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

Composition:

Active substance: methadone;

One tablet contains 5 mg, 10 mg, 25 mg, or 40 mg of methadone hydrochloride;

Excipients: lactose monohydrate; microcrystalline cellulose; pregelatinized starch; magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties:

5 mg and 10 mg tablets are white or almost white, cylindrical in shape, with a flat surface and beveled edges;

25 mg tablets are white or almost white, cylindrical in shape, with a flat surface, beveled edges, and a score line on one side;
40 mg tablets are white or almost white, cylindrical in shape, with convex surfaces, beveled edges, and a score line on one side.

Pharmacotherapeutic group.

Medicinal products used in opioid dependence. ATC code N07BC02.

Pharmacological Properties.

Pharmacodynamics. Methadone is a synthetic derivative of diphenylheptane and differs significantly from morphine and heroin in its chemical structure. However, the main pharmacological properties of these narcotic agents are similar: they cause suppression of the respiratory center function, increased smooth muscle tone, constipation, and other symptoms characteristic of opioid action.

Methadone has specific properties of a partial agonist at µ- and k-receptors of the brain's opioidergic system. The analgesic activity of the drug is achieved by inhibiting interneuronal transmission of pain impulses at spinal and supraspinal levels of the central nervous system (CNS). In addition to analgesia, methadone can produce pronounced psychotropic effects, including feelings of euphoria and unreal mental comfort.

The specific pharmacotherapeutic effects of methadone are based on two main mechanisms. First, as an opioid receptor agonist, methadone suppresses clinical manifestations of withdrawal symptoms in patients with opioid addiction. Second, prolonged use of methadone may lead to the development of cross-tolerance, resulting in reduced intensity of specific psychotropic effects in patients dependent on injectable narcotics (heroin, morphine, and others).

The effect of methadone begins 30–60 minutes after oral administration and rapidly reaches its maximum. The duration of action averages 6–8 hours, but in patients with physical dependence on opioids, it may increase to 22–48 hours.

Repeated administration of the drug leads to cumulative effects and development of prolonged sedative action.

Pharmacokinetics. The extent of methadone absorption after oral administration reaches 92%. The drug is rapidly distributed throughout body tissues. Biotransformation occurs predominantly in the liver, where methadone undergoes N-demethylation. Methadone and its metabolites are excreted from the body via the kidneys or through the biliary tract. When doses exceeding 160 mg per day are administered, renal elimination becomes the main excretion pathway, with up to 60% of methadone excreted unchanged. With prolonged use, the drug's elimination half-life varies widely—from 13 to 47 hours. The slowed clearance and presence of a cumulative effect are due to methadone binding to blood and tissue proteins.

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;
Moderate to severe pain not relieved by non-narcotic analgesics (for 5 mg and 10 mg tablets).

Contraindications.

Hypersensitivity to methadone hydrochloride or to any other component of the medicinal product;
Respiratory depression (in the absence of necessary resuscitation equipment);
Exacerbation period of bronchial asthma;
Accumulation of excess carbon dioxide in the blood;
Diarrhea associated with pseudomembranous colitis caused by cephalosporins, lincomycin, clindamycin, penicillins;
Diarrhea caused by poisoning;
Intestinal obstruction;
Concomitant use with monoamine oxidase inhibitors (MAOIs), as well as within 2 weeks after their discontinuation;
Increased intracranial pressure, head injuries.

Methadone-ZN is contraindicated in individuals dependent on "mild" narcotic drugs (e.g., codeine, pethidine, and similar opioid receptor agonists).

Interaction with other medicinal products and other types of interactions.

Opioid antagonists, mixed agonists/antagonists, partial agonists. Patients with heroin addiction or those receiving maintenance methadone therapy may experience withdrawal symptoms when taking opioid antagonists or mixed agonist/antagonist drugs. At least 20 hours should elapse between administration of buprenorphine and methadone.

Antihypertensive agents, including clonidine, prazosin, reserpine, and urapidil, may enhance the effect of methadone.

