Methadone Hydrochloride

Registered South African indications:

• Substitution treatment in opiate/opioid dependence
  - In conjunction with appropriate medical, social and psychological therapy

Click here for the active ingredient monograph for the indication of cough suppression

Registered South African contraindications

2mg/ml

• Hypersensitivity to the active ingredient or any of its excipients
• Respiratory depression
• Acute obstructive airway disease
• Concomitant administration of monoamine oxidase (MAO) inhibitors or administration within 2 weeks after finished MAO inhibitor treatment
• Contraindicated in children

10mg/ml

• Hypersensitivity to the active ingredient, benzoates, or any of its excipients
• Respiratory depression
• Use during an acute asthma attack
• Acute alcoholism
• Concurrent administration with MAO inhibitors or within 2 weeks of discontinuation of treatment with them
• Decreased level of consciousness or head injury
• Individuals with QT prolongation, including congenital long QT syndrome
• Severe hepatic impairment, as it may precipitate portosystemic encephalopathy in patients with severe liver damage

Contraindications registered in other jurisdictions

10mg/ml

• Hypersensitivity to the active substance or to any of the excipients listed
• Respiratory depression and obstructive airway disease; use during an acute asthma attack is not recommended
• Acute alcoholism
• Concurrent administration with MAO inhibitors, including moclobemide, or within two weeks of discontinuation of treatment with them
• Patients dependent on non-opioid drugs
• Use during labour is not recommended due to the prolonged duration of action increasing the risk of neonatal depression
• Methadone is not suitable for children (serious risk of toxicity)
• Raised intracranial pressure or head injury (further rise in intracranial pressure may occur)
• Phaeochromocytoma
• Risk of paralytic ileus (including drug-induced gastrointestinal hypotonia)

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment (2mg/ml) (South African recommendations)
• Mild to moderate hepatic impairment (10mg/ml) (South African recommendations)
• Hepatic impairment (10mg/ml) (Recommendations in other jurisdictions)
• Elderly
• Risk factors for prolonged QT interval
• Asthma 
• Seizure disorders
• Depressed respiratory reserve
• Hypotension
• Shock
• Prostatic hyperplasia
• Adrenocortical insufficiency
• Inflammatory or obstructive bowel disorders
• Myasthenia gravis
• Hypothyroidism
• Endocrinopathy (hypoadrenalism and hypogonadism)
• Co-administration with CNS depressants
• Rare hereditary condition of sorbitol/maltitol/lactitol/fructose intolerance (10mg/ml) (South African recommendations)
• May impair ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: sol

South African registered indications and dosages

Substitution treatment in opiate/opioid dependence
- In conjunction  with appropriate medical, social and psychological therapy

2mg/ml & 10mg/ml

• Oral (sol): Initial: 20mg, once daily; Titrate by 10mg increments over 3 weeks, usually to 70-80mg; After a stabilization period of 4 weeks, adjust dose based on individual symptoms and needs*; Maintenance: 60-120mg, dly (some individuals may require higher doses)

*Adjust dose based on individual symptoms and needs: The dose is adjusted until the patient feels well, does not feel a need for intoxication and is without clinical signs of psychomotor function effects or abstinence symptoms

Formulation strengths available in South Africa are 2mg/ml and 10mg/ml, take note of this when calculating the dose required, for example:
The initial dose of 20mg with the 10mg/ml formulation = 2ml
The initial dose of 20mg with the 2mg/ml formulation = 10ml

The dosage must be determined based on clinical evaluation supported by serum level monitoring (recommended serum level: 600-1200nmol/l or 200-400ng/ml)

Methadone is usually administered once daily. More frequent administration risks accumulation and overdose

If auto-induction occurs, adjust the dose upwards once or more to maintain the optimum effect

2mg/ml
Treatment with methadone assumes that the patient is taking part in a programme including drug-assisted rehabilitation for narcotics abuse, approved by a relevant authority

10mg/ml
Always dilute the 10mg/ml concentrate before use and take orally with or without food. Should not be injected. For use under medical supervision only
Max dose: 150mg/day (due to risk of QT-prolongation and Torsades de pointes)

