Methadone hydrochloride molteni

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METHADONE HYDROCHLORIDE MOLTENI (METHADONE HYDROCHLORIDE MOLTENI)

Composition:

Active substance: methadone;

1 ml of solution contains methadone hydrochloride 5 mg;

Excipients: sucrose, glycerol, sodium benzoate (E 211), citric acid monohydrate, lemon flavor, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, colorless or slightly yellow syrupy solution with a lemon odor.

Pharmacotherapeutic group.
Medicinal products 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 primarily affects the central nervous system and organs containing smooth muscle. Methadone exerts analgesic and sedative effects and also demonstrates detoxifying or maintenance effects in opioid dependence. Signs of analgesia appear within 30–60 minutes after administration.

Methadone causes a withdrawal syndrome similar to that induced by morphine; however, it is characterized by more gradual onset, moderately prolonged duration of action, and milder symptoms.

Pharmacokinetics.

Methadone is rapidly absorbed in the gastrointestinal tract (within 30 minutes after oral administration), reaching maximum blood concentration (Cmax) within 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 metabolized in the liver with the involvement of CYP3A4 and is excreted from the body in the form of metabolites via urine and feces. In patients who have not previously used opioids, the apparent mean elimination half-life is approximately 15 hours after a single dose, whereas with continuous 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 methadone concentration 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 drugs), as well as for maintenance treatment of patients with opioid addiction;
• For relief of severe pain (not controlled by non-narcotic analgesics) in patients with malignant tumors.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients; presence of contraindications to the use of opioids, such as respiratory depression (in the absence of necessary resuscitation equipment); acute exacerbation of bronchial asthma, CO2 retention in 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; biliary and urinary tract spasm; treatment of addicts dependent on weak opioids (pethidine, codeine), and treatment of patients dependent 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 stimulate hepatic metabolism of methadone. Concomitant use of Methadone Hydrochloride Molteni with CYP3A4 inducers may lead to withdrawal syndrome. Due to reported cases of such interactions, dose adjustment (increase) of methadone may be necessary in the presence of withdrawal symptoms. When therapy with CYP3A4 inducers is discontinued, methadone dosage should be reduced. CYP3A4 inhibitors (cannabinoids, clarithromycin, delavirdine, erythromycin, fluconazole, grapefruit juice, selective serotonin reuptake inhibitors (sertraline, fluvoxamine), itraconazole, ketoconazole, nefazodone) may cause increased methadone concentration.

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

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

Methadone increases plasma concentration of zidovudine both after oral and intravenous administration, and increases AUC of orally administered zidovudine more than after intravenous administration. These effects are due to inhibition of glucuronide conjugation of zidovudine, resulting in reduced renal clearance. During treatment with methadone, monitoring for possible zidovudine toxicity is required, and zidovudine dose should be reduced if toxicity occurs. Patients receiving both drugs 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, decreased plasma methadone concentration is observed. However, withdrawal syndrome does not always occur. Nevertheless, concomitant use of these drugs with methadone requires caution. At the same time, interaction with abacavir usually does not require dose adjustment.

Nevirapine may reduce methadone concentration by increasing its hepatic metabolism. Withdrawal syndrome has been reported with concomitant use of methadone and nevirapine. If nevirapine is prescribed to patients receiving Methadone Hydrochloride Molteni, careful monitoring for withdrawal symptoms is required, and methadone dose should be adjusted if necessary.

Efavirenz stimulates methadone metabolism via cytochrome P450 3A4. After 3 weeks of efavirenz treatment, mean Cmax and AUC of methadone are reduced by 48% and 57%, respectively. It is assumed that adding efavirenz to methadone therapy may lead to withdrawal syndrome, typically beginning after 2 weeks of efavirenz treatment but potentially lasting up to 28 days. Therefore, dose adjustment may be necessary.

Methadone is a weak base. Urine acidifiers (ammonium chloride) may increase renal clearance of methadone. In such cases, methadone dose may need to be increased.

Concomitant use of methadone with metamizole, an inducer of metabolic enzymes including CYP2B6 and CYP3A4, may lead to decreased plasma methadone concentration and potential reduction in clinical efficacy. Therefore, caution is advised when using metamizole and methadone together, and clinical response and/or drug levels should be monitored appropriately. Repeated oral administration of voriconazole leads to increased Cmax and AUC of the pharmacologically active enantiomer of methadone (R-methadone) in patients receiving maintenance methadone doses (30–100 mg once daily). Increased plasma methadone concentration may lead to toxic effects associated with QT interval prolongation. Dose reduction of methadone may be required.

Concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression, and death.

