Methadone-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MЕTADON-ZN (METHADONE-ZN)

Composition:

Active substance: methadone;

1 ml of solution contains methadone hydrochloride 1 mg or 5 mg;

Excipients: sodium benzoate (E 211); sucrose (saccharose); glycerol; citric acid, monohydrate (E 330); strawberry flavoring (containing ethyl acetate, propylene glycol); purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, colorless or yellowish or yellowish-brown viscous liquid with a characteristic strawberry odor.

Pharmacotherapeutic group.

Agents used in opioid dependence. ATC code N07BC02.

Pharmacological properties.

Pharmacodynamics.

Methadone is a synthetic agent with sedative and analgesic effects similar to those of morphine. By binding to opioid receptors, methadone competitively displaces short-acting opioids (such as morphine, heroin, etc.). Methadone acts primarily on the central nervous system and organs containing smooth muscle. It exerts analgesic and sedative effects and also demonstrates detoxification or maintenance effects in opioid dependence. Signs of analgesia appear within 30–60 minutes after administration.

Methadone causes a withdrawal syndrome similar to that produced by morphine, but characterized by more gradual onset, moderately prolonged duration, and milder symptoms.

Pharmacokinetics.

Methadone is rapidly absorbed from the gastrointestinal tract within 30 minutes after oral administration, reaching peak blood concentration in 3–4 hours.

Approximately 85% of methadone present in plasma is protein-bound, of which 44% is bound to albumin and 17% to globulins.

Methadone is primarily metabolized in the liver with the involvement of CYP3A4; initial metabolites are excreted in urine and bile along with a small amount of unchanged drug. In patients who have not previously used opioids, the apparent elimination half-life is approximately 15 hours after a single dose, whereas with repeated administration the apparent half-life is 22 hours. Individual variations are significant and may range from 10 to 80 hours, allowing once-daily dosing. Steady-state concentration of methadone may be achieved within 2–9 days.

Clinical characteristics.

Indications.

• For detoxification in the treatment of opioid dependence (heroin dependence and dependence on other morphine-like narcotics), as well as for maintenance therapy in patients with opioid addiction;
• Pain syndrome (moderate to severe pain not controlled by non-narcotic analgesics).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients; presence of contraindications to opioid use, e.g., respiratory depression (in the absence of necessary resuscitation equipment); acute exacerbation of bronchial asthma, accumulation of excess CO₂ in the blood, obstructive respiratory diseases; presence of or suspicion of intestinal obstruction; ulcerative colitis; diarrhea associated with pseudomembranous colitis caused by cephalosporins, lincomycin, clindamycin, penicillins; diarrhea resulting from poisoning (until toxic substances are eliminated from the gastrointestinal tract); increased intracranial pressure, head trauma; severe hepatic and renal insufficiency; spasms of the biliary and urinary tracts; narcotic dependence on weak opioids (pethidine, codeine); dependence on non-opioid drugs; acute alcoholism; concomitant use with monoamine oxidase inhibitors (including moclobemide) and within 2 weeks after their discontinuation.

Interaction with other medicinal products and other types of interactions.

Pharmacokinetic interactions

Methadone is a P-glycoprotein substrate; therefore, all drugs that inhibit its function (quinidine, verapamil) may increase methadone concentration.

Methadone is metabolized by the CYP3A4 isoenzyme.

Inducers of this isoenzyme (barbiturates, carbamazepine, phenytoin, St. John's wort, nevirapine, rifampicin) may enhance hepatic metabolism of methadone. Concurrent use of Methadone-ZH with CYP3A4 inducers may lead to withdrawal syndrome. Since cases of such interactions have been reported, methadone dosage should be increased in the presence of withdrawal symptoms. When therapy with CYP3A4 inducers is discontinued, methadone dosage should be reduced.

CYP3A4 inhibitors (cannabinoids (including cannabidiol), clarithromycin, delavirdine, erythromycin, fluconazole, grapefruit juice, selective serotonin reuptake inhibitors (sertraline, fluvoxamine), itraconazole, ketoconazole, nefazodone) may cause increased plasma methadone concentrations.

Excretion of methadone is reduced when co-administered with CYP3A4 inhibitors such as certain anti-HIV agents, macrolides, cimetidine, and antifungal drugs (since methadone is metabolized by the CYP3A4 isoenzyme).