Histamine H2-receptor antagonists, such as cimetidine, may reduce the protein binding of methadone, thereby increasing opioid blood levels.

Antiretroviral drugs. Nevirapine may reduce Methadone-ZN concentration due to increased metabolism in the liver. Withdrawal symptoms have been observed during concomitant use of Methadone-ZN and nevirapine. If nevirapine is prescribed to patients receiving Methadone-ZN, careful monitoring for withdrawal symptoms is required, and the dose of Methadone-ZN may need to be adjusted.

Concomitant use of efavirenz and Methadone-ZN in HIV-infected patients leads to decreased plasma concentration of Methadone-ZN and the appearance of withdrawal signs. An increase in the Methadone-ZN dose may be necessary.

Administration of ritonavir and ritonavir/lopinavir together with Methadone-ZN results in reduced plasma concentration of Methadone-ZN, although withdrawal symptoms do not always occur. However, concomitant use of these drugs with Methadone-ZN requires caution.

Administration of Methadone-ZN increases the area under the concentration-time curve (AUC) for zidovudine, which may lead to toxic effects.

Administration of Methadone-ZN reduces the AUC for didanosine and stavudine, with a more pronounced effect on didanosine. Meanwhile, the distribution of Methadone-ZN is not significantly altered.

Drugs inducing cytochrome P450 system metabolizing enzymes. Administration of rifampicin to patients stabilized on Methadone-ZN maintenance therapy leads to a significant decrease in serum methadone levels, resulting in withdrawal symptoms.

Administration of phenytoin (250 mg twice daily on the first day, followed by 300 mg once daily for 3–4 days) to patients undergoing methadone therapy leads to decreased Methadone-ZN concentration and development of withdrawal symptoms. These effects resolve after phenytoin discontinuation. Pharmacokinetic parameters of Methadone-ZN return almost completely to baseline levels after phenytoin withdrawal.

Administration of methadone together with other CYP3A4 inducers (e.g., St. John’s wort, phenobarbital, carbamazepine) may lead to withdrawal symptoms.

Cytochrome P450 inhibitors. Administration of drugs that inhibit the activity of cytochrome P450 isoenzyme 3A4 may lead to reduced clearance of Methadone-ZN. As a result, opioid effects may be enhanced or prolonged. When prescribing drugs that are inhibitors of this isoenzyme, such as antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), dose adjustment of Methadone-ZN may be necessary. Concomitant use of certain selective serotonin reuptake inhibitors (e.g., sertraline, fluvoxamine) with Methadone-ZN may lead to increased plasma levels of Methadone-ZN and the occurrence of toxic effects.

Repeated oral administration of voriconazole leads to increased maximum plasma concentration and AUC of the pharmacologically active enantiomer of Methadone-ZN (R-methadone) in patients receiving maintenance doses of Methadone-ZN (30–100 mg once daily). Increased plasma concentration of Methadone-ZN may lead to development of toxic effects associated with prolonged QT interval. Dose reduction of Methadone-ZN may be required.

Other drugs. Administration of meperidine at therapeutic doses to patients who are taking or have taken MAO inhibitors within the past 14 days may lead to severe adverse reactions. Although such reactions have not been reported with Methadone-ZN, if Methadone-ZN must be used in patients taking MAO inhibitors, a sensitivity test should be performed: small doses of the drug should be administered gradually over several hours while monitoring the patient’s condition. MAO inhibitor therapy should be discontinued at least 14 days before starting substitution therapy. Otherwise, life-threatening CNS depressant or stimulant effects, respiratory depression, and circulatory disturbances may occur.

Protease inhibitors. Concomitant use of Methadone-ZN with agenerase (amprenavir) results in a 25% and 13% reduction in maximum plasma concentration (Cmax) and AUC of R-methadone, respectively. Careful monitoring is required when Methadone-ZN and agenerase (amprenavir) are used together to avoid a reduction in the effective dose of Methadone-ZN, especially if ritonavir is also administered. Concomitant use of Methadone-ZN and agenerase (amprenavir) reduces AUC, Cmax, and minimum plasma concentration (Cmin) of agenerase (amprenavir) by 30%, 27%, and 25%, respectively.