Concomitant use of cannabidiol may increase methadone plasma concentration.

Concomitant use of Methadone Hydrochloride Molteni and sedative medicinal products such as benzodiazepines or related drugs increases the risk of sedation, somnolence, respiratory depression, coma, and death due to additive central nervous system (CNS) depressant effects. Due to these risks, the dose and duration of concomitant use should be limited and considered only when alternative treatment options are not feasible.

Other drugs. Use of meperidine at therapeutic doses in patients taking monoamine oxidase inhibitors (MAOIs) may lead to severe adverse reactions. Although such reactions have not been reported with methadone, if methadone must be used in patients taking MAOIs, a sensitivity test should be performed, administering small doses initially and gradually increasing them while monitoring the patient’s condition over several hours.

Concomitant use of methadone increases plasma levels of desipramine.

Pharmacodynamic interactions

Opioid antagonists (naloxone and naltrexone) produce pharmacological effects opposite to those 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 induce and enhance neurological, respiratory, and hypotensive effects. Additive or antagonistic effects depend on methadone dosage and are more commonly observed at low and moderate methadone doses. These drugs may precipitate withdrawal syndrome in patients undergoing long-term therapy.

In patients receiving concomitant methadone and drugs that impair cardiac conduction or electrolyte balance, cardiac disturbances may occur. Under such circumstances, monitoring of electrocardiogram parameters 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, paralyze ileal function. Octreotide, a synthetic somatostatin analogue, may reduce the analgesic effect of methadone and morphine; therefore, loss or complete absence of pain control should prompt consideration of discontinuing octreotide.

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

Concomitant use of Methadone Hydrochloride Molteni and agomelatine results in a 25% and 13% reduction in plasma Cmax and AUC for R-methadone, respectively. Careful monitoring of patients is required when Methadone Hydrochloride Molteni and agomelatine are used concomitantly to prevent a reduction in effective methadone dose, especially if ritonavir is also used. Concomitant use of Methadone Hydrochloride Molteni and agomelatine reduces AUC, maximum, and minimum concentrations of agomelatine by 30%, 27%, and 25%, respectively.

Changes in plasma methadone levels have been observed when verapamil is used concomitantly with Methadone Hydrochloride Molteni. An increase in Methadone Hydrochloride Molteni dose may be necessary.

Concomitant use of Methadone Hydrochloride Molteni with the non-nucleoside reverse transcriptase inhibitor rescriptor may require a reduction in Methadone Hydrochloride Molteni dose.

Particular caution should be exercised 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 required when combining methadone with drugs that disturb electrolyte balance (hypomagnesemia, hypokalemia), which may also contribute to QT interval prolongation. Such agents include diuretics, laxatives, and rarely mineralocorticoids.

Methadone reduces mexiletine absorption.

Methadone Hydrochloride Molteni should be used with caution in patients who are simultaneously prescribed other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, 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.

Sedation, confusion, and respiratory depression may occur with concomitant use of ciprofloxacin and methadone.

Methadone may affect the results of pregnancy tests.

Serotonergic medicinal products: 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 (TCAs). 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 dose escalation should be performed gradually to avoid serious toxic effects and respiratory depression.

The drug is intended for oral use only. It must not be used for injections.

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

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

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. For patients with CSA, consideration should be given to reducing the total opioid dose.

Incomplete cross-tolerance between methadone and other opioids

Patients tolerant to other opioids may exhibit partial tolerance to methadone, especially in individuals unresponsive to other µ-opioid receptor agonists. In such cases, determining the appropriate methadone dose can be challenging. Fatal cases have been reported when switching to methadone after prolonged use of other opioid antagonists.

A high degree of opioid tolerance does not eliminate the risk of toxic effects when using Methadone Hydrochloride Molteni.

Interaction with alcohol and drugs. Methadone exerts additive effects when used concomitantly with alcohol and other central nervous system (CNS) depressants, including other narcotic drugs. Methadone should be used cautiously at lower 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 with general anesthetics, phenothiazines, other hypnotic-sedative agents, tricyclic antidepressants, other CNS depressant drugs, and alcohol may result in CNS depression, profound sedation, coma, or respiratory depression.

Risk associated with concomitant use of sedative medicinal products such as benzodiazepines or related substances.

