NAME OF THE MEDICINE

METHADONE:

• SYRUP dosed at 1.33 mg/ml, 2.66 mg/ml and 4 mg/ml


• CAPSULE dosed at 1 mg, 5 mg, 10 mg, 20 mg, 40 mg
  List of excipients:
  
  
  
  • Carmellose sodium, sodium carboxymethyl starch (type A), magnesium stearate, colloidal anhydrous silica, lactose monohydrate.
  
  
  • Capsule shell: gelatin, titanium dioxide (E171), iron oxides (E172) red, black and yellow (only for cap).
  
  
  
  

THERAPEUTIC INDICATIONS

• Substitution treatment of major drug dependence on opioids within the framework of medical, social and psychological care.


• Treatment of moderate to intense cancer pain (ZORION in France)

Methadone acts on opioid receptors, the serotonin and norepinephrine reuptake system and acts on NMDA receptors (ketamine-like effect).

The treatment is reserved for adults and adolescents over 15 years old.

Dosage and method of administration.

Dosage

Substitution treatment.

• The capsule form is not intended for the implementation of methadone treatment.


• Transition from syrup form to capsule form


• The capsule form will be immediately prescribed at the dosage corresponding to the maintenance dosage reached with the syrup form.


• The first capsule intake should take place the day after the last syrup intake, at the usual time.


• The dosage is usually between 60 and 100 mg/day, although higher doses may be necessary in some patients.


• Subsequent dosage modifications will be based, as for the syrup form, on the clinical reassessment of the patient taking into account the associated management.

Treatment for cancer pain.

• Treatment must be initiated by a hospital team specialized in pain management or palliative care and experienced in the use of methadone.


• The dosage for each patient must be determined individually, depending on the clinical situation (previous analgesic treatment, addiction risk factors) and the therapeutic objective.


• Several protocols for converting opioid treatment to methadone have been studied and are currently used when initiating methadone treatment for cancer-related pain. The two protocols used in the clinical study that evaluated ZORYON (EQUIMETH2) did not demonstrate superior efficacy over each other (see Pharmacodynamic properties section). The two protocols used are detailed below:
  
  
  
  • Patient self-dose control protocol, without overlap with previous opioid treatment (“on demand” protocol, DEM)
    
    
    
    • This protocol is based on two principles to avoid any overdose:
      
      
      
      • Stopping the previous opioid with immediate relay to methadone without overlap,
      
      
      • Equilibration is done by administration on demand by the patient himself (there is no dose imposed by a regular schedule and the patient will only take a dose if he is in pain).
      
      
      
      
    
    
    • Conversion terms:
      
      
      
      • Conversion of the dosage of the opioid to be stopped into Morphine Oral Equivalent (MEO) according to the usual ratios. Checking other medications taken by the patient that may interact with methadone,
      
      
      • Stopping the previous opioid and administering methadone immediately, on demand, until the treatment is balanced, which occurs between the 4th and 6th day,
      
      
      • The unit dose of methadone represents 10% of the MEO dose per 24 hours, without exceeding 30 mg per dose,
      
      
      • After a 1st dose, a 2nd dose can be administered after one hour in the event of residual pain, without exceeding 6 doses/day,
      
      
      • A daily assessment is necessary: if the patient has taken more than 3 doses per 24 hours the unit dose is increased by 30 to 50%,
      
      
      • From the 6th day, possibility of switching to 2 doses per day if the dose has been stable for 48 hours. The 48-hour dose divided by 4 will be administered every 12 hours. In addition, if an interdose is necessary, 1/6th of the fixed 24-hour dose may be administered every 3 hours.
      
      
      
      
    
    
    
    
  
  
  • Fixed-dose conversion protocol with overlap with prior opioid therapy (3DS):
    
    
    
    • This protocol is based on the principle of a gradual transition to avoid a withdrawal syndrome linked to stopping the previous opioid.
    