Methadone reduces the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of didanosine and stavudine, thereby decreasing the bioavailability of these drugs. Additionally, methadone may delay absorption and increase first-pass metabolism of the aforementioned drugs.

Methadone increases plasma concentrations of zidovudine both after oral and intravenous administration, and increases the AUC of zidovudine to a greater extent after oral administration than after intravenous administration. These effects are due to inhibition of glucuronidation of zidovudine, resulting in reduced renal clearance. During methadone treatment, monitoring for possible zidovudine toxicity is recommended, and zidovudine dosage should be reduced if toxicity occurs. Patients receiving both drugs concurrently may develop typical withdrawal symptoms (severe headache, muscle pain, fatigue, irritability). Antiretroviral protease inhibitors may inhibit methadone metabolism. The most significant reactions occur with ritonavir; when ritonavir/lopinavir is used concomitantly with methadone, a decrease in plasma methadone concentration is observed. However, withdrawal syndrome does not always occur. Nevertheless, concomitant use of these drugs with methadone requires caution. Interaction with abacavir is also possible, though dose adjustment is generally not required.

Nevirapine may reduce methadone concentration by increasing its hepatic metabolism. Withdrawal syndrome has been reported with concurrent use of methadone and nevirapine. If nevirapine is prescribed to patients receiving Methadone-ZH, careful monitoring for withdrawal symptoms is necessary, and methadone dosage should be adjusted if needed.

Efavirenz enhances methadone metabolism via cytochrome P450 3A4. After three weeks of efavirenz therapy, mean maximum methadone concentration and AUC were reduced by 48% and 57%, respectively. It is presumed that adding efavirenz to methadone therapy may lead to withdrawal syndrome, typically beginning after two weeks of efavirenz treatment and potentially lasting up to 28 days. Therefore, dosage adjustment may be necessary.

Methadone is a weak base. Urine acidifying agents (ammonium chloride) may increase renal clearance of methadone. In such cases, methadone dosage should be increased.

Repeated oral administration of voriconazole leads to increased maximum plasma concentration and AUC of the pharmacologically active enantiomer of methadone (R-methadone) in patients receiving maintenance methadone doses (30–100 mg once daily). Elevated plasma methadone concentrations may lead to toxic effects, including QT interval prolongation. Methadone dosage reduction may be required.

Other drugs. Administration of meperidine at therapeutic doses to patients taking monoamine oxidase inhibitors may cause severe adverse reactions. Although such reactions have not been observed after methadone administration, if methadone is necessary in patients taking monoamine oxidase inhibitors, a sensitivity test should be performed: small doses of the drug should be administered gradually over several hours, with close monitoring of the patient's condition.

Concomitant use of methadone increases plasma desipramine levels.

Pharmacodynamic interactions

Opioid antagonists (naloxone and naltrexone) exert a pharmacological effect opposite to that of methadone. These drugs may block the effects of methadone and precipitate withdrawal syndrome.

Agonist/antagonists (butorphanol, nalbuphine, pentazocine) may partially block analgesia, respiratory depression, and central nervous system (CNS) disturbances associated with methadone use. When used concomitantly, they may enhance neurological, respiratory, and hypotensive effects. Additive or antagonistic effects depend on methadone dosage and are more common with low to moderate methadone doses. These drugs may precipitate withdrawal syndrome in patients undergoing long-term therapy.

In patients receiving concurrent treatment with methadone and drugs that impair cardiac conduction or electrolyte balance, cardiac disturbances may occur. In such cases, ECG monitoring is required.

Concomitant use of methadone and antidiarrheal agents (diphenoxylate and loperamide) may cause severe constipation and enhance CNS depressant effects. Opioid analgesics combined with antimuscarinic drugs may cause severe constipation or, with prolonged use, paralytic ileus. Octreotide, a synthetic somatostatin analogue, may reduce the analgesic effect of methadone and morphine; therefore, octreotide's effect should be considered if pain control decreases or is lost.

Domperidone and metoclopramide may increase the rate of methadone elimination, but not the extent of its absorption. Regarding methadone's effect on the gastrointestinal tract, it may exert antagonistic effects on domperidone/metoclopramide.