If switching from a combined agonist/antagonist (e.g. buprenorphine), reduce methadone dose gradually; If switching to sublingual buprenorphine (especially with naloxone), reduce methadone dose to 30mg/day initially
Substitution treatment with methadone should be prescribed by a doctor with experience of treating opiate/opioid dependent patients, preferably at centres that are specialised in the treatment of opiate/opioid dependency

Treatment must be stopped if it is insufficiently effective or if the patient cannot tolerate it. The effect must be evaluated in accordance with national guidelines. See additional prescribing points

Contraindicated (2mg/ml)
Not recommended for use (10mg/ml)

10mg/ml: There are no data available on the use in patients under 18 years. Therefore, the use of methadone is not recommended for children and adolescents

Pregnancy

South African recommendations

2mg/ml

• Caution; not recommended
• Neonatal abstinence syndrome, respiratory depression, and low birth weight have been reported in neonates after methadone treatment during pregnancy
• Methadone should not be administered during pregnancy

10mg/ml

• Caution; not recommended
• 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 and respiratory depression may occur in neonates of mothers who were treated with methadone chronically during pregnancy
• Studies in animals provided evidence of reproductive toxicity
• Limited data on the use of methadone in pregnancy in humans show no elevated risk of congenital abnormalities
• Methadone should not be administered to pregnant women due to possible adverse effects on the foetus and neonate, including: respiratory depression, low birth weight, neonatal withdrawal syndrome, and increased rate of stillbirths
• If maternal methadone substitution therapy is strongly indicated, careful monitoring is required
• It may be necessary to increase the dose of methadone 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 the daily dose to prevent high peak plasma concentrations and to compensate for 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 methadone 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 neonatal abstinence syndrome
• Dose adjustment (especially dose reduction) may be necessary within 1–2 weeks postnatal
• The use of methadone just before and during birth is advised against because of the risk of neonatal respiratory depression

Recommendations in other jurisdictions

• Caution
• There is no evidence of safety in human pregnancy for methadone
• A careful risk/benefit assessment should be made before administration to pregnant women due to possible adverse effects on the foetus and neonate, including respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths
• Methadone has not been associated with congenital malformations. It may be necessary to increase the dose of methadone if withdrawal symptoms develop, as increased clearance and reduced plasma levels have been reported during pregnancy
• Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate
• If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
• During labour, there is a risk of gastric stasis and inhalation pneumonia in the mother, as well as foetal distress. Methadone should not be used during labour
• Administration during labour may depress respiration in the neonate; an antidote for the child should be readily available

Breastfeeding

South African recommendations

• Caution; not recommended
• Methadone  is distributed into breast milk and should not be used during lactation

Recommendations in other jurisdictions

• Caution
• Methadone is excreted in breast milk at low levels
• The decision to recommend breastfeeding should consider clinical specialist advice and whether the woman is on a stable maintenance dose of methadone and any continued use of 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 sedation and breathing difficulties and seek immediate medical care if these occur
• Although the amount of methadone excreted in breast milk is not sufficient to fully suppress withdrawal symptoms in breastfed infants, it may attenuate the severity of neonatal abstinence syndrome. If it is necessary to discontinue breastfeeding, it should be done gradually to avoid increasing withdrawal symptoms in the infant
• Specialist care from obstetric and paediatric staff experienced in such management is required. If breastfeeding is
  considered, the dose of methadone should be as low as possible and the infant monitored to avoid sedation. Breastfed
  infants may develop physical dependence and exhibit withdrawal symptoms
• Reports of visual disorders have been noted in neonates following exposure to methadone during pregnancy; however, other factors have also been present, and a definitive causal link to methadone has not been established

Fertility

South African recommendations

2mg/ml

• No fertility data are available

10mg/ml

• 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

Recommendations in other jurisdictions

• No information available

South African recommendations

• Caution; dose adjustment recommended
  Caution should be exercised in the use of methadone in patients with renal impairment
  2mg/ml: A lower initial dose must be administered to patients with renal impairment (increased risk of convulsions)
  10mg/ml: The dose interval should be lengthened to a minimum of 32 hours if the glomerular filtration rate (GFR) is 10-50ml/min and to a minimum of 36 hours if the GFR is lower than 10ml/min