    
    • Conversion terms:
      
      
      
      • Conversion of the dosage of the opioid to be stopped into Morphine Oral Equivalent (MEO) according to the usual ratios. Checking other medications taken by the patient that may interact with methadone (see Interactions with other medications and other forms of interactions section),
      
      
      • Use of a conversion ratio (MEO: methadone) which varies depending on the MEO dosage of the old opioid:
        
        
        
        • 4:1 for patients who received between 30 and 90 mg of MEO per day (divide by the MEO dose to obtain the methadone dose to be administered),
        
        
        • 6:1 for patients who received between 90 and 300 mg of MEO per day,
        
        
        • 8:1 for patients who received more than 300 mg of MEO per day,
        
        
        
        
      
      
      
      
    
    
    • Distribution of methadone in 3 doses (24/3 dose) orally over 24 hours without exceeding 30 mg per dose,
    
    
    • Dosage reduction of old opioid by 50% at time of rotation and again the next day then discontinuation. There is an overlap of the two opioids for two days (to avoid a withdrawal syndrome from the first opioid and to allow time for methadone to saturate the fats).
    
    
    • Possibility for the patient to have 3 additional doses of the same dosage of methadone as the titration in the event of reappearance of pain from D1 to D3,
      Assessment of the risk of overdose on D4 - D5, in particular drowsiness and respiratory rate.
    
    
    • Adaptation of the methadone dosage according to the quality of relief and tolerance and maintaining 3 doses per day.
    
    
    
    
  
  
  
  


• The choice of protocol to use when initiating treatment is left to the discretion of the hospital team.

Titration phase

ECG monitoring should be performed in all patients with an examination before initiation of methadone and continued if necessary throughout treatment (see sections Contraindications, Warnings and Precautions and Interactions with Others medications and other forms of interactions).

The patient must be hospitalized during the titration phase, due to careful monitoring necessary to detect any sign of overdose, in particular to prevent and manage any risk of respiratory depression (see sections Contraindications, Warnings. warnings and precautions for use, Interactions with other drugs and other forms of interactions and Overdose). This risk is greatest during the first days after the introduction of treatment.

Once the optimal dosage has been achieved, treatment can be continued at home. The patient and those around him must be warned of the signs of overdose which should lead them to urgently consult a doctor.

The benefit of continuing treatment must be regularly reassessed with regard to analgesic needs and adverse effects.

Dosage adjustment

The dosage should be adjusted on a case-by-case basis based on average daily analgesic use until a balance between analgesic efficacy and tolerability is achieved. Dosage adjustment can be done every 24-48 hours. Any increase in dosage presents a risk of overdose which must be monitored. If adverse reactions are poorly tolerated, the next dose may be reduced or the intervals changed (e.g. every 8 hours or every 12 hours).

Conversion from methadone to other opioids

If it becomes necessary to replace ZORYON with another opioid, the duration and variability of the half-life of methadone should be considered (see section 5.2 Pharmacokinetic properties).

Administration mode

• The treatment will be administered in a single daily dose for replacement treatments and in 3 doses per day for analgesic treatments.


• The blister is secure. Due to the fatal risk in the event of accidental ingestion, particularly by a child or a naive or slightly dependent person, patients must be warned to put the blister packs in a safe place and never remove the capsules in advance from the blister. blister, keep blister packs out of the reach of children and do not take this medicine in front of children. An emergency service should be contacted immediately in the event of accidental ingestion or suspected ingestion.

Procedures for gradually stopping treatment

• The substitution treatment must be stopped by gradually reducing the dosage from 1 to 5 mg, in steps spaced at least one week apart. Particular caution is essential during this entire period. The patient will be monitored closely in order to detect, on the one hand, any clinical symptoms suggestive of a withdrawal syndrome for which an immediate return to the previous level is necessary and, on the other hand, any resumption of addictive behavior, which exposes the patient to a risk. of opioid overdose and which would be incompatible with the continuation of treatment with the capsule form (see section Prescribing and dispensing conditions).


• If treatment is stopped and then restarted, the same precautions as when initially initiating treatment and the gradual increase in doses must be taken due to the reduction in tolerance..

Contraindications

• Hypersensitivity to the active substance or any of the excipients mentioned.