Concomitant use of Methadone-ZH with agenerase reduces maximum plasma concentration and AUC of R-methadone by 25% and 13%, respectively. When Methadone-ZH and agenerase are used together, careful monitoring of patients is required to prevent a reduction in the effective dose of Methadone-ZH, especially if ritonavir is also used. Concomitant use of Methadone-ZH and agenerase reduces AUC, maximum, and minimum concentrations of agenerase by 30%, 27%, and 25%, respectively.

Concomitant use of Methadone-ZH with verapamil has been associated with changes in methadone plasma levels. An increase in Methadone-ZH dosage may be necessary.

Concomitant use of Methadone-ZH with a non-nucleoside reverse transcriptase inhibitor may require a reduction in Methadone-ZH dosage.

Particular caution is required when using agents that may prolong the QT interval in combination with methadone. Such agents include Class I and III antiarrhythmics, certain neuroleptics, tricyclic antidepressants, and calcium channel blockers. Caution is also advised when combining methadone with drugs that disturb electrolyte balance, which may also contribute to QT prolongation (e.g., hypomagnesemia, hypokalemia). Such agents include diuretics, laxatives, and certain mineralocorticoids.

Methadone reduces mexiletine absorption.

Methadone-ZH should be used with caution in patients who are concurrently receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives and hypnotics, tricyclic antidepressants, and other CNS depressants, as well as when consuming alcohol, because such combinations may lead to respiratory depression, arterial hypotension, profound sedation, and even coma. Concurrent use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression, and death.

Concomitant use of ciprofloxacin and methadone may lead to sedation, confusion, and respiratory depression.

Methadone may affect the results of pregnancy tests.

Interaction with serotonergic drugs. Serotonin syndrome may occur with concomitant use of methadone and meperidine, monoamine oxidase inhibitors (MAOIs), and serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants. Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.

Special precautions for use.

If, after discontinuation of the drug, it becomes necessary to resume its administration, the initial dose should be low, and dose escalation should be performed gradually to avoid serious toxic effects and respiratory depression.

The medicinal product is intended for oral use only. The oral solution must not be used for injection.

When switching abruptly from other opioids to methadone, there is a significant risk of respiratory depression; therefore, transition to methadone should be performed with caution.

Methadone may cause dependence of morphine type. Repeated administration of methadone may lead to psychological and physical dependence, as well as the development of tolerance. Therefore, methadone should be prescribed and used with the same caution as morphine.

Incomplete cross-tolerance between methadone and other opioids.

Tolerance to other opioids may result in partial tolerance to methadone, especially in patients who are not responsive to other μ-opioid receptor agonists. In such cases, determining the appropriate methadone dose may be difficult. Fatal cases have been reported following transition to methadone after prolonged use of other opioid antagonists.

A high degree of opioid tolerance does not exclude the possibility of toxic effects when using this drug.

Interaction with alcohol and drugs. Methadone exerts additive effects when used concomitantly with alcohol and other central nervous system (CNS)-depressant drugs, including other opioid narcotics. Methadone should be used cautiously at reduced doses in patients receiving other narcotic analgesics. Fatal cases have been reported in individuals who misuse benzodiazepines while taking methadone.

Interaction with other CNS depressants.

Concomitant use of methadone with general anesthetics, phenothiazines, other hypnotic-sedative agents, tricyclic antidepressants, and other medications that depress CNS activity—including alcohol—may result in CNS depression, profound sedation, or coma.

Anxiety states. Since methadone, when administered to tolerant individuals at steady maintenance doses, is not a tranquilizer, anxiety states may develop in patients receiving methadone maintenance therapy in response to stress or life problems. Methadone does not have anxiolytic properties; therefore, symptoms of anxiety or restlessness that arise during treatment should not be managed by increasing the methadone dose. The physician should not confuse these symptoms with withdrawal symptoms and should not attempt to treat such conditions by increasing the methadone dose. The effect of methadone in maintenance therapy is limited to control of opioid-related symptoms and does not extend to relief of anxiety states.

Head injuries and increased intracranial pressure. The effects of methadone—such as respiratory depression and increased cerebrospinal fluid pressure—are significantly more pronounced in patients with head injuries. The same danger exists in cases of other intracranial pathologies or pre-existing increased intracranial pressure. The side effects of opioids may mask neurological signs in patients with head trauma. Methadone is contraindicated in patients with increased intracranial pressure and in those with traumatic brain injury.

