Plain-language summary, compiled from the cited regulatory records
Methadone is an opioid analgesic used for pain management [1]. It belongs to the drug class of drugs used in opioid dependence [1].
Methadone Hydrochloride Injection is indicated for the management of severe and persistent pain that requires an opioid analgesic and cannot be adequately treated with alternative options, including immediate-release opioids [1]. Due to the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, opioid analgesics, including Methadone, should be reserved [1].
This medication is sold under several brand names [1]. There were no adverse event reports for this active ingredient in the last 12 months [2].
This is not medical advice. Consult a qualified healthcare professional.
GBOfficial regulatory label· revised May 22, 2026[1]
For the treatment of dependence on opioid drugs.
How to take
GBOfficial regulatory label
USUnited States· FDA
3 products
Uses
USOfficial regulatory label· revised December 31, 2025[2]
INDICATIONS AND USAGE 1. Methadone Hydrochloride Injection is indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.
Limitations of Use • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration (see WARNINGS ), and persist over the course of therapy, reserve opioid analgesics, including Methadone Hydrochloride Injection, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• Methadone Hydrochloride Injection is not indicated as an as-needed (prn) analgesic. 2. For use in temporary treatment of opioid dependence in patients unable to take oral medication. Limitations of Use • Injectable methadone products are not approved for the outpatient treatment of opioid dependence.
Drug interactions
Known interactions involving Methadone. Select one for details. This list is informational and not a complete interaction checker.
Showing 240 of 600. Type above to find a specific drug.
Interaction data compiled from DDInter (academic, CC-BY). Severity classification only - this is not a complete interaction checker and not medical advice.
[2]FDA DailyMed · 092d78eb-6423-49… · revised December 31, 2025 [PDF]
Information on this page is compiled from public regulatory records. Drugvu is not affiliated with any regulator or pharmaceutical manufacturer. This is not medical advice. Always consult a qualified healthcare professional.
4). The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).
4). Posology Adults: 10 – 20mg (10 – 20ml) should be taken as an initial daily dose by oral administration. The dose should be increased cautiously by 10 – 20mg daily until no signs of withdrawal or intoxication occur. The usual dose for maintenance is 40 – 60mg daily.
The dose can then be gradually decreased, when appropriate, until total withdrawal is achieved. P. - Sugar Free, should be used cautiously in elderly patients. 3). Method of administration For oral administration only
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
GBOfficial regulatory label· Adverse reactions· revised May 22, 2026[1]
Tabulated list of adverse reactions Adverse reactions frequency are defined using the following convention: 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 (cannot be estimated from the available data).
4), hallucinations, confusion, mood changes including dysphoria, decreased libido Nervous system disorders Not known Methadone may increase intra-cranial pressure, particularly when it is already raised. Dizziness, headache, drowsiness Eye disorders Not known Miosis, nystagmus1, strabismus1, visual acuity reduced1 Ear and labyrinth disorders Not known Vertigo Cardiac disorders Not known Cases of QT prolongation and torsade de pointes have been rarely reported.
Bradycardia, palpitations, tachycardia Vascular disorders Not known Hypotension, facial flushing Respiratory, thoracic and mediastinal disorders Not known Respiratory depression, Exacerbation of existing asthma, central sleep apnoea syndrome Gastrointestinal disorders Not known Nausea, vomiting, constipation, dry mouth, acute pancreatitis Hepatobiliary disorders Not known Biliary spasm, sphincter of Oddi dysfunction Skin and subcutaneous tissue disorders Not known Rashes, pruritus, urticaria, excessive sweating Renal and urinary disorders Not known Difficulty in micturation, ureteric spasm, antidiuretic effect Reproductive system and breast disorders Not known Erectile dysfunction, reductions in the ejaculate volume and seminal vesicular and prostatic secretions Unknown Drug withdrawal syndrome.
In prolonged use it should not be administered more than twice daily to avoid the risk of accumulation and overdosage. General disorders and administration site conditions Not known Hypothermia. Investigations Not known Globulins increased, blood albumin increased 1Visual effects have been reported in infants and children exposed to methadone during pregnancy.
Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for ‘MHRA Yellow Card’ in the Google Play or Apple App Store.
GBOfficial regulatory label· Warnings and precautions· revised May 22, 2026[1]
In the case of elderly or ill patients, repeated doses should only be given with extreme caution. Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2). Tolerance and dependence of the morphine type may occur.