• Children and adolescents under 15 years old.


• Situation at high risk of respiratory depression, in particular: patients with severe respiratory failure.


• Patients with established paralytic ileus.


• In combination with a opioid agonist-antagonist (buprenorphine, nalbuphine), with a partial opioid antagonist (naltrexone, nalmefene), with citalopram, escitalopram, domperidone, hydroxyzine, St. John's wort, sodium oxybate or piperaquine.

Special warnings and precautions for use.

Special warnings

• The medication is a opioid derivative whose prescription is exclusively reserved for opioid substitution treatment.


• The success of the treatment is strongly correlated with the dosage and the associated medico-psychological and socio-educational measures.


• Treatment may reveal psychiatric disorders requiring multidisciplinary care, adapted to each patient.

CNS and respiratory depression

• Cases of death from respiratory depression have been reported with methadone. The risk of respiratory depression and death is greater during the period of initiation of treatment and when resuming treatment after a withdrawal period (loss of tolerance).


• Taking methadone with alcohol or central nervous system depressants (such as tranquilizers, sedatives, hypnotics) may increase the risk of central nervous system depression.


• Concomitant use of methadone and sedative medications such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma, and death. Therefore, patients receiving central nervous system depressants and methadone should be monitored even more closely for signs of respiratory depression, sedation, and hypotension.


• Because of these risks, concomitant prescription of these sedative medications should be reserved for patients for whom no other treatment options exist.


• In the case of a decision to prescribe methadone concurrently with sedative medications, the lowest effective dose should be used and the duration of treatment should be as short as possible.


• The patient should be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, it is strongly recommended to inform the patient and those around them to be attentive to these symptoms.


• Concomitant use of methadone with alcoholic beverages or medications containing alcohol is not recommended.

Dependence and withdrawal syndrome

• Physical and psychological dependencies can appear during methadone treatment. Abrupt cessation of treatment leads to the appearance of an opioid withdrawal syndrome and a reduction in acquired tolerance.


• Withdrawal syndrome may present with the following symptoms: restlessness, watery eyes, sneezing, rhinorrhea, yawning, sweating, chills, tremors, mydriasis, irritability, anxiety, pain in the extremities, back pain, arthralgia, myalgia, muscle contracture, muscle spasm , weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate or heart rate, piloerection and fever.


• The appearance of this withdrawal syndrome will be avoided by gradually reducing the doses.

Abuse and misuse

• The risk of abuse and misuse of this medication should be monitored. Misuse may cause serious adverse effects which may be fatal. It is recommended during each consultation to check that the patient is not injecting.

Accidental ingestion

• The lethal dose of methadone is around 1 mg/kg for children and people who are naive or not very dependent on opioids. To avoid any risk of accidental ingestion, patients must be warned to keep the vials secure, never to open the vials in advance, to keep them out of the reach and sight of children and not to take this medicine in front of children. An emergency service should be contacted immediately in the event of accidental ingestion or suspected ingestion.

QT prolongation and torsade de pointes

• Cases of QT interval prolongation and torsades de pointes have been reported during methadone treatment, mainly at high doses (> 120 mg/day). Methadone should be administered with caution, under clinical, electrolyte and ECG monitoring, to patients at risk of QT interval prolongation, i.e. in cases of:
  
  
  
  • a known history of QT prolongation (congenital or acquired),
  
  
  • a family history of sudden death,
  
  
  • high dosage, greater than 120 mg/day,
  
  
  • advanced cardiac pathology,
  
  
  • drug treatments likely to cause torsades de pointes: class Ia antiarrhythmics (disopyramide, hydroquinidine, quinidine), class III antiarrhythmics (amiodarone, dronedarone, sotalol), certain antiparasitics (chloroquine, halofantrine, lumefantrine, pentamidine), arsenics, cocaine , certain macrolides (IV erythromycin, spiramycin), certain neuroleptics (amilsupride, chlorpromazine, cyamemazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, quetiapine, sulpiride, tiapride, zuclopenthixol), crizotinib, delamanid, hydroxychloroquine, moxifloxacin, mequitazine, prucalopride, sulfamethoxazole + trimethoprim, toremifene, vandetanib, vincamine IV.
  