Bronchial asthma and other respiratory disorders. The main risk associated with methadone use is the potential for respiratory depression. This issue is particularly significant in elderly patients, debilitated individuals, and in cases of hypoxia or hypercapnia, where even moderate therapeutic doses may substantially reduce pulmonary ventilation. Therefore, methadone is contraindicated in patients with hypercapnia, acute exacerbation of bronchial asthma, obstructive lung diseases, or respiratory depression (in the absence of appropriate resuscitation equipment). It should be prescribed with extreme caution in conditions associated with hypoxia or reduced respiratory reserve, including bronchial asthma in remission, marked obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression, or coma. In such patients, even usual therapeutic doses of methadone may cause depression of the respiratory center, especially when accompanied by increased airway resistance, potentially leading to respiratory arrest. In these cases, non-opioid analgesics are recommended; if they are insufficiently effective, methadone may be used only under close medical supervision.

Sleep-related breathing disorders. Opioids may cause sleep-related breathing disorders, including central sleep apnea (CSA) and nocturnal hypoxemia. Opioid use increases the risk of CSA in a dose-dependent manner. In patients with CSA, consideration should be given to reducing the total opioid dose.

Acute abdominal conditions. The use of methadone or other narcotic agents may interfere with establishing the correct diagnosis or appropriate treatment in patients presenting with symptoms of an "acute abdomen."

Hypotensive effect. Methadone may cause marked arterial hypotension in patients whose ability to maintain blood pressure is compromised due to hypovolemia or when used concomitantly with drugs such as phenothiazines or certain anesthetics. Use with particular caution in patients with arterial hypotension.

Outpatient use. Methadone may impair mental and physical abilities required for activities involving high risk (e.g., driving a car or operating machinery). Methadone, like other opioids, may cause orthostatic hypotension in outpatients.

Use in acute pain. In cases of physical trauma, postoperative pain, or other acute pain conditions in patients receiving maintenance doses of methadone, these low doses will not be effective for analgesia. In such cases, analgesics—including opioids—appropriate for managing similar pain syndromes in other patients should be prescribed. Since methadone induces opioid tolerance, higher doses of these agents may be required.

Risk of relapse in drug-dependent patients receiving methadone maintenance therapy. Abrupt discontinuation of opioids may lead to withdrawal syndrome, increasing the risk of returning to illicit drug use. This should be considered when evaluating the risk-benefit ratio of prescribing methadone maintenance therapy.

Opioid use disorders (abuse and dependence). Methadone is an opioid analgesic and, by itself, causes strong dependence. It has a long elimination half-life and may therefore accumulate. A single analgesic dose taken several times a day may lead to cumulative effects and potentially fatal outcomes. As with other opioids, repeated use of methadone may lead to tolerance and physical and/or psychological dependence. Tolerance manifests as the need for increasingly higher doses to maintain a certain effect (e.g., analgesia). Physical dependence is characterized by withdrawal syndrome following abrupt discontinuation of the drug or administration of its antagonist. Both tolerance and physical dependence may occur during prolonged opioid therapy.

Repeated use of the drug for pain relief may lead to opioid use disorder (OUD). Higher doses and longer duration of opioid therapy may increase the risk of developing OUD.

Before initiating and during treatment, the goals of therapy and a plan for discontinuation should be discussed with the patient (see section "Dosage and administration"). Patients should also be informed about the risks and signs of OUD before and during treatment. Patients should be advised to contact their physician if such signs appear.

Abuse or intentional misuse of the medicinal product may lead to overdose and/or death.

The risk of OUD is increased in patients with a personal or family history (parents or siblings) of substance use disorders (including alcohol-related disorders), in current tobacco users, and in patients with other psychiatric disorders (such as major depression, anxiety, or personality disorders).

Patients should be monitored for signs of drug-seeking behavior (e.g., requesting early prescription refills), which may necessitate review of concomitant opioid and psychoactive drug therapy (including benzodiazepines). Patients showing signs and symptoms of OUD should be referred to a specialist in addiction medicine.

Abrupt discontinuation of methadone therapy in physically dependent patients may lead to withdrawal syndrome. Both withdrawal and abstinence syndromes are characterized by symptoms such as anxiety, lacrimation, rhinorrhea, sweating, chills, yawning, myalgia, and miosis. Other symptoms may include irritability, back pain, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, elevated blood pressure, tachycardia, and increased respiratory rate.

