methadone 10 MG/ML Injectable Solution
Generic Name: METHADONE HYDROCHLORIDE
Brand Name: Methadone Hydrochloride
- Substance Name(s):
- METHADONE HYDROCHLORIDE
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.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Methadone Hydrochloride Injection, and monitor all patients receiving Methadone Hydrochloride Injection for the development of these behaviors and conditions.
Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., 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.
Patients at increased risk may be prescribed opioids such as Methadone Hydrochloride Injection, but use in such patients necessitates intensive counseling about the risks and proper use of Methadone Hydrochloride Injection along with the intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
Consider these risks when prescribing or dispensing Methadone Hydrochloride Injection.
Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused 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.
Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, 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.
Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Methadone Hydrochloride Injection.
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.
Closely monitor patients with risk factors for development of prolonged QT interval (e.g., 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.
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.
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Methadone Hydrochloride Injection with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol).
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.
Advise both patients and caregivers about the risks of respiratory depression and sedation when Methadone Hydrochloride Injection is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).
Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.
Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see PRECAUTIONS: Drug Interactions , Information for Patients ).
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.
Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., 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.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
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.
There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or concurrent administration of certain CNS depressant drugs (e.g., 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.
Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., 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 Use in Patients with Gastrointestinal Conditions 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.
Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
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.
Withdrawal Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., 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 abruptly discontinue Methadone Hydrochloride Injection (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 ).
DRUG INTERACTIONS
Drug Interactions Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6.
The concomitant use of Methadone Hydrochloride Injection and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of Methadone Hydrochloride Injection is achieved.
These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above.
After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease (see CLINICAL PHARMACOLOGY ), resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention: If concomitant use is necessary, consider dosage reduction of Methadone Hydrochloride Injection until stable drug effects are achieved.
Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the Methadone Hydrochloride Injection dosage until stable drug effects are achieved.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.
ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, Some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine) Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 Clinical Impact: The concomitant use of Methadone Hydrochloride Injection and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone (see CLINICAL PHARMACOLOGY ), resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone.
These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes.
After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase (see CLINICAL PHARMACOLOGY ), which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention: If concomitant use is necessary, consider increasing the Methadone Hydrochloride Injection dosage until stable drug effects are achieved.
Monitor for signs of opioid withdrawal.
If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider Methadone Hydrochloride Injection dosage reduction and monitor for signs of respiratory depression and sedation.
Examples: Rifampin, carbamazepine, phenytoin, St.
John’s Wort, Phenobarbital Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients closely for signs of respiratory depression and sedation (see WARNINGS , PRECAUTIONS ).
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents Clinical Impact: Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention: Monitor patients closely for cardiac conduction changes.
Examples: Drugs known to have potential to prolong QT interval : Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers.
Drugs capable of inducing electrolyte disturbances : Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome (see WARNINGS , PRECAUTIONS ).
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.
Discontinue Methadone Hydrochloride Injection if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome (see PRECAUTIONS ) or opioid toxicity (e.g., respiratory depression, coma) (see PRECAUTIONS ) .
Intervention: The use of Methadone Hydrochloride Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Methadone Hydrochloride Injection and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Methadone Hydrochloride Injection and/or the muscle relaxant as necessary.
Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Methadone Hydrochloride Injection is used concomitantly with anticholinergic drugs.
Anti-Retroviral Agents Nevirapine Based on the known metabolism of methadone, nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism.
Opioid withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly.
Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Efavirenz Coadministration of efavirenz in HIV-infected methadone-maintenance patients has resulted in decreased methadone plasma concentrations of methadone associated with signs of opioid withdrawal, and necessitating increases in methadone dose.
Ritonavir and Ritonavir/Lopinavir Reduced plasma methadone levels have been observed after administration of ritonavir alone or ritonavir/lopinavir combination.
Withdrawal symptoms were however, inconsistently observed.
Caution is warranted when administering methadone to patients receiving ritonavir-containing regimens in addition to other drugs known to decrease methadone plasma levels.
Zidovudine Experimental evidence suggests that methadone increases the area under the concentration-time curve (AUC) of zidovudine with possible toxic effects.
Didanosine and Stavudine Experimental evidence suggests that methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine.
Methadone disposition was not substantially altered.
Desipramine Blood levels of desipramine have increased with concurrent methadone therapy.
OVERDOSAGE
Clinical Presentation Acute overdose with Methadone Hydrochloride Injection can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.
Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.
Treatment of Overdose In the case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed.
Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated.
Cardiac arrest or arrhythmias will require advanced life-support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose.
For clinically significant respiratory or circulatory depression secondary to methadone overdose, administer an opioid antagonist.
Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to methadone overdose.
The physician must remember that methadone is a long-acting depressant (36 to 48 hours), whereas the antagonists act for much shorter periods (one to three hours).
Because the duration of opioid reversal is expected to be less than the duration of action of methadone in Methadone Hydrochloride Injection, carefully monitor the patient until spontaneous respiration is reliably reestablished.
If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, the administration of the usual dose of an opioid antagonist will precipitate an acute withdrawal syndrome.
The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered.