  
  • drug treatments known to cause hypokalemia, or to cause bradycardia, or to significantly inhibit the metabolism of methadone.
  
  
  
  

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.

Decreased sex hormones and increased prolactin

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

Hypoglycemia

Hypoglycemia has been observed in the context of methadone overdose or dose escalation. Regular monitoring of blood glucose is recommended when increasing the dose.

Serotonin syndrome

• Concomitant use of methadone with certain medications may result in serotonin syndrome requiring immediate discontinuation of treatment. Serotonin syndrome is manifested by the (possibly sudden) simultaneous or sequential appearance of a set of symptoms that may require hospitalization or, exceptionally, lead to death.


• These symptoms can be:
  
  
  
  • digestive (diarrhea),
  
  
  • neuropsychological (agitation, confusion, hypomania),
  
  
  • motor (myoclonus, tremor, hyperreflexia, rigidity, hyperactivity),
  
  
  • vegetative (changes in blood pressure, tachycardia, chills, hyperthermia, sweating, possibly coma).
  
  
  
  


• Stopping serotonergic substances usually results in rapid improvement. Treatment depends on the type and severity of symptoms.

Excipients with known effect

• This medicine contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases) should not take this medicine.


• This medicine contains 2.6 mg sodium per capsule, less than 1 mmol (23 mg) per capsule, that is to say it is essentially “sodium-free”. However, in patients controlling their dietary sodium intake, it is necessary to take into account the total number of METHADONE AP-HP capsules taken per day, which could provide a quantity of sodium greater than 23 mg.

Precautions for use

• Constipation is a known side effect of methadone. It is imperative to look for and manage constipation during treatment.


• Significant weight loss during treatment should lead to careful monitoring for any signs of overdose which could be caused by a sudden release of methadone into the bloodstream.


• Methadone should be used with caution in the elderly, pregnant women, patients with a pathology such as: asthma, severe respiratory, renal or hepatic insufficiency and diabetes.


• Opioids may increase cerebrospinal fluid pressure and lead to seizures: they should be used with caution in patients with head trauma, intracranial injuries, other circumstances in which cerebrospinal fluid pressure may be increased, or in case of history of epilepsy.


• Opioids can cause orthostatic hypotension. Opioids should be used with caution in patients with hypotension, hypovolemia, prostatic enlargement, or urethral stenosis.


• Opioid-induced miosis, changes in level of consciousness may interfere with patient assessment or alter the diagnosis or course of concomitant illness.


• Opioids should be used with caution in patients with myxedema, hypothyroidism, or adrenocortical insufficiency (e.g. Addison's disease).


• Because opioids can increase intracholedochal pressure, they should be used with caution in patients with bile duct dysfunction.

Interactions with other drugs and other forms of interactions

Substances likely to cause torsade de pointes

• This serious heart rhythm disorder can be caused by a number of medications, antiarrhythmic or not. Hypokalemia is a contributing factor, as is bradycardia or pre-existing prolongation of the QT interval, congenital or acquired.


• The medications causing this adverse effect include class Ia and III antiarrhythmics and certain neuroleptics. Other substances not belonging to these classes are also involved.


• For erythromycin and vincamine, only the forms administered intravenously are affected by this interaction.


• The use of a torsadogenic drug with another torsadogenic drug is generally contraindicated. However, some of them, due to their essential nature, are exceptions to the rule by only being not recommended with other torsadogens. These are methadone, hydroxychloroquine, antiparasitics (chloroquine, halofantrine, lumefantrine, pentamidine), arsenics, crizotinib, cotrimoxazole and neuroleptics.


• However, citalopram, escitalopram, domperidone, hydroxyzine and piperaquine do not follow this relaxation and are contraindicated with all torsadogens.

Sedative drugs

• Concomitant use of sedative medications with methadone increases the risk of sedation, respiratory depression, coma, and death due to the additive central nervous system (CNS) depressant effect.