Generally, abrupt discontinuation of methadone after prolonged use is not recommended.

Special considerations in specific patient groups.

Use with caution and starting with a low initial dose in elderly patients, debilitated patients, and those with impaired hepatic or renal function; in patients with hypothyroidism, Addison’s disease, benign prostatic hyperplasia, urethral stricture, hypopituitarism, shock, or seizures; in patients with inflammatory or obstructive bowel disorders, chronic/severe constipation, myasthenia gravis, congenital heart defects, uncompensated diabetes, oligemia, porphyria, frequent asthma attacks, respiratory disorders, or cor pulmonale. Use with caution in patients with ischemic heart disease or a family history of sudden cardiac death. Particular caution is required in patients with pheochromocytoma; worsening of arterial hypertension symptoms has been reported with concomitant use of diamorphine.

It should also be noted that methadone use may lead to respiratory depression.

Methadone should primarily be prescribed to patients in whom the benefits of opioid analgesia outweigh the known potential risks associated with the drug (cardiac conduction disturbances, respiratory depression, changes in mental status, postural hypotension).

Use in elderly patients. Dose selection should be cautious, starting with relatively low doses, considering that many elderly patients may have impaired liver, kidney, or cardiovascular function.

Use in patients with renal impairment. Safety data on methadone use in patients with renal insufficiency are lacking.

Use in patients with hepatic impairment. Data on methadone use in patients with hepatic dysfunction are limited. However, it should be noted that methadone is metabolized in the liver. Therefore, there is a risk of methadone accumulation in patients with impaired liver function.

Effect on cardiac conduction. Methadone is a cardiac potassium channel blocker and prolongs the QT interval. Cases of severe arrhythmias (ventricular fibrillation and flutter) have been reported with methadone use. These cases most commonly occurred with high methadone doses (over 200 mg/day). Most complications occurred during high-dose pain treatment, although cases have been reported during maintenance therapy in opioid-dependent patients.

Methadone should be used with particular caution in patients at increased risk of QT prolongation (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Methadone use in patients with a history of conduction disorders or arrhythmia risk is possible only with careful monitoring. QT prolongation has been observed in some patients without prior cardiac history, especially with high-dose methadone.

If QT prolongation occurs during methadone therapy, known risk factors should be addressed, including concomitant medications affecting cardiac function, drugs altering electrolyte balance, and drugs inhibiting methadone metabolism. When prescribing methadone for pain relief, the risk of QT prolongation and cardiac arrhythmias must be considered. This risk should be weighed against the potential benefits of pain relief and the availability of alternative therapies. Use with caution in patients with risk factors for prolonged QT interval: history of prolonged QT interval, progressive heart disease, ischemic heart disease, liver disease, or concomitant use of other QT-prolonging drugs.

Methadone therapy for analgesia in acute or chronic pain should only be initiated if the potential analgesic or palliative benefit outweighs the risk of life-threatening complications associated with high-dose methadone.

Individualized assessment of benefit versus risk, considering both patient history and clinical findings, is essential when using methadone. If risk factors are identified, careful monitoring of cardiovascular status—including QT interval analysis and arrhythmia detection—is required.

Adrenal insufficiency. Opioid analgesics may cause reversible adrenal insufficiency, requiring monitoring and glucocorticoid replacement therapy. Symptoms may include nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Reduction in sex hormone levels and increased prolactin levels. Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin levels. Symptoms include reduced libido, impotence, or amenorrhea.

Hypoglycemia. Hypoglycemia may occur with methadone overdose or dose escalation. Regular blood glucose monitoring is recommended during dose increases (see sections "Overdose" and "Adverse reactions").

Excipients. The medicinal product contains 8 g of sucrose per 20 ml dose. Use with caution in patients with diabetes mellitus. May be harmful to teeth. Patients with known sugar intolerances should consult their physician before taking this medicinal product.

The medicinal product contains 10 g of glycerin per 100 ml dose. May cause headache, gastrointestinal irritation, and diarrhea.

Use during pregnancy or breastfeeding.

Methadone passes into saliva, breast milk, amniotic fluid, and umbilical cord plasma.

Pregnancy. Methadone may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Pregnant women have significantly lower plasma methadone concentrations, reduced elimination half-life, and increased methadone clearance compared to the postpartum period. Therefore, methadone use during pregnancy may lead to withdrawal syndrome in some patients. Dose increases, shorter dosing intervals, or splitting the dose into multiple administrations may be necessary.

