Methadone

5 WARNINGS AND PRECAUTIONS 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. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.8) Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue methadone hydrochloride tablets if serotonin syndrome is suspected. ( 5.9 ) Ri s k of Life-Threatening Respiratory Depression in Patients with Chronic P u l monary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate closely, particularly during initiation and titration. ( 5.10 ) A d r e na l Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.11 ) S e v e r e Hypotension : Regularly evaluate during dose initiation and titration. Avoid use in patients with circulatory shock.( 5.12 ) Ri s k s of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Regularly evaluate for sedation and respiratory depression. Avoid use of methadone hydrochloride tablets in patients with impaired consciousness or coma. ( 5.13 ) 5.1 Addiction, Abuse and Misuse Methadone hydrochloride tablets contain methadone, a Schedule II controlled substance. As an opioid, methadone hydrochloride tablets expose users to the risks of addiction, abuse, and misuse.As long-acting opioids such as methadone hydrochloride tablets have pharmacological effects over an extended period of time, there is a greater risk for overdose and death [see DRUG ABUSE AND DEPENDENCE ( 9 ) ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed methadone hydrochloride tablets. 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 ( 6 )]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing methadone hydrochloride tablets, and reassess all patients receiving methadone hydrochloride tablets 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 abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as methadone hydrochloride tablets, but use in such patients necessitates intensive counseling about the risks and proper use of methadone hydrochloride tablets along with the frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see DOSAGE AND ADMINISTRATION ( 2.3 ) , WARNINGS AND PRECAUTIONS ( 5.2 ) ]. Abuse or misuse of methadone hydrochloride tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the methadone and can result in overdose and death [see OVERDOSAGE ( 10 ) ] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing methadone hydrochloride tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and 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. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of methadone, even when used as recommended. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, depending on the patient’s clinical status [ see OVERDOSAGE ( 10 )] . 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 tablets, the risk is greatest during the initiation of therapy or following a dosage increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Regularly evaluate patients for respiratory depression, when initiating therapy with methadone hydrochloride tablets and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of methadone hydrochloride tablets are essential [see DOSAGE AND ADMINISTRATION ( 2.4 , 2.5 )] . Overestimating the methadone hydrochloride tablets dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of methadone hydrochloride tablets, especially by children, can result in respiratory depression and death due to an overdose of methadone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [ see PATIENT COUNSELING INFORMATION ( 17 )]. 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 ( 2.5 ) ]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose : Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. For Patients Being Treated for Pain Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. [ see DOSAGE AND ADMINISTRATION ( 2.3) , WARNINGS AND PRECAUTIONS ( 5.1 , 5.3 ), OVERDOSAGE ( 10 ) ]. For Patients Being Treated for Opioid Addiction Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider recommending or prescribing an opioid overdose reversal agent for the emergency treatment of an opioid overdose, both when initiating and renewing treatment with methadone hydrochloride tablets. Advise patients and caregivers that an opioid overdose reversal agent, such as naloxone or nalmefene, may also be administered for a known or suspected overdose with methadone hydrochloride tablets itself [see OVERDOSAGE ( 10) ]. For patients being treated with methadone (regardless of indication), also consider prescribing or recommending such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered. 5.3 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 tablets with benzodiazepines and/or other CNS depressants (e.g., alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). For Patients Being Treated for Pain 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 DRUG INTERACTIONS ( 7 ) ] . 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. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending of prescribing an opioid overdose reversal agent [see DOSAGE AND ADMINISTRATION ( 2.3 ), WARNINGS AND PRECAUTIONS ( 5.2 )]. Advise both patients and caregivers about the risks of respiratory depression and sedation when methadone hydrochloride tablets are 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 DRUG INTERACTIONS ( 7 ) AND PATIENT COUNSELING INFORMATION ( 17 ) ] . For Patients Being Treated for Opioid Addiction Concomitant use of methadone and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone. As a routine part of orientation to methadone treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, or alcohol. Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at admission to methadone treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of methadone as a strategy to address benzodiazepine use in methadone-treated patients. However, if a patient is sedated at the time of methadone dosing, ensure that a medically-trained healthcare provider evaluates the cause of sedation, and delays or omits the methadone dose if appropriate. Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. For patients in methadone treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s methadone treatment and coordinate care to minimize the risks associated with concomitant use. If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients in methadone treatment for opioid use disorder [ see DOSAGE AND ADMINISTRATION ( 2.3 ), WARNINGS AND PRECAUTIONS ( 5.2 )]. In addition, take measures to confirm that patients are taking the medications prescribed and not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [see DRUG INTERACTIONS ( 7 )]. 5.4 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, 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. 5.5 Neonatal Opioid Withdrawal Syndrome Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of use of opioids for an extended period of time during pregnancy. The balance between the risks of NOWS and the benefits of maternal methadone hydrochloride tablet 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. 5.6 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com . The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint . 5.7 Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or Discontinuation of P450 3A4, 2B6, 2C19, or 2C9 Inducers Concomitant use of methadone hydrochloride tablets 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 dosage of methadone hydrochloride tablets is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone hydrochloride tablet-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of methadone hydrochloride tablets when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and evaluate patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation [see DRUG INTERACTIONS ( 7 ) ] . Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with methadone hydrochloride tablets may decrease methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone. When using methadone hydrochloride tablets with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, assess patients for signs or symptoms of opioid withdrawal and consider increasing the methadone hydrochloride tablets dosage as needed [see DRUG INTERACTIONS ( 7 ) ] . 5.8 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 ( 9.3 )]. 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 DOSAGE AND ADMINISTRATION ( 2.4 ); WARNINGS AND PRECAUTIONS ( 5.15 )]. 5.9 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 hydrochloride tablets 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 DRUG INTERACTIONS ( 7 ) ]. 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 tablets if serotonin syndrome is suspected. 5.10 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of methadone hydrochloride tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease Methadone hydrochloride tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of methadone hydrochloride tablets [see WARNINGS AND PRECAUTIONS ( 5.2 ) ] . Elderly, Cachectic, or Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS AND PRECAUTIONS ( 5.2 ) ] . Regularly evaluate patients, particularly when initiating and titrating methadone hydrochloride tablets and when methadone hydrochloride tablets are given concomitantly with other drugs that depress respiration [see WARNINGS AND PRECAUTIONS ( 5 ), DRUG INTERACTIONS ( 7 ) ] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.11 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. 5.12 Severe Hypotension Methadone hydrochloride tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an 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) [see DRUG INTERACTIONS ( 7 ) ] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of methadone hydrochloride tablets. In patients with circulatory shock, methadone hydrochloride tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of methadone hydrochloride tablets in patients with circulatory shock. 5.13 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 tablets 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 tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of methadone hydrochloride tablets in patients with impaired consciousness or coma. 5.14 Risks of Gastrointestinal Complications Methadone hydrochloride tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The methadone in methadone hydrochloride tablets 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. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see CLINICAL PHARMACOLOGY ( 12.2 )]. 5.15 Increased Risk of Seizures in Patients with Seizure Disorders The methadone in methadone hydrochloride tablets 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during methadone hydrochloride tablets therapy. 5.16 Withdrawal Do not rapidly reduce or abruptly discontinue Methadone Hydrochloride Tablets in a patient physically dependent on opioids. When discontinuing Methadone Hydrochloride Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of methadone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see DOSAGE AND ADMINISTRATION ( 2.6 ), DRUG ABUSE AND DEPENDENCE ( 9.3 )]. Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist, including Methadone Hydrochloride Tablets. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see DRUG INTERACTIONS ( 7 )]. 5.17 Risks of Driving and Operating Machinery Methadone hydrochloride tablets 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 tablets and know how they will react to the medication [see PATIENT COUNSELING INFORMATION ( 17 ) ] . 5.18 Hypoglycemia Cases of methadone-associated hypoglycemia have been reported, some resulting in hospitalization. In many cases, patients had predisposing risk factors (e.g., 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. 5.19 Laboratory Test Interactions False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.