• Among sedative medications: opioid derivatives (analgesics, cough suppressants and substitution treatments), neuroleptics, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (for example, meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedating H1 antihistamines, central antihypertensives, baclofen and thalidomide.


• The dosage and duration of treatment in case of concomitant use should be restricted.

Serotonergic drugs

Serotonin syndrome may occur when methadone is coadministered with pethidine, monoamine oxidase (MAO) inhibitors, and serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake (SNRIs) and tricyclic antidepressants (TCAs). Symptoms of serotonin syndrome may include mental status changes, autonomic nervous system instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

Contraindicated combinations

• Agonist-antagonist opioids: nalbuphine, buprenorphine


• Reduction of the effect of methadone by competitive receptor blockade.


• Partial opioid antagonists: naltrexone, nalmefene


• Risk of onset of a withdrawal syndrome.


• Citalopram, escitalopram


• Increased risk of ventricular rhythm disturbances, in particular torsade de pointes.


• Domperidone


• Increased risk of ventricular rhythm disturbances, in particular torsade de pointes.


• Hydroxyzine


• Increased risk of ventricular rhythm disturbances, in particular torsade de pointes.


• St. John's wort


• Decrease in methadone concentrations by St. John's Wort, with risk of withdrawal syndrome.


• Sodium oxybate, increased risk of respiratory depression, which can be fatal in the event of overdose.


• Piperaquine, increased risk of ventricular rhythm disturbances, in particular torsade de pointes.

Associations not recommended

• Alcohol (drink or excipient), increase by alcohol in the sedative effect of methadone. Impaired alertness can make driving vehicles and using machines dangerous. Avoid taking alcoholic beverages and medications containing alcohol.


• Apalutamide, risk of very significant reduction in methadone concentrations and loss of effectiveness by increase in their hepatic metabolism by apalutamide.


• Cotrimoxazole (sulfamethoxazole + trimethoprim), risk of ventricular disorders, in particular torsade de pointes. If the association cannot be avoided, regular clinical and electrocardiographic monitoring.


• Substances likely to cause torsades de pointes: Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide), class III antiarrhythmics (amiodarone, dronedarone, sotalol), certain antiparasitics* (halofantrine, lumefantrine, pentamidine, chloroquine), arsenics, cocaine, certain macrolides (IV erythromycin, spiramycin), certain neuroleptics (amisulpride, chlorpromazine, cyamemazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, quetiapine, sulpiride, tiapride, zuclopenthixol), crizotinib**, delamanid** , hydroxychloroquine, moxifloxacin, mequitazine, prucalopride, toremifene, vandetanib, vincamine IV. Increased risk of ventricular rhythm disturbances, in particular torsade de pointes. Clinical and electrocardiographic monitoring during the association. If possible, interrupt one of the 2 treatments. If the association cannot be avoided, prior control of QT and monitored ECG monitoring. If the association cannot be avoided, regular clinical and electrocardiographic monitoring.

Associations subject to precautions for use

• Anagrelide, increased risk of ventricular rhythm disturbances, in particular torsade de pointes. Clinical and electrocardiographic monitoring during the association.


• Azithromycin, clarithromycin, roxithromycin. Increased risk of ventricular rhythm disturbances, in particular torsade de pointes. Clinical and electrocardiographic monitoring during the association.


• Beta-blockers in heart failure: bisoprolol, carvedilol, metoprolol, nebivolol. Increased risk of ventricular rhythm disturbances, in particular torsade de pointes. Clinical and electrocardiographic monitoring.


• Bradycardias: class Ia antiarrhythmics, certain class III antiarrhythmics, bradycardias calcium antagonists (diltiazem, verapamil), anticholinesterases, beta-blockers, digoxin, pilocarpine, etc. Increased risk of ventricular rhythm disturbances, in particular torsade de pointes.

Clinical and electrocardiographic monitoring during the association.

• Cimetidine
  
  
  
  • Increased plasma concentrations of methadone with overdose and increased risk of QT interval prolongation and ventricular rhythm disturbances, including torsade de pointes.
  