Concomitant use of Methadone Hydrochloride Molteni and sedative medicinal products such as benzodiazepines or related substances may lead to sedation, respiratory depression, coma, or death. Due to these risks, concomitant prescription of these sedative agents should be limited to patients for whom alternative treatment options are not feasible. If concomitant use is deemed necessary, the lowest effective dose should be used, and treatment duration should be as short as possible. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, it is strongly recommended to inform patients and caregivers about the need to monitor for these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Anxiety states. Since methadone administered to patients with tolerance to it in constant maintenance doses is not a tranquilizer, anxiety states may develop in patients receiving maintenance therapy in response to stress and life problems. Methadone does not act against fear; therefore, symptoms of restlessness and anxiety occurring during therapy should not be treated by increasing the methadone dose. These symptoms should not be mistaken for withdrawal symptoms, and attempts to treat such conditions by increasing the methadone dose should be avoided. The action of methadone during maintenance therapy is limited to controlling opioid-related symptoms and does not extend to alleviating anxiety states.

Head injuries and increased intracranial pressure. In head injuries, respiratory depression and increased cerebrospinal fluid pressure caused by methadone may be significantly more pronounced. The same danger exists in other intracranial pathologies or in patients with previously observed increased intracranial pressure. Adverse effects of opioids may mask neurological symptoms in patients with head trauma. Contraindicated in patients with increased intracranial pressure and in patients with traumatic brain injury.

Bronchial asthma and other respiratory disorders. The main danger of methadone use lies in the potential for respiratory depression. This issue is particularly significant for elderly patients, debilitated patients, and in cases of hypoxia or hypercapnia, where even moderate therapeutic doses of the drug may significantly reduce pulmonary ventilation. Therefore, methadone is contraindicated in patients with hypercapnia, bronchial asthma in the acute phase, patients with obstructive lung diseases, and in respiratory depression (in the absence of necessary 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, and coma. In such patients, even usual therapeutic doses of methadone may cause depression of the respiratory center, especially when combined with increased airway resistance, potentially leading to respiratory arrest. In such cases, non-opioid analgesics are recommended; if they are insufficiently effective, methadone use may be considered only under appropriate monitoring.

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 acute abdomen.

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

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

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

Outpatient use. Methadone use may impair mental and physical abilities required for activities involving high-risk sources (driving a car, operating machinery). Like other opioids, methadone may cause orthostatic hypotension in outpatients.

Use for 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 indicated for similar pain syndromes in other patients, should be prescribed. Since methadone induces opioid tolerance, higher doses of these agents may be required.

Repeated use of Methadone Hydrochloride Molteni 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 initiating and during treatment with Methadone Hydrochloride Molteni, the treatment goals and discontinuation plan 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 Methadone Hydrochloride Molteni 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), current tobacco use, or those with existing psychiatric disorders (e.g., severe depression, anxiety, personality disorders).

Patients should be monitored for signs of drug-seeking behavior (e.g., requesting early prescription refills). This includes reviewing concomitant opioid and psychotropic drug therapy (e.g., benzodiazepines). Patients showing signs and symptoms of OUD should be referred to a specialist in addiction medicine.

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

Opioid use disorders (abuse and dependence).

Tolerance manifests as the need for increasing doses of opioids to maintain a certain effect, such as analgesia. Physical dependence is characterized by withdrawal syndrome after abrupt discontinuation of the drug or administration of an antagonist. Both tolerance and physical dependence may occur during long-term opioid therapy.

Abrupt discontinuation of methadone therapy in physically dependent patients may lead to withdrawal syndrome. Both withdrawal syndrome and abstinence syndrome are characterized by symptoms such as anxiety, lacrimation, rhinorrhea, 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 after prolonged use is not recommended.

As with other opioids, repeated use of methadone may lead to tolerance, physical and/or psychological dependence.

Special considerations in specific patient groups. Use with caution and at low initial doses in elderly patients, debilitated patients, patients with impaired liver or kidney function, hypothyroidism, Addison's disease, prostate hypertrophy, urethral stricture, hypopituitarism, shock, patients with seizures; inflammatory or obstructive intestinal disorders, patients with chronic/severe constipation, myasthenia gravis, patients with congenital heart defects, uncompensated diabetes, oligemia, hematoporphyria, frequent asthmatic attacks, respiratory disorders, patients with cor pulmonale, patients with ischemic heart disease; patients with a family history of sudden cardiac death. Particular caution is required in patients with pheochromocytoma; increased symptoms of arterial hypertension have been reported with diamorphine use.

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

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

Use in elderly patients. Dose selection should generally 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. There are no data on the safety of methadone use in patients with renal insufficiency.

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

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, but not exclusively, occurred with high-dose methadone (over 200 mg/day). Most complications occurred with doses used for pain relief, 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 interval prolongation (e.g., cardiac hypertrophy, concomitant use of diuretics, hypokalemia, hypomagnesemia). Methadone 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 methadone. When 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 rhythm disturbances must be considered. This risk should be weighed against the potential benefits of treatment for pain relief and the availability of alternative therapies. Use with caution in patients at risk of prolonged QT interval: history of prolonged QT interval, progressive heart disease, ischemic heart disease, liver disease, concomitant use of other drugs that prolong the QT interval.