3), convulsive disorders, depressed respiratory reserve, hypotension, shock, prostatic hyperplasia, adrenocortical insufficiency, inflammatory or obstructive bowel disorders, myasthenia gravis or hypothyroidism. In cases of hepatic or renal impairment the use of methadone should be avoided or given in reduced doses.
P. - Sugar Free, contains benzoic acid and dyes. Benzoic acid is a mild irritant to the skin, eyes and mucous membrane. It may increase the risk of jaundice in newborn babies. E110 can cause allergic-type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.
4g of sorbitol. Unsuitable in hereditary fructose intolerance. Can cause stomach upset and diarrhoea. 19% v/v of ethanol. Harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease as well as for pregnant women and children.
May modify the effect of other medicines. Cases of QT interval prolongation and torsade de pointes have been reported during treatment with methadone, particularly at high doses (>100mg/d). g. e. 5). In patients with recognised risk factors of QT prolongation, or in case of concomitant treatment with drugs that have a potential for QT prolongation, ECG monitoring is recommended prior to methadone 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 100mg/d, and at seven days after titration. Opioid Use Disorder (abuse and dependence) Methadone is an opioid analgesic and is highly addictive in its own right.
It 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. As with other opioids, tolerance, physical, and/or psychological dependence may develop upon repeated administration of methadone.
P. - Sugar Free may result in overdose and/or death. , major depression, anxiety and personality disorders). , too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines).
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
GBOfficial regulatory label· Contraindications· revised May 22, 2026[1]
1. • Respiratory depression, obstructive airways disease and during an acute asthma attack, • Patients dependent on non-opioid drugs, • Concurrent administration with monoamine oxidase inhibitors (including moclobemide) or within 2 weeks of discontinuation of them.
8). • Where there is a risk of paralytic ileus. 5). • Use during labour (prolonged duration of action increases the risk of neonatal depression). • Methadone is not suitable for children (serious risk of toxicity).
This is not medical advice. Consult a qualified healthcare professional.
In this patient population, parenteral methadone is to be used only for patients unable to take oral medication, such as hospitalized patients. Conditions for Distribution and Use of Methadone Products for the Treatment of Opioid Addiction Code of Federal Regulations, Title 42, Sec 8.
Methadone products when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by opioid treatment programs (and agencies, practitioners or institutions by formal agreement with the program sponsor) certified by the Substance Abuse and Mental Health Services Administration and approved by the designated state authority.
12). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment. Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval, and injunction precluding operation of the program.
07(c)), to facilitate the treatment of the primary admitting diagnosis. 07(b)).
How to take
USOfficial regulatory label· revised December 31, 2025[2]
DOSAGE AND ADMINISTRATION
Important General Information Consider the following important factors that differentiate methadone from other opioids: • The peak respiratory depressant effect of methadone occurs later and persists longer than its peak pharmacologic effect.
• A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other opioid agonists.
• There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based conversion ratios between methadone and other opioids are not accurate when applied to individuals. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity.
• Steady-state plasma concentrations are not attained until 3 to 5 days after initiation of dosing . • Methadone has a narrow therapeutic index, especially when combined with other drugs. , immediate-release opioid) than to overestimate the 24-hour methadone dosage and manage an adverse reaction due to an overdose.
While useful tables of opioid equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. Frequently reevaluate patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to methadone.
Methadone Hydrochloride Injection for Management of Pain Methadone Hydrochloride Injection should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
Consider the following important factors that differentiate methadone from other opioid analgesics: • There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals.
• The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. • With repeated dosing, the potency of methadone increases due to systemic accumulation.
• Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose and may take longer in some patients. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals (see WARNINGS ).
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Methadone Hydrochloride Injection for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse (see WARNINGS ).
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Methadone Hydrochloride Injection. Consider this risk when selecting an initial dose and when making dose adjustments (see WARNINGS ).
Methadone Hydrochloride Injection multiple-dose vials may be administered intravenously, subcutaneously or intramuscularly. The absorption of subcutaneous and intramuscular methadone has not been well characterized and appears to be unpredictable.
Local tissue reactions may occur. Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 5 mg to 10 mg every 8 to 12 hours, slowly titrated to effect.
