenance therapy The recommended daily dose of the fixed combination should not exceed 16 mg (buprenorphine content). Permissible daily dose ranges are determined by the physician individually, depending on the patient's somatic condition, severity, and clinical course of the disease (recommended doses are from 4 to 16 mg). During further treatment, the Buprexon-ZN dose must be adjusted (increased or decreased) to the optimal therapeutic level that ensures effective control of the main clinical manifestations of opioid withdrawal syndrome. The daily dose of the fixed combination should be increased or decreased gradually, changing it by 2–4 mg per day (depending on the patient's individual condition). Dose reduction and discontinuation of therapy The decision to discontinue Buprexon-ZN after maintenance therapy or short-term stabilization of the patient's condition should be justified as part of a comprehensive treatment plan for the drug-dependent patient. Gradual or abrupt discontinuation of the fixed combination is permitted. According to the results of some uncontrolled clinical studies of drugs similar to Buprexon-ZN, gradual dose reduction should be preferred at the end of treatment. After treatment, patients require monitoring due to the risk of relapse. Special patient groups Elderly patients The safety and efficacy of the buprenorphine/naloxone combination for patients aged 65 years and older have not been established. Patients with hepatic insufficiency Patients who are carriers of hepatitis virus and/or have liver dysfunction are at risk of accelerated liver damage. Regular monitoring of liver function is recommended. The effect of hepatic insufficiency on the pharmacokinetics of buprenorphine and naloxone is unknown. Since the active substances are extensively metabolized, plasma levels are expected to be higher in patients with moderate and severe hepatic insufficiency. Pharmacokinetics may be altered in patients with impaired liver function; lower initial doses and careful dose titration are recommended for patients with mild and moderate hepatic insufficiency. Patients with renal insufficiency Dosing should be prescribed with caution for patients with severe renal insufficiency (creatinine clearance < 30 ml/min). Children. Buprexon-ZN, like similar combination medicinal products containing buprenorphine and naloxone, is not recommended for the treatment of patients under 16 years of age due to insufficient clinical data on safety and efficacy of use. Overdose. Symptoms. With sublingual administration of the fixed combination, overdose is unlikely. In case of accidental oral overdose, possible symptoms include nausea, vomiting and/or speech disturbances, drowsiness, amblyopia, miosis, arterial hypotension. Respiratory depression due to CNS depression is the main symptom requiring intervention in case of overdose, as it may lead to respiratory arrest and fatal outcome. Treatment. First aid includes immediate gastric lavage. General resuscitation measures should be taken, including careful monitoring of respiratory and cardiac activity. Symptomatic treatment of respiratory depression and standard intensive care measures should be performed. Airway patency and assisted or controlled ventilation should be ensured. The patient should be transferred to an environment where full resuscitation facilities are available. If the patient vomits, measures should be taken to prevent aspiration of vomitus. The use of an opioid antagonist (i.e., naloxone) is recommended, despite the moderate effect it may have in reversing respiratory symptoms caused by buprenorphine compared to its effect on full opioid agonists. It should be considered that naloxone is eliminated from the body faster than buprenorphine; therefore, repeated naloxone infusions are necessary due to the risk of recurrence of overdose symptoms. Initial naloxone doses may reach 2 mg (not more than 10 mg) and should be repeated every 2–3 minutes until a satisfactory effect is achieved. If necessary, use respiratory analeptics. Adverse reactions. Reports of adverse reactions were mostly related to withdrawal syndrome (abdominal pain, diarrhea, muscle pain, anxiety, increased sweating). The adverse effect of Buprexon-ZN analogs is considered dose-dependent. Typical adverse reactions: Nervous system disorders: headache, migraine, dizziness, arterial hypertension, paresthesia, drowsiness, amnesia, seizure, hyperkinesia, speech disorder, tremor, hepatic encephalopathy, syncope. Cardiovascular system disorders: arterial hypertension, vasodilation, angina pectoris, bradycardia, myocardial infarction, palpitations, tachycardia, arterial hypotension, palpitation, orthostatic hypotension. Respiratory system disorders: cough, respiratory depression, dyspnea, yawning, asthma, bronchospasm. Gastrointestinal disorders: constipation, nausea, abdominal pain, diarrhea, dyspepsia, flatulence, vomiting, mouth ulcers, discoloration of the tongue, dental caries (including caries, tooth fracture, and tooth loss). Eye disorders: amblyopia, lacrimal apparatus disorders, conjunctivitis, miosis. Infections and infestations: influenza, pharyngitis, rhinitis, urinary tract infections, vaginal infections. Blood and lymphatic system disorders: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocytopenia. Immune system disorders: hypersensitivity (e.g., rash, urticaria, pruritus, bronchospasm), angioneurotic edema, anaphylactic shock. Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hyperlipidemia, hypoglycemia. Psychiatric disorders: insomnia, anxiety, depression, decreased libido, restlessness, pathological thinking, abnormal dreams, agitation, apathy, depersonalization, drug dependence, euphoria, hostility, hallucinations. Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, rash, urticaria, acne, alopecia, exfoliative dermatitis, dry skin, angioderma. Musculoskeletal and connective tissue disorders: back pain, arthralgia, muscle spasms, muscle pain, arthritis. Ear and labyrinth disorders: vertigo. Kidney and urinary system disorders: abnormal urine findings, albuminuria, urinary disorders, hematuria, nephrolithiasis, urinary retention. Reproductive system disorders: erectile dysfunction, amenorrhea, ejaculation disorders, menorrhagia, metrorrhagia. General disorders: drug withdrawal syndrome, asthenia, chest pain, chills, fever, malaise, pain, peripheral edema, hypothermia, increased sweating. Investigations: abnormal liver function tests, decreased body weight, elevated blood creatinine. Hepatobiliary disorders: elevated liver transaminase levels and jaundice, usually with a favorable clinical course, liver necrosis, hepatitis, hepatorenal syndrome. Injuries, poisonings, and procedural complications: injury, heat stroke. In cases of drug abuse with intravenous administration, local reactions have been recorded, sometimes septic (abscess, cellulitis), and potentially serious acute hepatitis and other infectious diseases such as pneumonia, endocarditis. In patients with pronounced drug dependence, initial administration of buprenorphine/naloxone may promote the development of drug withdrawal syndrome. Neonatal withdrawal syndrome has been observed in newborns when women received buprenorphine during pregnancy. The nature of the syndrome may vary depending on the type of narcotic drugs used. Unconsciousness was not detected. Reporting of adverse reactions. Reporting of adverse reactions after drug registration is of great importance. This allows monitoring of the benefit-risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua. Shelf life. 3 years. Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Store out of reach of children. Packaging. 10 tablets per blister, 1 or 5 blisters per box. Prescription category. Prescription only. Manufacturer. Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu". Manufacturer's location and address of business activity. Ukraine, 61002, Kharkiv region, Kharkiv, Kuikivska Street, 41.