Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Umsebe Healthcare, Unit 20, Sunclare Building, 3rd Floor, 21 Dreyer Street, Claremont, Cape Town, 7708, South Africa
It is advisable to reduce the dose for older patients, patients with renal disorders or severe chronic hepatic disorders, and patients in poor general condition.
Methadone is a substance of dependence, has a long half-life and can therefore accumulate. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possible death.
Tolerance and dependence may occur as with morphine. The risks of dependence are increased in individuals of current or past history of substance misuse disorders e.g., alcohol use disorder, opioid use disorder, drug use disorder.
MISYO can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.
Abrupt cessation of treatment can lead to withdrawal symptoms which, although similar to those with morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual.
MISYO should be used with caution in patients with asthma, chronic obstructive pulmonary disease or cor pulmonale and in patients with very limited respiratory reserve, a pre-existing impairment of respiratory function, hypoxia or hypercapnia. Even at the usual therapeutic doses for narcotics, these patients can experience a reduction in respiratory activity with a concomitant increase in airway resistance culminating in apnoea. In patients predisposed to such atopic phenomena, pre-existing asthma, skin eruptions and blood count changes (eosinophilia) can be exacerbated. Asthma may be exacerbated due to histamine release.
Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two.
The symptoms and signs of overdosage and toxicity of methadone are essentially those for morphine, though it is said that methadone has a greater respiratory depressive effect and a lesser sedative effect than an equi-analgesic dose of morphine. Toxic doses are highly variable, regular usage giving tolerance. Pulmonary oedema is a frequent corollary of overdosage whilst the dose-related histamine-releasing property of methadone may account for at least some of the urticaria and pruritus associated with methadone administration.
Concomitant treatment with other medicines with CNS depressant activity is not advised due to the potential for CNS and respiratory depression (see also section 4.5).
The respiratory depressant effects of methadone and its capacity to elevate cerebrospinalfluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increased intracranial pressure. Furthermore, opiates/opioids produce side effects that may obscure the clinical course of patients with head injuries. In such patients, MISYO must be used with caution and only if it is deemed essential.
MISYO has the potential to increase intracranial pressure especially where it is already raised.
Concomitant use of MISYO and sedative medicines such as benzodiazepines or related medicines may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe MISYO concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers must be informed and made aware of these symptoms (see section 4.5).
Caution is required in case of mild or moderate hepatic impairment, since these patients may be at risk of increased systemic exposure to methadone after multiple dosing. The usual dose of MISYO can be continued in patients with stable chronic liver disease. When there may be impaired liver function following hepatitis B or C infection or prolonged alcohol use, the MISYO dose must be monitored carefully. Particular care must be taken whenever doses of over 50 mg are prescribed.
Caution should be exercised in the use of MISYO in patients with renal impairment. The dose interval should be lengthened to a minimum of 32 hours if the glomerular filtration rate (GFR) is 10–50 ml/min and to a minimum of 36 hours if the GFR is lower than 10 ml/min.
Methadone may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early.
Hypoglycaemia has been observed in the context of methadone overdose or dose escalation. Regular monitoring of blood sugar is recommended during dose escalation (see section 4.8 and section 4.9).
Opiate/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.
Long-term use of opiate/opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.
As there is a risk of greater respiratory depression in neonates the use of MISYO in children and adolescents under 18 years of age is not recommended owing to a lack of clinical findings on efficacy and safety.
Babies born to mothers receiving MISYO may suffer withdrawal symptoms.
MISYO should be used with caution in patients with convulsive disorders, hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis.
MISYO should be used with caution and in reduced dosage in patients who are concomitantly using other narcotic analgesics, general anaesthetics, phenothiazines, other tranquillisers, sedative hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol) (see 4.5 Interactions with other medicinal products and other forms of interaction).
Cases of QT interval prolongation and torsades de pointes have been reported during treatment with methadone, particularly at high doses (>100 mg/day). MISYO should be administered with caution to patients at risk for development of prolonged QT interval, e.g. in case of:
In patients treated with a combined agonist/antagonist (e.g. buprenorphine), the dose should be reduced gradually when the MISYO treatment is initiated. If the MISYO treatment is interrupted and a switch to sublingual buprenorphine treatment is planned (especially in combination with naloxone), the MISYO dose should be reduced to 30 mg/day initially to avoid withdrawal symptoms caused by buprenorphine/naloxone.