Pregnant women should be informed about the potential consequences of methadone use for both themselves and their child. Methadone use during pregnancy should be under medical supervision.

Infants born to women who used opioids during the four weeks before delivery may be physically dependent. Therefore, such infants should be monitored for at least two weeks for possible withdrawal symptoms (irritability, seizures, poor feeding, diarrhea, high-pitched crying).

Labour and delivery. As with any opioid, use of methadone shortly before delivery, especially at high doses, may cause respiratory depression in the newborn. Therefore, methadone is not recommended for obstetric analgesia. Mixed agonist-antagonist opioids should not be used for labor analgesia in patients on long-term methadone therapy, as they may precipitate acute withdrawal.

Breastfeeding. Methadone passes into breast milk and therefore is not recommended during breastfeeding. Considering the risk of serious adverse reactions in infants and the benefit of treatment for the mother, it is recommended to either discontinue breastfeeding or methadone use.

Methadone is excreted into breast milk at low plasma levels. When deciding whether to recommend breastfeeding, consultation with other physicians is advised, considering whether the woman is on a stable maintenance methadone dose and whether there is ongoing use of illicit substances.

If breastfeeding is recommended, the methadone dose should be as low as possible. Breastfeeding women should be informed and closely monitor the infant for signs of sedation and breathing difficulties, seeking immediate medical help if such signs occur. Although the amount of methadone excreted in breast milk is insufficient to fully suppress withdrawal symptoms in breastfed infants, it may reduce the severity of neonatal abstinence syndrome. Mothers taking methadone are advised to wean gradually from breastfeeding to prevent withdrawal syndrome in the infant.

Ability to affect reaction speed when driving or operating machinery.

Methadone may impair mental and physical abilities required for activities involving high risk (e.g., driving a car or operating machinery).

Method of Administration and Dosage

Methadone-ZN is administered orally.

Methadone-ZN should only be used in specialized medical facilities and must be prescribed by a specialist experienced in treating drug-dependent patients. Patients receiving this medication must remain under close medical supervision.

During prolonged treatment, patients also require appropriate psychological and social support.

Immediately before administration, Methadone-ZN is diluted in 100 mL of liquid to prevent its injection.

Opioid Dependence Treatment

Regarding opioid dependence treatment, this medicinal product is intended for daily use according to the medical conclusion outlined in the treatment protocol. A single detoxification treatment cycle should not exceed 21 days; the next cycle should not begin earlier than 4 weeks after completion of the previous one. The dosing regimens listed below are recommended, but may still be adjusted based on clinical assessment. At the initial stage, a single dose of 20–30 mg of methadone is usually sufficient to reduce withdrawal symptoms. A higher dose of methadone may be prescribed if withdrawal symptoms persist or reappear. In patients who are physically dependent on high doses, dose escalation may be necessary. Typically, an adequate dose is 40 mg daily, administered as a single dose or in divided doses. Stabilization may last 2–3 days, after which the methadone dose is gradually reduced. The rate of dose reduction is determined individually for each patient. A daily reduction of the total daily dose by 10% is generally well tolerated by inpatients. Outpatients may require a slower dose reduction over a longer period. If methadone is administered for longer than three weeks, this procedure is considered maintenance therapy, even if the ultimate goal is complete discontinuation.

For patients with established opioid addiction, maintenance therapy may be applied if previous comprehensive interventions have not yielded positive results.

Such treatment may also be prescribed for patients with confirmed opioid use or for HIV-infected patients under immunologically critical conditions or those with AIDS, if the physician determines that alternative treatment programs are less promising regarding opioid abstinence. When properly implemented, substitution therapy can also eliminate the so-called "cold turkey" syndrome, characterized by compulsive heroin-seeking behavior driven by the addict's overwhelming desire to obtain the drug.

There is no need to perform systemic naloxone challenge tests in patients with severe heroin dependence known to the treatment center. However, urine testing for morphine is essential. Urine analysis is mandatory during methadone treatment to monitor the presence of narcotic drugs and psychotropic substances according to physician instructions. Testing for excessive alcohol levels is also necessary. If opioid substances are detected in urine, the case must be reassessed immediately.