Concomitant administration of viracept (nelfinavir) with Methadone-ZN has been associated with changes in Methadone-ZN plasma levels. An increase in Methadone-ZN dose may be required.

Non-nucleoside reverse transcriptase inhibitors. Concomitant use of Methadone-ZN with rescriptor (delavirdine) may require a reduction in Methadone-ZN dose.

Desipramine. Concomitant use with Methadone-ZN increases desipramine plasma levels.

Potentially arrhythmogenic agents. Particular caution should be exercised when using agents that may prolong the QT interval in combination with Methadone-ZN. Such agents include Class I and III antiarrhythmics, certain neuroleptics, tricyclic antidepressants, and calcium channel blockers. Caution is also advised when combining Methadone-ZN with drugs that disturb electrolyte balance, which may also contribute to QT prolongation (hypomagnesemia, hypokalemia). These include diuretics, laxatives, and occasionally mineralocorticoids.

Interaction with other CNS depressants. Methadone-ZN should be used cautiously in patients receiving concomitant administration of other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, tricyclic antidepressants, and other CNS depressants, including alcohol, as such combinations may lead to respiratory depression, arterial hypotension, profound sedation, and even coma. Concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression, and death.

Cannabidiol. Concomitant use of cannabidiol may lead to increased methadone plasma concentration.

Interaction with serotonergic drugs. Serotonin syndrome may occur when methadone is used concomitantly with 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 it is necessary to resume administration of the drug after its discontinuation, the initial dose should be low and increased gradually to avoid serious toxic effects and respiratory depression.

Methadone-ZN is intended for oral use only. The drug must not be used for injection.

Use of Methadone-ZN may lead to morphine-type dependence. Repeated use of Methadone-ZN may result in psychological and physical dependence, as well as development of tolerance. Therefore, the same caution should be exercised when using Methadone-ZN as when using morphine.

There is a significant risk of respiratory depression when abruptly switching from other opioids to Methadone-ZN; therefore, transition to Methadone-ZN should be performed cautiously.

Incomplete cross-tolerance between methadone and other opioids. Partial tolerance to Methadone-ZN may occur in patients tolerant to other opioids, particularly in those sensitive to other µ-opioid receptor agonists. In such cases, determining the appropriate dose of Methadone-ZN is difficult. Fatal cases have been reported when switching to Methadone-ZN after prolonged use of other opioid antagonists.

High levels of opioid tolerance do not eliminate the possibility of toxic effects when using Methadone-ZN.

Interaction with alcohol and narcotics. Methadone-ZN exerts additive effects when used concomitantly with alcohol and other central nervous system (CNS)-depressant drugs, including other opioid narcotics. Fatal cases have been reported in individuals abusing benzodiazepines while taking Methadone-ZN.

Anxiety states. Since Methadone-ZN, when used in constant maintenance doses by patients tolerant to it, is not a tranquilizer, anxiety states may develop in patients undergoing maintenance therapy in response to stress and life problems. Physicians should not confuse these symptoms with withdrawal symptoms and should not attempt to treat such conditions by increasing the dose of Methadone-ZN. The effect of Methadone-ZN 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. In head injuries, respiratory depression and increased cerebrospinal fluid pressure induced by Methadone-ZN are significantly more pronounced. The same danger exists in other intracranial pathologies or in patients with previously observed elevated intracranial pressure. Side effects of opioids may mask the true clinical condition in patients with head injuries.

Bronchial asthma and other respiratory disorders. The main danger in using Methadone-ZN is the potential for respiratory depression. This issue is particularly important in elderly patients, debilitated individuals, and in conditions associated with hypoxia or hypercapnia, where even moderate therapeutic doses may significantly reduce pulmonary ventilation.