In patients with recognised risk factors for QT-prolongation, or in case of concomitant treatment with substances that have a potential for QT-prolongation, ECG monitoring is recommended prior to MISYO treatment, with a further ECG test at dose stabilisation. ECG monitoring is recommended, in patients without recognised risk factors for QT-prolongation, before dose titration above 100 mg/day and at seven days after titration.
Caution should be exercised in patients who are concurrently taking central nervous system (CNS) depressants.
MISYO 10 mg/ml concentrate for oral solution contains 300 mg of sorbitol, liquid noncrystallising (E420) (which is equivalent to 210 mg of sorbitol), which may have a laxative effect. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. Patients with the rare hereditary condition of sorbitol/maltitol/lactitol/intolerance should not take MISYO.
MISYO 10 mg/ml concentrate for oral solution contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-free’.
Methadone is a substrate of p-glycoprotein; all medicines that inhibit P-glycoprotein (e.g. quinidine, verapamil, ciclosporin), may therefore raise the serum concentration of methadone. The pharmacodynamic effect of methadone may also increase because of increased blood brain barrier passage.
Methadone is a substrate of CYP3A4 (see section 5.2). By induction of CYP3A4, clearance of methadone will increase and the plasma levels decrease. Inducers of this enzyme (barbiturates, carbamazepine, phenytoin, nevirapine, rifampicin, efavirenz, amprenavir, spironolactone, dexamethasone, Hypericum perforatum (St John’s Wort)), may induce hepatic metabolism. For instance, after three weeks' treatment with 600 mg efavirenz daily, the mean maximal plasma concentration and AUC decreased by 48% and 57% respectively, in patients treated with methadone (35–100 mg daily).
The consequences of enzyme induction are more marked if the inducer is administered after treatment with methadone has begun. Abstinence symptoms have been reported following such interactions and hence, it may be necessary to increase the MISYO dose. If treatment with a CYP3A4 inducer is interrupted, the MISYO dose should be reduced.
Co-administration of MISYO with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of methadone with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and MISYO are administered concurrently; clinical response and/or medicine levels should be monitored as appropriate.
Methadone is a substrate of CYP3A4 (see section 5.2). By inhibition of CYP3A4 clearance of methadone is lowered. Concomitant administration of CYP3A4 inhibitors (e.g. cannabinoids, clarithromycin, delavirdine, erythromycin, ciprofloxacin, fluconazole, grapefruit juice, cimetidine, itraconazole, ketoconazole, fluoxetine, fluvoxamine, nefazodone and telithromycin) may result in increased plasma concentrations of methadone. A 40–100% increase of the quote between the serum levels and the methadone dose has been shown with concomitant fluvoxamine treatment. If these medicinal products are prescribed to patients on MISYO maintenance treatment, one should be aware of the risk of overdose. Dose adjustment may be necessary.
Methadone is a weak base. Acidifiers of the urine (such as ammonium chloride and ascorbic acid) may increase the renal clearance of methadone. Patients that are treated with MISYO are recommended to avoid products containing ammonium chloride.
Some protease inhibitors (amprenavir, nelfinavir, abacavir, lopinavir/ritonavir and ritonavir/saquinavir) seem to decrease the serum levels of methadone. When ritonavir is administered alone, a two-fold AUC of methadone has been observed. The plasma levels of zidovudine (a nucleoside analogue) increase with methadone use after both oral and intravenous administration of zidovudine. This is more noticeable after oral than after intravenous use of zidovudine. These observations are likely caused by inhibition of zidovudine glucuronidation, and therefore decreased clearance of zidovudine. During treatment with MISYO, patients must be carefully monitored for signs of toxicity caused by zidovudine, which may require a reduction in the zidovudine dose. Because of mutual interactions between zidovudine and methadone (zidovudine is a CYP3A4 inducer), typical opiate/opioid abstinence symptoms may develop during concomitant use (headache, myalgia, fatigue and irritability).
Methadone delays the absorption and increases the first pass metabolism of stavudine and didanosine, which results in a decreased bioavailability of stavudine and didanosine.
MISYO may double the serum levels of desipramine.