In each individual case, the physician determines the dosage to prevent heroin craving, taking into account the patient's psychophysical condition and relevant pathological changes.

Maintenance therapy aims to prevent respiratory depression or other effects of acute intoxication.

If an adult patient has been using significant doses of heroin up to the day of admission, the initial dose of the drug may be 20 mg, followed by another 20 mg or 40 mg of Methadone-ZN after 4 or 8 hours. If opioid tolerance is low at the start of treatment, the initial dose may be halved. In case of any doubt, it is better to reduce the initial dose. If withdrawal symptoms occur, an additional 10 mg of the drug may be administered. Subsequently, the dose should be individually adjusted up to a maximum of 80 mg per day, depending on tolerance and need. In most cases, a dose below 80 mg per day is sufficient for adults.

The maximum daily dose for adults is 120 mg per day.

For pregnant women with opioid dependence, maintenance doses of methadone should be as low as possible to prevent withdrawal syndrome (usually below 80 mg per day). In later stages of pregnancy, the dose may need to be increased by 10–20 mg or divided into two doses.

Pain Management

Before initiating methadone therapy, a treatment strategy including duration and goals should be agreed upon with the patient according to the pain management protocol. During therapy, the physician should maintain frequent contact with the patient to assess the need for continued treatment, consider discontinuation, and adjust doses if necessary. When a patient no longer requires methadone therapy, gradual dose reduction is recommended to prevent withdrawal symptoms (see section "Special Instructions"). Inadequate pain control should prompt consideration of tolerance development and progression of the underlying disease (see section "Special Instructions").

The methadone dose must be carefully titrated according to the intensity of pain and the patient's response to the drug. Initiating treatment and dose titration is safest starting with a low initial dose, followed by gradual dose adjustments.

Generally, methadone should not be used for severe pain in patients who have not previously used opioid medications.

Typically, adults receive the drug orally at a dose of 2.5–10 mg every 4 hours during the first 3–5 days. The dose is slowly titrated until the desired effect is achieved, after which a fixed dose is administered every 8–12 hours depending on the patient's condition and response to treatment.

Elderly patients should receive the drug once daily.

Children

The safety and efficacy of methadone in children have not been studied.

Overdose

In cases of significant methadone overdose, respiratory depression occurs (reduced respiratory rate and/or decreased tidal volume, Cheyne-Stokes respiration, cyanosis), excessive drowsiness progresses to stupor or coma, pinpoint pupils are observed, miosis may alternate with mydriasis, muscle weakness, cold and clammy skin, bradycardia, and arterial hypotension may develop. Hypoglycemia has been reported. Toxic leukoencephalopathy has been observed in methadone overdose. In children, overdose symptoms include drowsiness, lethargy, pinpoint pupils, and dyspnea. In severe overdose, especially after oral ingestion, respiratory arrest, circulatory collapse or shock, cardiac arrest, and fatal outcome are possible.

Treatment

First and foremost, adequate respiratory rhythm, fresh air supply, and proper supportive ventilation must be ensured, along with ECG monitoring. If the patient is severely symptomatic from overdose, particularly a child who accidentally ingested a large methadone dose, effective narcotic antagonists that counteract potentially fatal respiratory depression should be administered.

The physician must always remember that methadone is a long-acting depressant (36–48 hours), whereas antagonists used to treat overdose effects have a shorter duration of action (1–3 hours). Therefore, the patient must remain under continuous observation to prevent recurrent respiratory depression, and if necessary, repeated antagonist treatment should be administered. Other respiratory stimulants are not indicated if the diagnosis is confirmed and respiratory depression is solely due to methadone overdose.

If there is no clinically significant respiratory or cardiovascular impairment, antagonist drugs should not be prescribed. Narcotic antagonists administered intravenously (naloxone, nalorphine, and levallorphan) are the primary therapeutic agents for relieving intoxication symptoms.

These therapeutic agents should be administered repeatedly until the patient's condition improves. When naloxone is used, the risk of subsequent respiratory depression caused by the narcotic antagonist is lower.

If needed, oxygen, intravenous fluids, vasoconstrictors, and other supportive measures should be applied.

In patients physically dependent on opioids, administration of an opioid antagonist may precipitate acute withdrawal syndrome, the severity of which depends on the degree of physical dependence and the dose of the antagonist used. Administration of antagonists in cases of significant respiratory depression in physically dependent patients should be performed with extreme caution, using doses lower than normally accepted (10–20% of the recommended dose) during titration.