Therefore, Methadone-ZN should be prescribed with extreme caution in conditions associated with hypoxia, hypercapnia, or reduced respiratory reserve, such as bronchial asthma, chronic obstructive pulmonary disease, marked obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression, or coma. In such patients, even usual therapeutic doses of Methadone-ZN may cause depression of the respiratory center along with increased airway resistance, potentially leading to respiratory arrest. In these cases, non-opioid analgesics are recommended; if they are insufficiently effective, Methadone-ZN may be used only under appropriate 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 developing CSA in a dose-dependent manner. For patients with CSA, consideration should be given to reducing the total opioid dose.

Hypotensive effect. Use of Methadone-ZN may lead to pronounced arterial hypotension in patients whose ability to maintain blood pressure is impaired due to reduced blood volume or concomitant use of drugs such as phenothiazines or certain anesthetics.

Use in outpatient settings. Use of Methadone-ZN may impair mental and physical abilities required for working with high-risk sources (e.g., driving vehicles, operating machinery). Methadone-ZN, 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-ZN, these small doses will not be effective for analgesia. In such cases, analgesics—including opioids indicated for similar pain syndromes in other patients—should be prescribed. Since Methadone-ZN induces opioid tolerance, higher doses of these drugs may be required.

Risk of relapse in drug-dependent patients receiving methadone maintenance therapy. Sudden discontinuation of opioids may lead to withdrawal syndrome. This increases the risk of patients returning to self-administration of narcotics, which should be considered when evaluating the risk/benefit ratio of prescribing maintenance methadone therapy.

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

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

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

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

The risk of developing 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 pre-existing psychiatric disorders (such as severe depression, anxiety, or personality disorders).

Patients should be monitored for signs of addictive behavior (e.g., requesting early prescription refills), which may necessitate review of concomitant opioid and psychotropic drug therapy (including benzodiazepines). Patients showing signs and symptoms of OUD should be referred for consultation with an addiction specialist.

Abrupt discontinuation of Methadone-ZN therapy in physically dependent patients may lead to withdrawal syndrome. Both withdrawal and abstinence syndromes are characterized by symptoms such as restlessness, increased lacrimation, rhinorrhea, excessive sweating, chills, yawning, myalgia, and miosis. Other symptoms may also develop: irritability, back pain, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, elevated blood pressure, increased heart rate, and increased respiratory rate.

Generally, abrupt discontinuation of Methadone-ZN after prolonged use is not recommended.

Special considerations in specific patient groups. Methadone-ZN should be prescribed cautiously and with low initial doses in certain patient groups (elderly patients, debilitated patients, patients with severe hepatic or renal dysfunction; in hypothyroidism, Addison’s disease, prostate hyperplasia, urethral stricture). It should also be noted that use of Methadone-ZN may lead to respiratory depression.

Methadone-ZN should primarily be prescribed to patients in whom the benefit of opioid analgesia outweighs the known risks associated with use of this drug (cardiac conduction disturbances, respiratory depression, changes in mental status, postural hypotension).

The drug should be used with particular caution in patients with acute alcoholism or seizure disorders; with caution in patients with adrenocortical insufficiency, prostate hyperplasia, arterial hypotension, inflammatory or obstructive intestinal disorders, or myasthenia gravis.

The drug should also be used cautiously in patients with ischemic heart disease; in those with a family history of sudden cardiac death; and when used concomitantly with drugs that prolong the QT interval.

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

Use in patients with renal impairment. Data on the safety of Methadone-ZN in patients with renal impairment are lacking.

Use in patients with hepatic impairment. Data on the use of Methadone-ZN in patients with hepatic dysfunction are insufficient; however, it should be noted that Methadone-ZN is metabolized in the liver. Therefore, hepatic impairment increases the risk of methadone accumulation.

