Methadone Hydrochloride

Introduction

Methadone hydrochloride is a mu-agonist; a synthetic opioid with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle.
Methadone _Manufactured by Faran Shimi Pharmaceutical Company_ is available in two dosage forms:
*Tablet (5, 20 and 40mg): 10 tablets are packed in a blister and 10 blisters are packaged in one box with a leaflet.
*Oral Solution (25mg/5ml): each 250ml bottle is packaged in one box with a leaflet.

Indications

Methadone is indicated for the:

• Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate (Methadone is not indicated as an as-needed analgesic).
• Detoxification treatment of opioid addiction (heroin or other morphine-like drugs).
• Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. It should be used as part of a complete treatment plan to include counseling and psychosocial support.

Patient Information for Methadone

Important Information

Dosing

Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse and misuse.

• Adults:

Opioid use disorder:

Initial: 20 to 30mg (as a single dose) when there are no signs of sedation or intoxication and patient shows symptoms of withdrawal; maximum dose: 30mg. observe patients for over sedation and withdrawal symptoms for 2 to 4 hours after initial dose.
Maintenance: Titrate to a dosage, which prevents opioid withdrawal symptoms for 24 hours, prevents craving, attenuates euphoric effect of self-administered opioids, and tolerance to sedative effects of methadone, usual range: 80-120mg/day.

Pain management (Opioid-naïve):

Gradual titration: Initial: 2.5mg every 8 hours; may increase dose by 2.5mg per dose or 5mg per day every 5 to 7 days.
Faster titration: 2.5mg every 6 to 8 hours; may increase dose by 2.5mg per dose as often as every day over about 4 days.
• Renal Impairment:
CrCl ≥10 mL/minute: No dosage adjustment necessary.
CrCl <10 mL/minute: Administer 50% to 75% of normal dose.

• Hepatic Impairment:
No dosage adjustment necessary, Initiate at lower doses and titrate slowly; monitor closely for respiratory and CNS depression.

• Pediatrics:

Pain, severe:

• Infants ≤6 months, nonventilated: 0.025-0.05mg/kg/dose every 4 to 8 hours.
• Infants >6 months, Children, and Adolescents, nonventilated:
Patient weight<50 kg: 0.1-0.2mg/kg/dose every 4 to 8 hours.
Patient weight≥50 kg: 5-10mg every 4 to 8 hours.

Iatrogenic opioid dependency:

Prevention: Once methadone dose is stabilized, a weaning schedule of 10% to 20% reduction of the original dose every 24 to 48 hours has been recommended.
Treatment: Initial: 0.05 to 0.1mg/kg/dose every 6 hours.
• Geriatrics:
A lower initial oral dose of 10 to 20mg has been recommended for patients more than 65 years of age.

Administration

Administer with or without food. Titrate slowly with dose increases no more frequent than every 3 to 5 days. When discontinuing methadone for pain management, reduce dose gradually by 15% to 50% every 2 to 4 days to prevent signs or symptoms of withdrawal.

Major Interactions (Risk X)

Alcohol (Ethyl), Azelastine (Nasal), Bromperidol, Citalopram, Clarithromycin, Conivaptan, Domperidone, Eluxadoline, Entrectinib, Fexinidazole, Flupentixol, Fusidic Acid, Idelalisib, Itraconazole, Ketoconazole (Systemic), Lefamulin, Monoamine Oxidase Inhibitors, Moxifloxacin (Systemic), Nilotinib, Opioids (Mixed Agonist / Antagonist), Orphenadrine, Oxomemazine, Paraldehyde, Pimozide, Piperaquine, Posaconazole, Probucol, Quetiapine, Ribociclib, Sparfloxacin, Thalidomide, Thioridazine.

Pregnancy

Neonatal opioid withdrawal syndrome is an expected and treatable outcome of use of methadone during pregnancy. Neonatal opioid withdrawal syndrome may be life threatening if not recognized and treated in the neonate. The balance between the risks of neonatal opioid withdrawal syndrome and the benefits of maternal methadone use may differ based on the risks associated with the mother's underlying condition, pain, or dependence.

Breast-Feeding

Methadone is present in breast milk. The decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Contraindications & Cautions

Contraindications

Hypersensitivity (e.g., anaphylaxis) to methadone or any component of the formulation; significant respiratory depression; acute or severe bronchial asthma; hypercarbia; GI obstruction (e.g. paralytic ileus).

Warnings/Precautions

• CNS depression: May impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (e.g., operating machinery or driving).
• Constipation: Consider preventive measures (e.g. stool softener, increased fiber) to reduce the potential for constipation.
• Hypotension: Use with caution in patients with hypovolemia, cardiovascular disease (e.g., acute MI), or drugs that may exaggerate hypotensive effects (phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration.
• Respiratory depression: Monitor for respiratory depression, especially during initiation of methadone or following a dose increase.
• QT prolongation: Closely monitor patients with risk factors for development of QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of methadone.
• Adrenocortical insufficiency (e.g., Addison disease): Use with caution.
• Biliary tract impairment (e.g., acute pancreatitis): Use with caution.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution.
• Psychosis: Use with caution in patients with toxic psychosis.
• Seizure: Use with caution in patients with a history of seizure disorders.
• Thyroid dysfunction: Use with caution.

Side Effects

Central nervous system: Agitation, confusion, disorientation, dizziness, physical dependence, euphoria, hallucination, headache, insomnia, sedation, seizure.
Dermatologic: Diaphoresis, pruritus, skin rash, urticarial.
Gastrointestinal: Nausea, abdominal pain, anorexia, biliary tract spasm, constipation, vomiting, xerostomia.
Endocrine & metabolic: Adrenocortical insufficiency, amenorrhea, antidiuretic effect, decreased libido, decreased plasma testosterone, hypokalemia, hypomagnesemia, weight gain.
Respiratory: Pulmonary edema, respiratory depression.
Ophthalmic: Visual disturbance.
Neuromuscular & skeletal: Bone fracture, osteoporosis, weakness.
Hematologic: Thrombocytopenia (reversible).
Genitourinary: Decreased ejaculate volume, male genital disease, prostatic disease, urinary retention, spermatozoa disorder (morphologic abnormalities).
Cardiovascular: Bradycardia, cardiac arrhythmia, cardiac failure, cardiomyopathy, ECG changes, edema, flushing, hypotension, palpitations, phlebitis, shock, syncope, tachycardia, ventricular fibrillation, ventricular tachycardia, prolonged QT interval on ECG, extrasystoles.