Administration of opioid antagonists at standard doses in physically dependent patients may trigger acute withdrawal syndrome. Opioid antagonists should not be used in physically dependent individuals unless absolutely necessary.

Acidification of urine increases methadone excretion.

Methadone is not removed by peritoneal dialysis or hemodialysis.

Side effects.

Heroin withdrawal. At the initial stage of methadone maintenance therapy, patients stop receiving heroin, which leads to typical signs of withdrawal syndrome. These should be differentiated from adverse effects associated with methadone use. The most characteristic signs of withdrawal syndrome (both from heroin and other opioids) include: lacrimation, rhinorrhea, sneezing, yawning, excessive sweating, elevated temperature, goosebumps, alternating sensations of heat and cold, restlessness, irritability, weakness, depression, pupillary dilation, tremor, tachycardia, abdominal cramps, body aches, involuntary twitching, anorexia, nausea, diarrhea, intestinal spasms, and weight loss.

Initial dose. Special attention must be paid to individual selection of the initial dose. Excessively high doses during the initial period may cause adverse effects.

The main danger associated with methadone use is respiratory depression and arterial hypotension. Methadone administration may lead to cardiac arrest, respiratory arrest, and shock. Fatal cases have been reported.

The most commonly observed adverse reactions are: dizziness, restlessness, feeling of emptiness in the head, sedative effect, nausea, vomiting, excessive sweating, orthostatic hypotension. In such cases, methadone dose reduction may be considered.

Some of these effects, particularly in outpatients, may be alleviated by placing the patient in a horizontal position.

Other adverse reactions reported with methadone use:

General reactions: asthenia, weakness, flushing, development of tolerance, hypothermia.

Cardiovascular system: arrhythmia, bradycardia, extrasystoles, tachycardia, palpitations, atrial flutter and fibrillation, ventricular fibrillation, QT interval prolongation, torsades de pointes arrhythmia (especially with high-dose methadone), cardiomyopathy, heart failure, arterial hypotension, phlebitis, syncope, T-wave inversion.

Gastrointestinal tract: abdominal pain, anorexia, spasms of the biliary tract and gallbladder, biliary dyskinesia, constipation, dry mouth (xerostomia), glossitis.

Nervous system: headache, excitation, confusion, seizures, disorientation, dysphoria, euphoria, insomnia, visual disturbances, blurred vision, miosis, dry eyes, vertigo, hallucinations, hyperexcitability, dependence.

Blood system: in opioid addicts with chronic hepatitis, transient thrombocytopenia has been described.

Metabolism: edema, fluid retention, lower limb edema, hypokalemia, hypomagnesemia, hypoglycemia, loss or increase in body weight.

Respiratory system: pulmonary edema, worsening of bronchial asthma; dryness in the nose, respiratory depression (especially with high-dose methadone), central sleep apnea syndrome.

Skin: urticaria, skin rash, hemorrhagic urticaria; eczema, pruritus, swelling.

Urinary and reproductive system: antidiuretic effect; dysmenorrhea, amenorrhea; urinary retention; urinary elimination problems; decreased libido and potency, impotence, elevated prolactin levels with long-term use, galactorrhea.

Use in patients with impaired liver function: during long-term methadone maintenance therapy, adverse effects gradually diminish over several weeks, although certain side effects such as excessive sweating and constipation may persist.

Methadone is an opioid receptor agonist; therefore, dependence of the same type as with morphine may develop during treatment.

Hypersensitivity reactions, including shock and dyspnea, may occur during methadone use.

Withdrawal syndrome: restlessness, lacrimation, rhinorrhea, sneezing, sweating, cold sensations, tremor/trembling, goosebumps, yawning, myalgia, mydriasis, irritability, body, back, and joint pain, weakness, abdominal cramps, sleep disturbances, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, increased heart rate, increased respiratory rate, elevated body temperature.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

After opening the bottle, store for no more than 28 days.

Storage conditions.

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

Keep out of reach of children.

Packaging.

200 ml or 1000 ml in bottles, supplied with the appropriate number of dosing devices.

200 ml or 1000 ml in bottles with a dosing device, packed in a box.

Prescription status. Prescription only.

Manufacturer.

Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and location of business activity.

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