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

Methadone-ZN should be used with particular caution in patients at increased risk of QT interval prolongation (e.g., cardiac hypertrophy, concomitant use of diuretics, hypokalemia, hypomagnesemia). Use in patients with a history of conduction disorders or at risk of arrhythmias is possible only with careful monitoring. QT interval prolongation has also been observed in some patients without prior cardiac dysfunction, especially with high-dose use. When QT prolongation occurs during Methadone-ZN therapy, known risk factors should be addressed, including concomitant medications affecting cardiac function, drugs altering electrolyte balance, and drugs that may inhibit methadone metabolism. When prescribing Methadone-ZN for pain relief, the risk of QT prolongation and cardiac arrhythmias must be considered. This risk should be weighed against the potential benefits of treatment for pain relief and alternative therapeutic options.

Methadone-ZN therapy for acute or chronic pain should only be initiated if the potential favorable analgesic or palliative effect outweighs the risk of life-threatening complications associated with high-dose use of this drug.

Individualized assessment of potential benefit versus risk is required when using Methadone-ZN, considering both patient history and clinical findings. If risk factors are identified, careful monitoring of cardiovascular status—including QT interval duration and occurrence of arrhythmias—is necessary.

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

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

Hypoglycemia. Hypoglycemia has been observed with methadone overdose or dose escalation. Regular monitoring of blood glucose levels is recommended during dose increases (see sections "Overdose" and "Adverse reactions").

Excipients. Due to the presence of lactose, the drug should not be administered to patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

If a patient has known sugar intolerance, consultation with a physician is required before taking this medication.

Use during pregnancy or breastfeeding.

Methadone-ZN penetrates saliva, breast milk, amniotic fluid, and umbilical cord plasma.

Pregnancy

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

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

When prescribing the drug to a pregnant woman, she must be informed about possible consequences of its use for both herself and the child. Use of Methadone-ZN during pregnancy should be under close medical supervision.

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

Labor and delivery

As with other opioids, use of Methadone-ZN shortly before delivery may cause respiratory depression in the newborn, especially with high doses; therefore, Methadone-ZN is not recommended for obstetric analgesia. Opioid drugs with mixed agonist-antagonist properties should not be used for labor analgesia in patients who have been using Methadone-ZN long-term, as these drugs may precipitate acute withdrawal.

Breastfeeding period

Methadone-ZN passes into breast milk and therefore is not recommended for administration to breastfeeding mothers. The risk of serious adverse reactions in infants must be weighed against the benefit of treatment for the mother, and a decision must be made whether to discontinue breastfeeding or methadone use.

Methadone is excreted in breast milk at low plasma levels. The decision to recommend breastfeeding should involve physician consultation and consider whether the woman is on a stable maintenance dose of methadone and whether there is any ongoing illicit drug use. 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-ZN are advised to wean their infants from breastfeeding gradually to prevent abstinence syndrome in the newborn.

Ability to affect reaction speed when driving or operating machinery.

Use of Methadone-ZN may impair mental and physical abilities required for working with high-risk sources (e.g., driving vehicles, operating machinery).

Method of Administration and Dosage.

The medication is administered only in specialized facilities. Patients receiving the medication must be under close medical supervision and receive appropriate psychological and social support.

Initial Dosing for Short-Term Detoxification

The dose is individualized according to the patient's clinical condition and subjective well-being, depending on the severity of withdrawal symptoms. The general principle is gradual dose adjustment to establish the minimum effective maintenance dose.

At the beginning of therapy, the average daily dose is 20 mg of methadone hydrochloride for patients with unknown or undefined opioid tolerance, and 40 mg of methadone hydrochloride for patients with known opioid tolerance and a prolonged history of opioid use. In exceptional cases, the initial daily dose may be increased up to 100 mg.

The first dose should be taken in the morning. In individual cases, an additional dose may be administered in the evening of the first day to prevent withdrawal symptoms. In any case, the dose must always be sufficient to keep withdrawal symptoms within an acceptable range.

If such symptoms are present, the dose should be gradually increased by 10–20 mg. The maximum daily dose for adults is 120 mg per day.