If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
DESCRIPTION
Methadone Hydrochloride Injection USP, 10 mg/mL is an opioid analgesic.
Each milliliter of Methadone Hydrochloride Injection contains 10 mg (0.029 mmol) of methadone hydrochloride, equivalent to 8.95 mg of methadone free base.
Methadone hydrochloride is a white, crystalline material that is water-soluble.
Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-hepatanone hydrochloride.
Its molecular formula is C 21 H 27 NO•HCl and it has a molecular weight of 345.91.
Methadone hydrochloride has a melting point of 235°C, and a pKa of 8.25 in water at 20°C.
Its octanol/water partition coefficient at pH 7.4 is 117.
A solution (1:100) in water has a pH between 4.5 and 6.5.
Methadone hydrochloride has the following structural formula: Methadone Hydrochloride Injection is a sterile injectable solution containing the following inactive ingredients: chlorobutanol, 0.5%, as a preservative, and sodium chloride.
The pH of the sterile injectable solution may have been adjusted during manufacturing with sodium hydroxide and/or hydrochloric acid.
Methadone Hydrochloride Structural Formula
HOW SUPPLIED
Methadone Hydrochloride Injection USP, 200 mg/20 mL (10 mg/mL) is available in: NDC 67457-217-20 20 mL Multi-Dose Vials: One vial per carton Store at 20° to 25°C (68° to 77°F), with excursions permitted between 15° to 30°C (59° to 86°F).
[See USP Controlled Room Temperature.] Protect from light.
Store in carton until contents have been used.
Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A.
Manufactured by: Alcami Corporation Charleston, SC 29405 U.S.A.
PC-3374H Revised: 10/2019 MI:MTHDIJ:R5
GERIATRIC USE
Geriatric Use Clinical studies of Methadone Hydrochloride Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Elderly patients (aged 65 years or older) may have increased sensitivity to methadone.
In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.
Titrate the dosage of Methadone Hydrochloride Injection slowly in geriatric patients and monitor closely for signs of respiratory depression (see WARNINGS , PRECAUTIONS ).
Methadone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
MECHANISM OF ACTION
Mechanism of Action Methadone hydrochloride is a mu-agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle.
The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction.
The methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe.
Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor.
The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown.
INDICATIONS AND USAGE
1.
For the management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate.
Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses (see WARNINGS: Addiction, Abuse, and Misuse ) reserve Methadone Hydrochloride Injection for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: • Have not been tolerated, or are not expected to be tolerated, • Have not provided adequate analgesia, or are not expected to provide adequate analgesia.
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.
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.
Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards (42 CFR 8.12).
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.
Regulatory Exceptions to the General Requirement for Certification to Provide Opioid Agonist Treatment: During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis.
During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21CFR 1306.07(b)).
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 years have not been established.
PREGNANCY
Pregnancy There are no pharmacokinetic studies of parenteral methadone in pregnancy.
The disposition of oral methadone has been studied in approximately 30 pregnant patients in 2 nd and 3 rd trimesters.
Elimination of methadone was significantly changed in pregnancy.
Total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women.
The terminal half-life of methadone is decreased during second and third trimesters.
The decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients.
The dosage may need to be increased or the dosing interval decreased in pregnant patients receiving methadone (see DOSAGE AND ADMINISTRATION ).
BOXED WARNING
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; LIFE-THREATENING QT PROLONGATION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; and TREATMENT OF OPIOID ADDICTION Addiction, Abuse, and Misuse Methadone Hydrochloride Injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death.
Assess each patient’s risk prior to prescribing Methadone Hydrochloride Injection, and monitor all patients regularly for the development of these behaviors and conditions (see WARNINGS ).
Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Methadone Hydrochloride Injection.
The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period.
Monitor for respiratory depression, especially during initiation of Methadone Hydrochloride Injection or following a dose increase (see WARNINGS ).
Life-Threatening QT Prolongation QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone.
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.
Closely monitor patients with risk factors for development of prolonged QT interval, a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of Methadone Hydrochloride Injection (see WARNINGS ).
Neonatal Opioid Withdrawal Syndrome Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of use of Methadone Hydrochloride Injection during pregnancy.
NOWS may be life-threatening if not recognized and treated in the neonate.
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.
Advise the patient of the risk of NOWS so that appropriate planning for management of the neonate can occur (see WARNINGS ).
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The concomitant use of Methadone Hydrochloride Injection with all cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression.
In addition, discontinuation of concomitantly used cytochrome P450 3A4 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration.
Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that result in an increase in methadone levels (see WARNINGS , PRECAUTIONS: Drug Interactions ).
Risks From Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS , PRECAUTIONS: Drug Interactions ).
• Reserve concomitant prescribing of Methadone Hydrochloride Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.
Conditions for Distribution and Use of Methadone Products for the Treatment of Opioid Addiction For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration (see INDICATIONS AND USAGE ).
INFORMATION FOR PATIENTS
Information for Patients Addiction, Abuse, and Misuse Inform patients that the use of Methadone Hydrochloride Injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death (see WARNINGS ).