Recommendations in other jurisdictions

• Caution; dose adjustment recommended (10mg/ml)
  In cases of  renal impairment the use of methadone should be avoided or given in reduced doses (10mg/ml)

South African recommendations

2mg/ml

• Caution; dose adjustment recommended
  Dose adjustment may be necessary in cases of impaired hepatic function
  A lower initial dose must be administered to patients with hepatic impairment (opioids metabolised in liver)

10mg/ml

• Mild to moderate: Caution; dose adjustment recommended
  It is advisable to reduce the dose
  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 methadone 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 methadone dose must be monitored carefully
  Particular care must be taken whenever doses of over 50mg are prescribed
• Severe: Contraindicated

Recommendations in other jurisdictions

10mg/ml

• Caution; dose adjustment recommended
  In cases of hepatic impairment the use of methadone should be avoided or given in reduced doses
  As with other opioids, methadone may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early

South African recommendations

2mg/ml

• Caution; no information available
  Caution must be exercised when this medication is administered to elderly or ill patients. They are at increased risk of
  hypotension and syncope

10mg/ml

• Caution; dose adjustment recommended
  Caution must be exercised when treating elderly patients, as they may require a reduced dose

Recommendations in other jurisdictions

10mg/ml

• Caution; dose adjustment recommended
  In the case of the elderly or ill patients, repeated doses should be given with extreme caution
  In the case of elderly or ill patients, repeated doses should only be given with extreme caution

Central Nervous System Disorders

• Increased intracranial pressure
• Dizziness
• Headache
• Drowsiness
• Dependence
• Hallucinations
• Confusion
• Dysphoria
• Decreased libido

Cardiovascular Disorders

• QT prolongation
• Torsade de pointes
• Bradycardia
• Palpitations
• Tachycardia
• Hypotension
• Facial flushing

Respiratory Disorders

• Respiratory depression
• Exacerbation of existing asthma

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Dry mouth

Hepatobiliary Disorders

• Biliary spasm

Genitourinary Disorders

• Difficulty in micturation
• Ureteric spasm
• Antidiuretic effect
• Erectile dysfunction
• Reductions in the ejaculate volume and seminal vesicular and prostatic secretions

Endocrine and Metabolic Disorders

• Adrenal insufficiency
• Increased prolactin concentrations
• Decreased testosterone concentrations

Skin and Subcutaneous Tissue Disorders

• Rashes
• Pruritus
• Urticaria
• Excessive sweating

Immune, Blood and Lymphatic System Disorders

• Lymphocytosis

Sensory Disorders

• Miosis
• Vertigo

• Alcohol
• Opiates
• Barbiturates
• Benzodiazepines
• Monoamine oxidase inhibitors
• Moclobemide
• CYP3A4 inhibitors
• CYP3A4 inducers
• Naloxone
• Naltrexone
• Buprenorphine
• Primoquine
• Pentazocine
• Urinary acidifiers
• Domperidone
• Nucleoside reverse transcriptase inhibitors
• Drugs affected cardiac conduction

• Vital signs
• ECG

Treatment discontinuation

2mg/ml

• If treatment must be stopped, this must be done by gradual dose reduction. The dose may be reduced relatively rapidly to start with, but reduction must be slow in the final phase (from 20mg daily and downwards)

10mg/ml

• Treatment discontinuation should be gradual with a dose reduction of 5-10mg in weekly steps over several weeks to months. The dose may be reduced relatively rapidly to start with, however special care is required in the final phase from 20mg daily and downwards
• During this period of gradual dose reduction, it is necessary to pay attention to any recurrence of withdrawal symptoms which would require a return to the previous dosage, and to any resumption of addictive behaviours

Methadone is a full mu-opioid agonist and N-methyl-D-aspartate antagonist . It is a synthetic opioid with pharmacological properties similar to morphine.  

Oral solution 2mg/ml

• Equity Methadone (Equity) originator

Oral solution 10mg/ml

• Misyo 10mg/ml (Umsebe)