  
  • Reinforced clinical and electrocardiographic monitoring: if necessary, adaptation of the methadone dosage during treatment with cimetidine and after its cessation.
  
  
  
  


• Ciprofloxacin, levofloxacin, norfloxacin. Increased risk of ventricular rhythm disturbances, in particular torsade de pointes.


• Fluvoxamine

Increased plasma concentrations of methadone with overdose and increased risk of QT interval prolongation and ventricular rhythm disturbances, including torsade de pointes.

Reinforced clinical and electrocardiographic monitoring: if necessary, adaptation of the methadone dosage during treatment with the antidepressant and after its cessation.

• Hypokalemic agents: amphotericin B IV, glucocorticoids, hypokalemic diuretics alone or in combination, stimulant laxatives, licorice, rhubarb, castor, tetracosactide. Increased risk of ventricular rhythm disturbances, in particular torsade de pointes. Correct any hypokalemia before administering methadone and perform clinical, electrolyte and electrocardiographic monitoring.


• Enzyme inducers: carbamazepine, phenobarbital, oxcarbazepine, primidone, phenytoin, fosphenytoin, rifabutin, rifampicin, efavirenz, nevirapine, dabrafenib, enzalutamide, eslicarbamazepine, lumacaftor, pitolisant. Decrease in plasma concentrations of methadone, with risk of onset of a withdrawal syndrome, due to increased hepatic metabolism. Increase the frequency of methadone intake (2 to 3 times per day instead of once per day).


• Ritonavir-boosted protease inhibitors

Decrease in plasma concentrations of methadone with risk of onset of a withdrawal syndrome due to increased hepatic metabolism by ritonavir.

Regular clinical monitoring and possible adaptation of the methadone dosage.

• Ondansetron. Increased risk of ventricular rhythm disturbances, in particular torsade de pointes. Clinical and electrocardiographic monitoring during the association.


• Voriconazole

Increased plasma concentrations of methadone with risk of overdose and increased risk of QT prolongation and ventricular rhythm disturbances, including torsade de pointes.

Clinical and electrocardiographic monitoring and possible adaptation of the methadone dosage.

Associations to take into account

• AMorphine-like cough suppressants (dextromethorphan, noscapine, pholcodine), true morphine cough suppressants (codeine, ethylmorphine)


• Increased risk of respiratory depression and increased risk of sedation, coma and death due to potentiation of the central nervous system depressant effect. The dose and duration of concomitant use should be limited.


• Other sedative medications
  Increased central depression: Impaired alertness can make driving vehicles and using machines dangerous.
  Barbiturates


• Increased risk of sedation and respiratory depression which may lead to coma and death, particularly in the elderly. The doses and duration of the combination should be limited as much as possible.


• Benzodiazepines and related drugs
  Increased risk of sedation and respiratory depression which may lead to coma and death, particularly in the elderly. The doses and duration of the combination should be limited as much as possible.


• Nicotine replacement treatments
  Risk of overdose when replacing tobacco with replacement therapy.


• Atropinic drugs
  Significant risk of colic akinesia, with severe constipation.


• Other drugs causing serotonin syndrome (amitriptyline, methylene blue, bupropion, citalopram, clomipramine, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iproniazid, linezolid, lithium, St. John's wort, milnacipran, moclobemide, oxitriptan, paroxetine, pethidine, sertraline, tramadol, trimipramine, tryptophan, venlafaxine)


• Risk of appearance or increase of serotonin syndrome in the event of combination of these medications.


• Quetiapine, Possible increase in methadone concentrations, with signs of overdose.

Fertility, pregnancy and breastfeeding

Pregnancy

• Methadone crosses the placental barrier. Given the available data and the maternal and fetal benefit, the use of methadone is possible during pregnancy whatever the term.


• During pregnancy, larger doses of methadone are sometimes necessary for balanced treatment.
  Chronic use of methadone by the mother at the end of pregnancy, whatever the dose, can cause an opioid


• withdrawal syndrome in the newborn, the onset of which can be delayed from several hours to a few days.