Instruct patients not to share Methadone Hydrochloride Injection with others and to take steps to protect Methadone Hydrochloride Injection from theft or misuse.
Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Methadone Hydrochloride Injection or when the dosage is increased, and that it can occur even at recommended dosages (see WARNINGS ).
Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Symptoms of Arrhythmia Instruct patients to seek medical attention immediately if they experience symptoms suggestive of an arrhythmia (such as palpitations, near syncope, or syncope) when taking methadone (see WARNINGS ).
Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if Methadone Hydrochloride Injection are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider (see WARNINGS , PRECAUTIONS: Drug Interactions ).
Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs.
Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop.
Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications (see WARNINGS , PRECAUTIONS: Drug Interactions ).
MAOI Interaction Inform patients to avoid taking Methadone Hydrochloride Injection while using any drugs that inhibit monoamine oxidase.
Patients should not start MAOIs while taking Methadone Hydrochloride Injection (see PRECAUTIONS: Drug Interactions ).
Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition.
Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.
Advise patients to seek medical attention if they experience a constellation of these symptoms (see WARNINGS ).
Hypotension Inform patients that Methadone Hydrochloride Injection may cause orthostatic hypotension and syncope.
Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) (see WARNINGS ).
Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained Methadone Hydrochloride Injection.
Advise patients how to recognize such a reaction and when to seek medical attention (see CONTRAINDICATIONS , ADVERSE REACTIONS ).
Pregnancy Neonatal Opioid Withdrawal Syndrome Advise women that if they are pregnant while being treated with Methadone Hydrochloride Injection, the baby may have signs of withdrawal at birth and that withdrawal is treatable (see BOXED WARNING , WARNINGS: Neonatal Opioid Withdrawal Syndrome , PRECAUTIONS: Pregnancy ) Embryo-Fetal Toxicity Inform female patients of reproductive potential that Methadone Hydrochloride Injection can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy (see PRECAUTIONS: Pregnancy ).
Lactation Instruct nursing mothers using Methadone Hydrochloride Injection to watch for signs of methadone toxicity in their infants, which include increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness.
Instruct nursing mothers to talk to the baby’s healthcare provider immediately if they notice these signs.
If they cannot reach the healthcare provider right away, instruct them to take the baby to the emergency room or call 911 (or local emergency services) (see PRECAUTIONS: Lactation ).
Infertility Inform patients that chronic use of opioids may cause reduced fertility.
It is not known whether these effects on fertility are reversible (see PRECAUTIONS: Females and Males of Reproductive Potential ).
Driving or Operating Heavy Machinery Inform patients that Methadone Hydrochloride Injection may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery.
Advise patients not to perform such tasks until they know how they will react to the medication (see WARNINGS ).
Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see CLINICAL PHARMACOLOGY: Pharmacodynamics , ADVERSE REACTIONS ).
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.
Methadone Hydrochloride Injection for Management of Pain Methadone Hydrochloride Injection should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
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 consistent with individual patient treatment goals (see WARNINGS ).
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 (see WARNINGS ).
Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Methadone Hydrochloride Injection and adjust the dosage accordingly (see WARNINGS ).
Methadone Hydrochloride Injection 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.
Initiation of Therapy in Opioid Non-Tolerant Patients When parenteral methadone is used as the first analgesic in patients who are not already being treated with, and tolerant to, opioids, the usual intravenous methadone starting dose is 2.5 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.
Conversion from Oral Methadone to Parenteral Methadone Conversion from oral methadone to parenteral methadone should initially use a 2:1 dose ratio (e.g., 10 mg oral methadone to 5 mg parenteral methadone).
Switching Patients to Parenteral Methadone from Other Chronic Opioids Switching a patient from another chronically administered opioid 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.
It is safer to underestimate a patient’s 24-hour methadone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour methadone dosage and manage an adverse reaction due to an overdose.
The dose conversion scheme below is derived from various consensus guidelines for converting chronic pain 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.
Oral Morphine to Intravenous Methadone Conversion for Chronic Administration Total Daily Baseline Oral Morphine Dose Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Dose Estimated Daily Intravenous Methadone as Percent of Total Daily Oral Morphine Dose The total daily methadone dose derived from the table above may then be divided to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
1000 mg < 5% < 3% Table 2.
Parenteral Morphine to Intravenous Methadone Conversion for Chronic Administration (Derived from Table 1, Assuming a 3:1 Oral:Parenteral Morphine Ratio) Total Daily Baseline Parenteral Morphine Dose Estimated Daily Parenteral Methadone Requirement as Percent of Total Daily Morphine Dose The total daily methadone dose derived from the table above may then be divided to reflect the intended dosing schedule (i.e., 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.
Methadone Hydrochloride Injection for Treatment of Opioid Dependence Detoxification and Maintenance Treatment of Opioid Dependence For detoxification and maintenance of opiate dependence, methadone should be administered in accordance with the treatment standards cited in 42CFR Section 8.12, 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.
Several small studies have demonstrated significantly lower trough methadone plasma concentrations and shorter methadone half-lives in women during their pregnancy compared to after their delivery.
During pregnancy a woman’s methadone dose may need to be increased, or their dosing interval decreased.
Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.