Methadone therapy for analgesia in acute or chronic pain should only be initiated when the potential beneficial analgesic or palliative effect outweighs the risk of potentially life-threatening complications associated with high-dose use of this drug.

Individualized assessment is required when balancing potential benefits against potential risks, taking into account both patient history and clinical findings. If risk factors are identified, careful monitoring of cardiovascular status, including QT interval and arrhythmias, is necessary.

The product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicine.

Use during pregnancy or breastfeeding.

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

Pregnancy

Methadone may be used during pregnancy only if the potential benefit to the pregnant woman outweighs the potential 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, methadone use during pregnancy may lead to withdrawal syndrome in some patients. Dose increases, shorter dosing intervals, or splitting doses into multiple administrations may be necessary.

When prescribing methadone to a pregnant woman, she must be informed about the possible consequences of drug use for both herself and the child. Methadone use during pregnancy should be conducted under strict medical supervision.

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

Labor and delivery

As with all opioids, methadone use shortly before delivery may cause respiratory depression in the newborn, especially with high doses; therefore, methadone is not recommended for obstetric analgesia. Mixed agonist-antagonist narcotic drugs should not be used for pain relief during labor in patients who have been using methadone long-term, as these drugs may trigger acute withdrawal syndrome.

Breastfeeding

Methadone is excreted in breast milk in low concentrations. The decision on whether breastfeeding is possible should be made based on a clinical assessment by a healthcare professional, including the woman's condition (whether she is on a stable methadone maintenance dose) and the presence or absence of ongoing use of unauthorized psychoactive substances.

If the decision is made to breastfeed, the methadone dose should be as low as possible. Women breastfeeding during methadone therapy should be advised to closely monitor the infant for possible signs of sedation or breathing difficulties and to seek immediate medical help if such signs occur. Although the amount of methadone transferred into breast milk is insufficient to fully suppress withdrawal symptoms in infants, it may alleviate the course of neonatal abstinence syndrome.

If breastfeeding must be discontinued, it should be done gradually, as abrupt cessation may worsen withdrawal symptoms in the infant.

Ability to affect reaction speed when driving or operating machinery.

Methadone use may impair mental and physical abilities required for activities involving high-risk sources (driving a car, operating machinery).

Method of Administration and Dosage.

The drug is intended for oral use only.

Patients receiving Methadone Hydrochloride Molteni must be under close supervision and receive appropriate psychological and social support.

Treatment of Opioid Dependence

Regarding the treatment of opioid dependence, this medication is intended for daily administration according to the medical assessment outlined in the treatment protocol. The duration of 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 outlined below are recommended, but may still be adjusted based on clinical evaluation. Initially, a single dose of 20–30 mg of methadone is usually sufficient to alleviate withdrawal symptoms. A higher dose of methadone may be prescribed if withdrawal symptoms are not controlled or reappear. In patients physically dependent on high opioid doses, there may be a need to increase the dosage level. Generally, an adequate dosage level is 40 mg daily, administered as a single dose or in divided doses. Stabilization may take 2–3 days, after which the methadone dose should be gradually reduced.

The frequency of methadone administration after dose reduction should be individually determined for each patient. A daily reduction of the total daily dose by 10% is generally well tolerated by inpatients. For outpatients, a slower dose reduction over a longer period may be necessary. If methadone is administered for longer than three weeks, this procedure is considered maintenance therapy rather than detoxification or treatment of acute withdrawal syndrome, even if the ultimate goal is complete discontinuation.

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

Such treatment may also be prescribed for patients with confirmed opioid addiction, or for HIV-infected patients in critical immunological conditions or those with AIDS, if the physician determines that other treatment programs are less likely to succeed in achieving abstinence from opioids. When properly administered, substitution therapy can also eliminate the so-called "craving," characterized by compulsive heroin-seeking behavior driven by the intense desire of the addicted patient to obtain the drug.

There is no need to perform systemic testing using naloxone in patients with severe heroin dependence known to the treatment center; however, testing for morphine in body fluids remains essential. Urine testing is mandatory during methadone treatment to monitor the presence of narcotic drugs and psychotropic substances as directed by the physician. Testing for excessive alcohol levels is also required. If opioid substances are detected in urine, the case must be reassessed.