Naloxone and naltrexone counteract the effects of methadone and induces abstinence. Similarly, buprenorphine and pentazocine may precipitate withdrawal symptoms.
Medicines with a sedative effect on the central nervous system may result in increased respiratory depression, hypotension, strong sedation or coma; therefore, it may be necessary to reduce the dose of one or both of the medicines. With MISYO treatment, the slowly eliminated substance methadone, gives rise to a slow tolerance development, and every dose increase may after 1–2 weeks give rise to symptoms of respiratory depression. The dose adjustments must therefore be made with caution and the dose increased gradually and with careful observation.
Anaesthetics, sedative-hypnotics (including barbiturates, chloral hydrate and chlormethiazole), anxiolytics phenothiazines, antipsychotics and tricyclic antidepressants may increase the general depressant effects of methadone when used concomitantly (see 4.4 Special warnings and precautions for use). Antipsychotics may enhance the sedative effects and hypotensive effects of MISYO.
The concomitant use of opiates/opioids with sedative medicines such as benzodiazepines or related medicines increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).
Concomitant use of MISYO and peristalsis inhibiting medicines (loperamide and diphenoxylate) may result in severe obstipation and increase the CNS depressant effects.
Opiate/opioid analgesics, in combination with antimuscarinics, may result in severe obstipation or paralytic ileus, especially in long-term use.
MISYO should not be combined with medicines that may prolong the QT interval such as antidysrhythmics (sotalol, amiodarone, and flecainide), antipsychotics (thioridazine, haloperidol, sertindole, and phenotiazines), antidepressants (paroxetine, sertraline) or antibiotics (erythromycin, clarithromycin).
Serotonergic syndrome may occur with concomitant administration of MISYO with pethidine, monoamine oxidase (MAO) inhibitors and serotonin medicines such as Selective Serotonin Re-uptake Inhibitor (SSRI), Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) and tricyclic antidepressants (TCAs). The symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
Concomitant administration of MAO-inhibitors may result in reinforced CNS-inhibition, serious hypotonia and or apnoea. MISYO should not be combined with MAO-inhibitors and two weeks after such treatment (see section 4.3).
Maintenance patients on a stable dose of MISYO who experience physical trauma, postoperative pain or other causes of acute pain cannot be expected to derive analgesia from their stable dose of methadone regimens. Such patients should be given analgesics, including opiates/opioids that would be indicated in other patients experiencing similar nociceptive stimulation. Due to the opiate/opioid tolerance induced by MISYO, when opiates/opioids are required for management of acute pain in methadone patients, somewhat higher and/or more frequent doses will often be required than would be the case for other, non-tolerant patients.
MISYO may delay gastric emptying, thereby invalidating test results.
Delivery of technetium Tc 99m disofenin to the small bowel may be prevented because MISYO may cause constriction of the sphincter of Oddi and increased biliary tract pressure; these actions result in delayed visualization and thus resemble obstruction of the common bile duct.
Cerebrospinal fluid pressure may be increased; effect is secondary to respiratory depressioninduced carbon dioxide retention.
Plasma amylase or lipase levels may be increased because MISYO can cause contractions of the sphincter of Oddi and increased biliary tract pressure; the diagnostic utility of determination of these enzymes may be compromised for up to 24 hours after the medication has been given.
MISYO may modify urine tests and give a positive result in doping control.
MISYO may interfere with urine testing for pregnancy.
Methadone administered to pregnant women for the management of opiate/opioid addiction has the potential for several adverse effects on the foetus and the neonate. Withdrawal symptoms/respiratory depression may occur in neonates of mothers who were treated with methadone chronically during pregnancy. Studies in animals provided evidence of reproductive toxicity (see section 5.3). However, limited data on the use of methadone in pregnancy in humans show no elevated risk of congenital abnormalities.
MISYO should not be administered to pregnant women, because of possible adverse effects on the foetus and neonate including respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths. However, if maternal MISYO substitution therapy is strongly indicated, careful monitoring is required.