• If used regularly during pregnancy, neonatal monitoring should be carried out to prevent the risk of respiratory depression or withdrawal syndrome in the newborn.

Feeding with milk

• Small amounts of methadone are excreted in breast milk. The decision to recommend breastfeeding should take into account the advice of a specialist. Consideration should be given to whether the woman is receiving a stable maintenance dose of methadone and whether she continues to use illicit substances.


• If breastfeeding is considered, the dose of methadone should be as low as possible. Prescribers should advise breastfeeding women to monitor the infant for signs of sedation and respiratory depression and to contact urgent medical help immediately if this occurs. Although the amount of methadone excreted in breast milk is not sufficient to completely prevent withdrawal symptoms in breastfed infants, it may lessen the severity of neonatal withdrawal syndrome. If it is necessary to stop breastfeeding, this should be done gradually as abrupt weaning could increase withdrawal symptoms in the infant.

Fertility

• Chronic use of opioids can lead to reduced fertility in women and men of childbearing age.


• Studies in men enrolled in methadone substitution programs have shown that methadone decreases serum testosterone and markedly depresses ejaculate volume and sperm motility.

Effects on ability to drive and use machines.

Methadone has a major influence on the ability to drive or use machines during and after treatment. When taken with alcohol or central nervous system depressants, the effect is likely to be more pronounced (see sections 4.4 and 4.5). The time frame after which these activities can be safely resumed is extremely patient. -dependent and must be decided by the doctor.

Side effects

• In subjects drug-dependent on opioids when methadone treatment is initiated, the most common adverse effects are: euphoria, dizziness, drowsiness, nausea, vomiting, constipation, sedation, increased sweating, dysuria, edema.


• In opioid-dependent subjects treated with methadone in the maintenance phase, the most common adverse effects are: increased sweating, nausea, constipation.
  Since the marketing of METHADONE AP-HP capsules, fatal cases of accidental ingestion, particularly in children, have been reported.


• The adverse reactions below are listed by system organ and frequency. Frequencies from clinical trials are classified as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (frequency cannot be estimated from the available data).


• The frequency of the side effects listed below is not known:

Organ/Class System	Side effects
Blood and lymphatic system disorders	Thrombocytopenia
Endocrine disorders	Hyperprolactinemia
Metabolism and nutrition disorders	Diminished appetite Hypoglycemia
Psychiatric conditions	Euphoric mood Insomnia Hustle Decreased libido Confusional state Addiction Disorientation Hallucination
Nervous system disorders	Drowsiness Sedation Headache Dizzy feeling Syncope Convulsion
Endocrine disorders	Hypogonadism Adrenal insufficiency
Eye conditions	Visual defects Myosis
Heart conditions	Cardiac arrest Bradycardia Palpitations Torsade de pointes Tachycardia Arrhythmia
Vascular disorders	Hypotension Shock Congestive flush
Respiratory, thoracic and mediastinal disorders	Respiratory depression Respiratory arrest
Gastrointestinal disorders	Dry mouth Nausea, Vomiting Constipation Abdominal pain
Hepatobiliary disorders	Bile pain
Skin and subcutaneous tissue disorders	Hyperhidrosis Pruritus Rash Urticaria
Kidney and urinary tract disorders	Dysuria Urinary retention
Reproductive system and breast disorders	Gynecomastia Amenorrhea Dysmenorrhea Dyserection Galactorrhea
General disorders and administration site conditions	Edema Asthenia Fatigue Faintness Peripheral edema
Investigations	Prolonged QT interval on electrocardiogram Weight increased Decreased blood testosterone

Overdose

Symptoms

• The main symptom requiring medical intervention in the event of an overdose is respiratory depression, secondary to depression of the central nervous system, as it can lead to respiratory arrest and death.


• Other signs of an overdose include nausea, vomiting, hypoglycemia, sedation, miosis, arterial hypotension, bradycardia, severe bradypnea, pulmonary edema, severe drowsiness which may progress to stupor or even coma.


• These signs have been observed in fatal cases of accidental ingestion, particularly in children.