Patients should be reminded that the medication has a prolonged effect, as methadone accumulates in tissues.

Changing the Type of Therapy

When switching a patient from levomethadone to methadone hydrochloride, the dose should be adjusted according to a 1:2 ratio (levomethadone : methadone hydrochloride), i.e., 5 mg of levomethadone is equivalent in efficacy to 10 mg of methadone hydrochloride. In some cases, this substitution may require additional dose adjustments.

Maintenance Therapy

During maintenance treatment, the medication should be titrated to a dose at which opioid withdrawal symptoms do not occur over 24 hours, craving for opioids is reduced, euphoric effects of opioids are blocked or diminished, and the patient is no longer sensitive to the sedative effects of methadone. Clinical stability is usually achieved at a daily dose of 80–120 mg in most cases.

Discontinuation of Therapy After a Period of Maintenance Treatment

Discontinuation of replacement therapy should be performed gradually, with a slow reduction of the daily dose over several weeks or months. There are significant differences in methadone dose reduction protocols among patients who choose to discontinue methadone therapy under medical supervision. Generally, it is recommended to reduce the dose by less than 10% of the established maintenance dose, with dose reductions occurring every 10–14 days. Patients must be informed about the high risk of relapse to opioid dependence after discontinuation of methadone maintenance therapy.

Pain Syndrome

Before initiating methadone therapy, the treatment strategy—including duration and goals—should be discussed and agreed upon with the patient, in accordance with pain management protocols. During therapy, the physician should maintain frequent contact with the patient to assess the need for continued treatment, consider the possibility of discontinuation, and adjust doses if necessary. When the patient no longer requires methadone therapy, a gradual dose reduction is recommended to prevent withdrawal symptoms (see section "Special Precautions"). In the absence of adequate pain control, tolerance development and progression of the underlying disease should be considered (see section "Special Precautions").

The dose must be carefully individualized based on the intensity of pain and the patient's response to the medication. The safest approach to initiating methadone therapy and dose titration is to start with a low initial dose and gradually adjust it.

Methadone should generally not be used to treat severe pain in patients who have not previously received other opioid medications.

Typically, adults are prescribed an oral dose of 2.5–10 mg every 4 hours during the first 3–5 days. The dose is gradually titrated until the desired effect is achieved. Subsequently, a fixed dose is administered every 8–12 hours, depending on the patient's condition and response to treatment.

Elderly patients should receive the medication once daily.

For a 2.5 mg dose, methadone hydrochloride in a formulation with the appropriate strength should be prescribed.

Method of Administration and Duration of Therapy

Tablets should be taken with sufficient fluid (1 glass of water).

Patients should be informed that oral administration is the only effective and safe route of administration for this medication.

The duration of therapy depends on the success of substitution treatment and the patient's subjective well-being, in accordance with general principles of substitution therapy. The goal of therapy is for the patient to discontinue the use of illicit opioids. The duration of therapy may vary from a short-term course (e.g., as a substitute for illicit substances during inpatient treatment) to long-term therapy.

Children

The safety and efficacy of Methadone-ZN in children have not been studied.

Overdose.

Clinical Manifestations. In significant overdose, Methadone-ZN causes respiratory depression (decreased respiratory rate and/or reduced tidal volume, Cheyne-Stokes respiration, cyanosis), stupor or coma, pinpoint pupils, muscle weakness, cold and clammy skin, and sometimes bradycardia and arterial hypotension. Hypoglycemia has been reported. Toxic leukoencephalopathy has been observed in cases of methadone overdose.

Treatment. Particular attention should be given to restoring adequate respiration; controlled ventilation should be used if necessary. In overdose cases involving individuals without tolerance to the drug, effective antagonists can be administered to counteract potentially life-threatening respiratory depression.

It should be noted that Methadone-ZN is a long-acting medication (36–48 hours), whereas its antagonists act for only 1–3 hours.

Therefore, careful monitoring of the patient is essential. If opioid antagonists are required, repeated administration may be necessary. If the physician is certain that respiratory depression is solely due to Methadone-ZN overdose, respiratory stimulants are not indicated.