It may be necessary to increase the dose of MISYO if withdrawal symptoms develop. Increased clearance and reduced plasma levels have been reported during pregnancy. Considering the well-being of the foetus, it may be advisable to split up the daily dose in order to prevent high peak plasma concentrations and to compensate the accelerated degradation of methadone, thus preventing withdrawal symptoms. Dose reduction or withdrawal during pregnancy must always be carried out under careful monitoring of the mother and only after a stringent risk/benefit assessment. Medicine withdrawal of the neonate must be carried out at an adequate intensive care unit for children, as treatment with MISYO may lead to habituation and addiction of the foetus as well as to withdrawal symptoms in the neonate, which require treatment. Approximately 60–80% of the neonates require hospitalised treatment due to the neonatal abstinence syndrome. Dose adjustment (especially dose reduction) may be necessary within 1–2 weeks postnatal. The use of MISYO just before and during birth is advised against because of the risk of neonatal respiratory depression.
Methadone is excreted in breastmilk and MISYO should not be used during lactation.
Methadone does not appear to impair human female fertility. Studies in men on methadone maintenance programmes have shown that methadone reduces serum testosterone and markedly depresses the ejaculate volume and sperm motility. The sperm counts of methadone subjects were twice that of controls but this reflected the lack of dilution from seminal secretions.
MISYO has a major influence on the ability to drive and use machines, during and after treatment, as it may cause drowsiness and reduce alertness. The time after which such activities may be safely resumed is extremely patient-dependent and must be decided by the medical practitioner.
The adverse effects of methadone are most commonly nausea and vomiting, that is observed in approximately 20 % of the patients that go through methadone outpatient treatment, where the medicinal control is often unsatisfactory.
Long term use of MISYO may lead to morphine-like dependence.
The most serious adverse effect of methadone is respiratory depression, which may emerge during the stabilisation phase. Apnoea, shock and cardiac arrest have occurred.
Adverse reactions listed below are classified according to frequency and system organ class. These reactions are more frequently observed in non-opiate/opioid-tolerant individuals.
| System organ class (MedDRA) | Frequency | Adverse event |
|---|---|---|
| Blood and lymphatic system disorders | Not known | Reversible thrombocytopenia has been reported in opiate/opioid-dependent patients with chronic hepatitis |
| Endocrine disorders | Less frequent | Hypothyroidism |
| Not known | Raised prolactin levels with long-term administration | |
| Metabolism and nutrition disorders | Frequent | Fluid retention |
| Not known | Anorexia, hypokalaemia, hypomagnesaemia, hypoglycaemia | |
| Psychiatric disorders | Frequent | Euphoria, hallucinations, sleep disturbances |
| Less frequent | Dysphoria, agitation, insomnia, disorientation | |
| Nervous system disorders | Frequent | Sedation, dizziness, confusion, headache |
| Less frequent | Syncope | |
| Eye disorders | Frequent | Blurred vision, miosis, dry eyes |
| Less frequent | Visual disturbances | |
| Ear and labyrinth disorders | Frequent | Vertigo |
| Not known | Hearing loss | |
| Cardiac disorders | Less frequent | Bradycardia, palpitations, cases of prolonged QT interval and torsade de pointes have been reported, especially with high doses of methadone |
| Vascular disorders | Less frequent | Facial flush, hypotension (particularly at high doses), shock |
| Respiratory, thoracic and mediastinal disorders | Less frequent | Pulmonary oedema, exacerbation of asthma, dry nose, respiratory depression (particularly at high doses), respiratory arrest |
| Gastrointestinal disorders | Frequent | Nausea, vomiting, constipation |
| Less frequent | Xerostomia, glossitis, intestinal hypomotility (ileus) | |
| Hepatobiliary disorders | Less frequent | Bile duct dyskinesia |
| Skin and subcutaneous tissue disorders | Frequent | Transient rash, sweating |
| Less frequent | Pruritus, urticaria, other rash and in very uncommon cases bleeding urticaria | |
| Renal and urinary disorders | Less frequent | Urinary retention, anti-diuretic effect |
| Reproductive system and breast disorders | Frequent | Decreased libido |
| Less frequent | Reduced potency, galactorrhoea, dysmenorrhoea and amenorrhoea | |
| General disorders and administration site condition | Frequent | Fatigue, drowsiness |
| Less frequent | Oedema of the lower extremities (limbs), asthenia, oedema, hypothermia | |
| Investigations | Frequent | Weight increase |
In long term use of methadone, as for maintenance treatment, the undesirable effects diminish successively and progressively during a period of several weeks however, constipation and perspiration often remain.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
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