• In some cases, coma may be associated with hypothermia or hypoglycemia.Rare cases of hearing loss, most of the time reversible, have been reported in the context of methadone overdose.


• As with other opioids, cases of encephalopathy have been reported.

Treatment

• An opioid overdose is treated by administering an opioid receptor antagonist, such as naloxone. The long duration of action of methadone (up to 48 hours) may require repeated antagonist administration.


• Symptomatic treatment of respiratory depression and hypotension should include standard resuscitation measures.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: DRUGS USED IN OPIA DEPENDENCE, ATC code: N07BC02.

Methadone is a full opioid receptor agonist, like morphine, which acts primarily on µ receptors. Like other opiates, it has analgesic and antitussive properties and causes a pharmacological dependence syndrome. However, its euphoric properties are weak at effective therapeutic doses and over the long term.

Pharmacokinetic properties

Absorption

Due to its fat-soluble nature, methadone administered orally is well absorbed by the digestive tract, the plasma peak is observed 2.5 to 4 hours after administration. It undergoes a first-pass hepatic effect.

Distribution

• Methadone binds to albumin and other plasma and tissue proteins, which may explain its cumulative effects and its slow elimination rate (its plasma protein binding rate is 60% to 90%). Methadone tissue concentrations (lung, liver, kidney) are higher than the plasma concentration. It diffuses across the placenta and is excreted in milk.


• Inter-individual variations in plasma concentrations are observed in opioid-dependent subjects. For patients receiving 100 or 120 mg/day of methadone, the plasma half-life of the product is very variable, ranging from 13 to 47 hours (average: 25 hours).

Biotransformation

• Methadone is metabolized mainly in the liver where it undergoes N-demethylation and cyclization without conjugation. The metabolites are inactive.


• In vitro and in vivo studies have shown that cytochrome P3A4 has little influence on the distribution, metabolism and clearance of methadone. Furthermore, the cytochromes CYP2B6 and CYP2C19 have stereoselective effects on its metabolism, CYP2B6 preferentially metabolizing S-methadone and CYP2C19 R-methadone. Metabolism of methadone depends mainly on the CYP2B6 isoenzyme; the clinical relevance of the effect of substances inhibiting this isoenzyme is uncertain.

Elimination

• Methadone is excreted by glomerular filtration and then undergoes renal reabsorption. Its renal clearance decreases with increasing urinary pH.


• Urinary excretion is dose-dependent and represents the main route of elimination. After administration of a single dose of methadone, 20% is excreted in the urine unchanged and 13% in metabolized form. 20 to 40% of the initial dose is also excreted in the feces in metabolized form via bile. Methadone can be found in sweat and saliva.

Preclinical safety data

• The LD50 in rats is 95 mg/kg (oral route).


• The IV LD50 in mice is 20 mg/kg.

Chronic toxicity

In a one-year toxicity study in dogs, methadone administered in capsule form, at daily doses ranging from 5 to 20 mg/kg, resulted in reduced weight gain, dose-related sedation, excessive salivation and vomiting, hyper irritability, increased heart rate and ventricular complex. These changes disappeared in the recovery period. At the highest dose, ECG changes were still noticeable after 6 weeks of recovery. No histopathological changes in the heart were observed at the time of sacrifice. After 6 and 12 months of treatment, no abnormalities were observed in terms of organ weight, pathology or histopathology whatever the dose.

Carcinogenesis

• A carcinogenesis study in mice showed a significant increase in pituitary adenomas at 15 mg/kg/day, but not at 60 mg/kg/day.


• A carcinogenicity study carried out in rats did not show a treatment-related increase in the incidence of tumors in either male or female rats.

Mutagenesis

Methadone has shown some genotoxic activity in in vitro assays, but mostly in unvalidated assays and/or at an excessive level of toxicity. It appeared to be mutagenic in in vivo tests in mice, but not in rats. No final conclusions can be drawn regarding the genotoxic potential and extrapolation of these data to humans is difficult.

Fertility

Published studies show that methadone treatment of male rats can impair reproductive function. Methadone produces significant regression of the secondary sexual organs and testes of male mice and rats.