Opioid antagonists should not be used in the absence of clinically significant respiratory or cardiovascular depression. In patients with physical opioid dependence, administration of opioid antagonists may precipitate acute withdrawal syndrome. The severity of withdrawal depends on the degree of physical dependence and the dose of the antagonist administered. In cases of severe respiratory depression in physically dependent patients, opioid antagonists should be used with extreme caution, and the antagonist should be titrated using doses lower than usual (10–20% of the recommended dose).

In cases of intoxication, intravenous injections of naloxone or nalmefene may be administered. Because the half-life of naloxone is shorter than that of methadone, multiple naloxone injections may be required until the patient's condition stabilizes. Intravenous naloxone infusions may also be used.

Oxygen, intravenous fluids, vasopressors, and other supportive therapies may be administered as indicated.

Warning. Administration of opioid antagonists at usual doses to individuals with physical opioid dependence may precipitate acute withdrawal syndrome. The use of opioid antagonists in physically dependent individuals should be avoided unless absolutely necessary.

Adverse reactions.

Heroin withdrawal.

At the beginning of substitution therapy, withdrawal symptoms are often observed, such as anxiety, anorexia, spontaneous involuntary twitching movements, goosebumps, depression, diarrhea, vomiting, fever, yawning, weight loss, nausea, sneezing, pupil dilation, irritability, rhinorrhea, physical pain, dizziness, excessive lacrimation, profuse sweating, intestinal spasms, tachycardia, tremor, restlessness, stomach cramps, involuntary muscle twitching, alternating chills and hot flashes. The frequency and severity of adverse effects gradually decrease over several weeks.

Initial dose.

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

The most dangerous adverse reactions associated with methadone use are respiratory depression and arterial hypotension.

Fatal outcomes have been reported.

The most commonly observed adverse reactions are dizziness, sedative effect, nausea, vomiting, and increased sweating. In such cases, the methadone dose may be reduced.

Use in patients with impaired liver function.

During long-term maintenance methadone therapy, adverse effects gradually diminish over several weeks, although increased sweating and constipation may persist.

Other adverse reactions reported during methadone use.

Blood system: bleeding, reversible thrombocytopenia, eosinophilia.

Psychiatric disorders: euphoria, depressive state, hallucinations, dysphoria, convulsive seizures, dependence.

Nervous system: drowsiness, sedative effect, confusion, unconsciousness, disorientation, headache, fatigue, insomnia, excitement.

Eye disorders: visual disturbances (dysopia).

Cardiovascular system: palpitations, bradycardia, edema, arterial and orthostatic hypotension, cardiac arrest, circulatory failure, shock, T-wave inversion, arrhythmia, extrasystoles, flutter and ventricular fibrillation/tachycardia, QT interval prolongation, bigeminy, syncope, cardiomyopathy, heart failure, phlebitis.

Respiratory system: respiratory depression, respiratory arrest, pulmonary edema, worsening of bronchial asthma, central sleep apnea syndrome.

Gastrointestinal tract: vomiting, nausea, dry mouth, constipation, abdominal pain, anorexia, glossitis.

Hepatobiliary system: biliary tract spasm.

Skin and subcutaneous tissue: excessive sweating, urticaria, skin rashes, pruritus, flushing, hot flashes.

Renal and reproductive system: urinary retention and micturition disorders, amenorrhea, decreased libido and/or potency.

Other: hypokalemia, hypomagnesemia, hypoglycemia, loss or increase in body weight, asthenia, weakness, development of tolerance.

Methadone-ZN is a µ-opioid receptor agonist; therefore, dependence of the same type as with morphine may develop during treatment with this drug.

Shelf life. 5 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

Tablets 5 mg, 10 mg, and 25 mg; 10 tablets per blister; 10 blisters per carton.

Tablets 40 mg; 10 tablets per blister; 5 or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

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

Methadone-zn