More frequent administration may be required during methadone initiation in order to maintain adequate analgesia, and extreme caution is necessary to avoid overdosage, taking into account methadone's long elimination half-life. , 10 mg oral methadone to 5 mg parenteral methadone).
Conversion from other Opioid Analgesics to Parenteral Methadone Switching a patient from another opioid analgesic to methadone requires caution due to the uncertainty of dose conversion ratios and incomplete cross-tolerance. Deaths have occurred in opioid tolerant patients during conversion to methadone.
The potency of methadone relative to other opioid analgesics is nonlinear and increases with increasing dose. Table 1 provides an estimated conversion factor for use when converting patients from another opioid to methadone. Because of the high inter-patient variability in absorption, metabolism, and relative potency, it is critical to avoid overestimating the methadone dose which can lead to fatal respiratory depression.
The dose conversion scheme below is derived from various consensus guidelines for converting patients to methadone from morphine. The guidelines used to construct this table, however, were all designed for converting patients from oral morphine to oral methadone.
The third column assumes a 2:1 ratio for converting from oral to intravenous methadone. Clinicians should consult published conversion guidelines to determine the equivalent morphine dose for patients converting from other opioids. Consider the following when using the information in Table 1: • This is not a table of equianalgesic doses.
• The conversion factors in this table are only for the conversion from another oral opioid analgesic to methadone hydrochloride tablets. • The table cannot be used to convert from methadone hydrochloride tablets to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1. , for administration every 8 hours, divide total daily methadone dose by 3). Less than 100 mg 20% to 30% 10% to 15% 100 mg to 300 mg 10% to 20% 5% to 10% 300 mg to 600 mg 8% to 12% 4% to 6% 600 mg to 1000 mg 5% to 10% 3% to 5% Greater than 1000 mg Less than 5% Less than 3% Table 2.
, for administration every 8 hours, divide total daily methadone dose by 3). 10 mg to 30 mg 40% to 66% 30 mg to 50 mg 27% to 66% 50 mg to 100 mg 22% to 50% 100 mg to 200 mg 15% to 34% 200 mg to 500 mg 10% to 20% Note: Equianalgesic methadone dosing varies not only between patients, but also within the same patient, depending on baseline morphine (or other opioid) dose.
Tables 1 and 2 have been included in order to illustrate this concept and to provide a safe starting point for opioid conversion. Methadone dosing should not be based solely on these tables. Methadone conversion and dose titration methods should always be individualized to account for the patient's prior opioid exposure, general medical condition, concomitant medication, and anticipated breakthrough medication use.
The endpoint of titration is achievement of adequate pain relief, balanced against tolerability of opioid side effects. If a patient develops intolerable opioid related side effects, the methadone dose, or dosing interval, may need to be decreased.
12, including limitations on unsupervised administration. Injectable methadone products are not approved for the outpatient treatment of opioid dependence. Parenteral methadone should be used only for patients who are unable to take oral medication, such as during hospitalization.
The patient's oral methadone dose should be converted to an equivalent parenteral dose using the considerations above. Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms (see PRECAUTIONS ).
Presentation of these symptoms has been associated with an increased risk of susceptible patients to relapse to illicit drug use and should be considered when assessing the risks and benefit of methadone use. Considerations for Management of Acute Pain During Methadone Maintenance Treatment Maintenance patients on a stable dose of methadone 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 opioids, that would be indicated in other patients experiencing similar nociceptive stimulation. Due to the opioid tolerance induced by methadone, when 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.
Dosage Adjustment During Pregnancy Methadone clearance may be increased during pregnancy. During pregnancy, a woman's methadone dose may need to be increased, or the dosing interval decreased (see PRECAUTIONS: Pregnancy ).
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
USOfficial regulatory label· Adverse reactions· revised December 31, 2025[2]
ADVERSE REACTIONS
The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse (see WARNINGS ) • Life Threatening Respiratory Depression (see WARNINGS ) • QT Prolongation (see WARNINGS ) • Neonatal Opioid Withdrawal Syndrome (see WARNINGS ) • Interactions with CNS Depressants (see WARNINGS ) • Serotonin Syndrome (see WARNINGS ) • Adrenal Insufficiency (see WARNINGS ) • Severe Hypotension (see WARNINGS ) • Gastrointestinal Adverse Reactions (see WARNINGS ) • Seizures (see WARNINGS ) • Withdrawal (see WARNINGS ) • Hypoglycemia (see WARNINGS ) The following adverse reactions associated with the use of methadone were identified in clinical studies or post-marketing reports.
Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension.
Respiratory arrest, shock, cardiac arrest, and death have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain.
In such individuals, lower doses of methadone are advisable. Other adverse reactions that have been reported in patients (including opioid addicts taking methadone for detoxification or maintenance) receiving methadone include the following: Body as a Whole : asthenia (weakness), edema, headache Cardiovascular: Arrhythmias, bigeminal rhythms, bradycardia, extrasystoles, tachycardia, Torsade de Pointes, ventricular fibrillation, ventricular tachycardia.
ECG abnormalities, prolonged QT interval, T-wave inversion, cardiomyopathy, flushing, heart failure, hypotension, palpitations, phlebitis, syncope Digestive: Abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis Hematologic and Lymphatic: Reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis.
Metabolic and Nutritional:
Hypokalemia, hypomagnesemia, weight gain Central Nervous System: Agitation, confusion, seizures, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances, congenital oculomotor disorders (nystagmus, strabismus) Respiratory: Pulmonary edema Skin and Appendages: Intramuscular and Subcutaneous: Local tissue reactions (pain, erythema, swelling), particularly with continuous subcutaneous infusion Intravenous: Pruritis, urticaria, other skin rashes, and rarely, hemorrhagic urticaria Special Senses: Visual disturbances Urogenital: Antidiuretic effect, amenorrhea, urinary retention or hesitancy, reduced libido and/or potency Serotonin Syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal Insufficiency :
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis:
Anaphylaxis has been reported with ingredients contained in Methadone Hydrochloride Injection.
Androgen Deficiency:
Cases of androgen deficiency have occurred with use of opioids for an extended period of time.
Hyperalgesia and Allodynia:
Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration (see WARNINGS ).
Hypoglycemia:
Cases of hypoglycemia have been reported in patients taking methadone (see WARNINGS ).
Opioid-Induced Esophageal Dysfunction (OIED):
Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term (see WARNINGS). Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021.
Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n = 978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n = 1,244).
Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: • approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and • approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse (defined in DRUG ABUSE AND DEPENDENCE ), respectively, as measured with a validated self-reported instrument.
A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n = 220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months.
New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry.
Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. 5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal.
Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.
The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.
USOfficial regulatory label· Warnings and precautions· revised December 31, 2025[2]
WARNINGS
Addiction, Abuse and Misuse Methadone Hydrochloride Injection contains methadone, a Schedule II controlled substance. As an opioid, Methadone Hydrochloride Injection exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Methadone Hydrochloride Injection.
Addiction can occur at recommended doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use (see ADVERSE REACTIONS ; Postmarketing Experience).
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Methadone Hydrochloride Injection, and reassess all patients receiving Methadone Hydrochloride Injection for the development of these behaviors and conditions.
, major depression). The potential for these risks should not, however, prevent the prescribing of Methadone Hydrochloride Injection for the proper management of pain in any given patient. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use.
Consider these risks when prescribing or dispensing Methadone Hydrochloride Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory depression and death.
, naloxone, nalmefene), depending on the patient’s clinical status. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Methadone Hydrochloride Injection, the risk is greatest during the initiation of therapy or following a dosage increase.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
USOfficial regulatory label· Contraindications· revised December 31, 2025[2]
CONTRAINDICATIONS
g. anaphylaxis) or any other ingredient in Methadone Hydrochloride Injection.
This is not medical advice. Consult a qualified healthcare professional.
For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered. Respiratory depression Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two and may exacerbate asthma due to histamine release Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs: Concomitant use of methadone and sedative drugs such as benzodiazepines or related drugs 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 methadone 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. 5). Drug dependence, tolerance and potential for abuse Prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses.
, major depression). Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.
Patients should be closely monitored for signs of misuse, abuse, or addiction. The clinical need for continuing opioid substitution therapy should be reviewed regularly. Drug withdrawal syndrome Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with methadone.
The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).
Drug withdrawal syndrome may occur upon abrupt […]
To reduce the risk of respiratory depression, proper dosing and titration of Methadone Hydrochloride Injection are essential. Overestimating the Methadone Hydrochloride Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Methadone Hydrochloride Injection should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as; asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression or coma.
In these patients even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose.
Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper (see DOSAGE AND ADMINISTRATION ).
Life-Threatening QT Prolongation Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day).
Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most patients on the lower doses typically used for maintenance, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors.
However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. The effects of methadone on the QT interval have been confirmed in in vivo laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in in vitro studies.
, cardiac hypertrophy, concomitant diuretic use, hypokalemia and hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone.
Evaluate patients developing QT prolongation while on methadone treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs that might cause electrolyte abnormalities, and drugs that might act as inhibitors of methadone metabolism.
Only initiate methadone hydrochloride tablets therapy for pain in patients for whom the anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias that have been reported with high doses of methadone.
The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied. , alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids).
Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone.
Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see PRECAUTIONS: Drug Interactions ). If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use.
In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.
Follow patients closely for signs and symptoms of respiratory depression and sedation. Neonatal Opioid Withdrawal Syndrome Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit.
Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Advise the patient of the risk of NOWS so that appropriate planning for management of the neonate can occur. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly (see PRECAUTIONS: Pregnancy ).
The balance between the risks of NOWS and the benefits of maternal Methadone Hydrochloride Injection use may differ based on the risks associated with the mother’s underlying condition, pain or addiction, and the risks of the alternative treatments.
• For management of pain, prescribers should discuss all available treatment options with females of reproductive potential, including non-opioid and non-pharmacologic options. • Untreated opioid addiction often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes.
NOWS can result from in utero exposure to opioids regardless of the source. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy. Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or Discontinuation P450 3A4, 2B6, 2C19, or 2C9 Inducers Concomitant use of Methadone Hydrochloride Injection with CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, may increase plasma concentrations of methadone, prolong opioid adverse reactions, and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Methadone Hydrochloride Injection is achieved.
Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Methadone Hydrochloride Injection-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of Methadone Hydrochloride Injection when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation.
Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with Methadone Hydrochloride Injection may decrease methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone.
When using Methadone Hydrochloride Injection with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, follow patients for signs or symptoms of opioid withdrawal and consider increasing the Methadone Hydrochloride Injection dosage as needed.
Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect (see Dependence).
Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia.
If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety) (see WARNINGS ; DOSAGE AND ADMINISTRATION ).
Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of methadone with serotonergic drugs. , cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (see PRECAUTIONS: Drug Interactions ).
This may occur within the recommended dosage range. , nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Methadone Hydrochloride Injection if serotonin syndrome is suspected.
Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.
If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.
Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
Severe Hypotension Methadone Hydrochloride Injection may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. , phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Methadone Hydrochloride Injection.
In patients with circulatory shock, Methadone Hydrochloride Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Methadone Hydrochloride Injection in patients with circulatory shock.
, those with evidence of increased intracranial pressure or brain tumors), Methadone Hydrochloride Injection may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Methadone Hydrochloride Injection.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Methadone Hydrochloride Injection in patients with impaired consciousness or coma. Risks of Gastrointestinal Complications Methadone Hydrochloride Injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The methadone in Methadone Hydrochloride Injection may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. , dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate (see CLINICAL PHARMACOLOGY: Pharmacodynamics ).
Increased Risk of Seizures in Patients with Seizure Disorders The methadone in Methadone Hydrochloride Injection may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures.
Monitor patients with a history of seizure disorders for worsened seizure control during Methadone Hydrochloride Injection therapy. , buprenorphine) analgesics in patients who are receiving a full opioid agonist, including Methadone Hydrochloride Injection.
In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms (see PRECAUTIONS: Drug Interactions ). When discontinuing Methadone Hydrochloride Injection, gradually taper the dosage (see DOSAGE AND ADMINISTRATION ) .
Do not rapidly reduce or abruptly discontinue Methadone Hydrochloride Injection in patients who may be physically dependent on opioids (see DRUG ABUSE AND DEPENDENCE ). Risks Driving and Operating Machinery Methadone Hydrochloride Injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.
Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Methadone Hydrochloride Injection and know how they will react to the medication (see PRECAUTIONS: Information for Patients ). Hypoglycemia Cases of methadone-associated hypoglycemia have been reported, some resulting in hospitalization.
, diabetes). The relationship between methadone and hypoglycemia is not fully understood but may be dose dependent. If hypoglycemia is suspected, monitor blood glucose levels, and manage the patient as clinically appropriate.