In each individual case, dosage is determined by the physician 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 had 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 Hydrochloride Molteni 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. An additional 10 mg of the drug may be administered if withdrawal symptoms appear. 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

The dose of Methadone Hydrochloride Molteni must be carefully titrated according to the severity of pain and the patient's response to the drug. Initiation of treatment and dose titration should begin with a low initial dose, with gradual dose adjustments.

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

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

Elderly patients should receive the drug once daily.

Treatment Goals and Discontinuation

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

Children

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

Overdose

In cases of significant methadone overdose, respiratory depression (reduced respiratory rate and/or decreased tidal volume, Cheyne-Stokes respiration, cyanosis) occurs, along with excessive drowsiness progressing to stupor or coma. Pinpoint pupils are observed; miosis may alternate with mydriasis. Muscle weakness, cold and clammy skin, bradycardia, and arterial hypotension may also occur. In children, overdose has been reported to cause drowsiness, lethargy, pinpoint pupils, and dyspnea. In severe overdose, especially after oral ingestion, respiratory arrest, circulatory collapse or shock, cardiac arrest, and death may occur. Toxic leukoencephalopathy has been observed in cases of methadone overdose. Hypoglycemia may also occur.

Treatment

First and foremost, adequate respiratory rhythm must be ensured, with fresh air supply and appropriate supportive ventilation, along with ECG monitoring. For accidental ingestion of a large methadone dose, especially by a child, effective narcotic antagonists are available to counteract potentially fatal respiratory depression.

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 recurrence of respiratory depression, and repeated antagonist treatment may be necessary. Respiratory stimulants are not indicated if the diagnosis is confirmed and respiratory depression is solely due to methadone overdose.

Narcotic antagonists should not be administered if there is no clinically significant respiratory or cardiovascular depression. Narcotic antagonists administered intravenously (naloxone, nalorphine, levallorphan) are the primary therapeutic agents for reversing intoxication symptoms.

These agents should be administered repeatedly until the patient's condition is satisfactory. When naloxone is used, the risk of subsequent respiratory depression caused by the antagonist is less likely.

Appropriate supportive measures include oxygen, intravenous fluids, vasopressors, and other supportive therapies.

In patients with physical opioid dependence, 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 antagonist administered. Use of antagonists in physically dependent patients with significant respiratory depression should be performed with extreme caution, using titrated doses much lower than usual (10–20% of the recommended dose).

Administration of opioid antagonists at standard doses in physically dependent patients may trigger acute withdrawal syndrome. Opioid antagonists should be avoided in physically dependent individuals unless absolutely necessary.

Acidification of urine increases methadone excretion.

Methadone is not removed by peritoneal dialysis or hemodialysis.

Adverse reactions.

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

Initial dose. Particular attention must be paid to the 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, or shock. Fatal outcomes have been reported.

The most commonly observed adverse reactions are: dizziness, restlessness, feeling of emptiness in the head, sedative effect, nausea, vomiting, increased 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 during methadone use:

General reactions: asthenia, weakness, hot flushes, development of tolerance, hypothermia;

Cardiovascular system: arrhythmia, bradycardia, extrasystoles, tachycardia, palpitations, ventricular flutter and fibrillation, QT interval prolongation, torsade 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, excitement, insomnia, confusion, seizures, disorientation, dysphoria, euphoria, insomnia, visual disturbances, blurred vision, miosis, dry eyes, vertigo, hallucinations, hyperexcitability;

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

Metabolism: edema, fluid retention, lower limb edema, hypokalemia, hypomagnesemia, loss or gain of body weight, hypoglycemia;

Respiratory system: pulmonary edema, worsening of bronchial asthma; nasal dryness, 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 voiding difficulties, decreased libido and potency, impotence, elevated prolactin levels with prolonged use, galactorrhea;

Psychiatric disorders: dependence.

Use in patients with impaired liver function: during long-term methadone maintenance therapy, adverse effects gradually diminish over several weeks, although increased 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.

Adverse effects related to excipients are possible: the product contains glycerin, which in large doses may cause headache, stomach upset, and diarrhea.

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

Shelf life. 3 years.

Storage conditions.

Store in the original vial, protected from light, at a temperature not exceeding 25°C.

Keep out of reach of children.

The solution should be used within 2 months after the first opening of the vial.

Packaging.

1000 ml of the product in a vial with a screw cap, tamper-evident seal, sealed with a polyethylene liner, supplied with a measuring cap.

Prescription category. Prescription only.

Manufacturer.

L. Molteni & C. dei F.lli Alitti Società di Esercizio S.p.A.

Manufacturer's address and place of business.

S.S. 67 (Tosco Romagnola), Località Granatico – 50018 Scandicci, Italy.