Drug Interactions between dexamethasone / ketorolac / moxifloxacin and methadone

MONITOR CLOSELY: Coadministration with inducers of various CYP450 isoenzymes may decrease the plasma concentrations of methadone, which is metabolized by CYP450 3A4, 2B6, 2C19, 2C9, and 2D6. Reduced analgesic efficacy or withdrawal symptoms may occur in patients maintained on methadone following the addition of an inducer. Conversely, discontinuation of the inducer may increase methadone plasma concentrations and potentiate the risk of overdose and fatal respiratory depression. The interaction has been reported with several moderate and potent inducers including rifampin, phenytoin, phenobarbital, nevirapine, and efavirenz. In one report, evidence of withdrawal was observed in 21 of 30 patients maintained on methadone who received rifampin for tuberculosis, compared to zero out of 26 who received other antituberculous agents. In a study of 11 patients on stable methadone maintenance treatment, mean methadone peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 48% and 57%, respectively, following initiation of antiretroviral therapy containing efavirenz 600 mg once a day. Nine patients developed symptoms consistent with methadone withdrawal an average of 8 to 10 days after start of efavirenz, which required a 22% mean increase in methadone dosage. In a similar study with nevirapine given at 200 mg once daily for 2 weeks followed by 200 mg twice daily, the reduction in mean methadone Cmax and AUC was 36% and 52%, respectively, in 8 patients stabilized on methadone treatment. Withdrawal symptoms occurred in six patients 8 to 10 days after start of nevirapine, and methadone dosage was subsequently increased an average of 16%. Dosage increases of up to 100% and eventual discontinuation of the non-nucleoside reverse-transcriptase inhibitor have also been described in some reports.

MANAGEMENT: Caution is advised if methadone is prescribed with CYP450 2B6, 2C19, 2C9 and/or 3A4 inducers. Pharmacologic response to methadone should be monitored more closely whenever an inducer is added to or withdrawn from therapy, and the dosage adjusted as necessary.

MONITOR CLOSELY: Methadone can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. High dosages of methadone alone have been associated with QT interval prolongation and torsade de pointes. In a retrospective study of 17 methadone-treated patients who developed torsade de pointes, the mean daily dose was approximately 400 mg (range 65 to 1000 mg) and the mean corrected QT (QTc) interval on presentation was 615 msec. The daily methadone dose correlated positively with the QTc interval. Fourteen patients had at least one predisposing risk factor for arrhythmia (hypokalemia, hypomagnesemia, concomitant use of a medication known to prolong the QT interval or inhibit the metabolism of methadone, and structural heart disease), but these were not predictive of QTc interval. It is not known if any of the patients had congenital long QT syndrome.

MANAGEMENT: Caution is recommended if methadone is used in combination with other drugs that can prolong the QT interval, particularly in the setting of chronic pain management or methadone maintenance for opioid dependency where high dosages may be employed. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. If taking drugs that also cause CNS-depressant or orthostatic effects (e.g., sedating antihistamines, psychotropic drugs like tricyclic antidepressants, phenothiazines, and neuroleptics), patients should be made aware of the possibility of additive effects with methadone and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

MONITOR: The combined use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. In a large, case-control study of elderly patients, those who used corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease and GI hemorrhage of 14.6 compared to those who used neither. Corticosteroid use was associated with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the GI mucosa during coadministration. Some investigators have also suggested that the primary effect of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than cause de novo ulcerations.

MANAGEMENT: Caution is advised if corticosteroids and NSAIDs are used together, especially in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.

MONITOR: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of central nervous system toxicity sometimes associated with fluoroquinolone use. The interaction has been reported most often with enoxacin. It may occur with other fluoroquinolones as well, but is poorly documented. The exact mechanism of interaction is unknown. Some investigators suggest that the piperazine ring of fluoroquinolones may inhibit the binding of gamma-aminobutyric acid (GABA) to brain receptors and that NSAIDs may synergistically add to this effect. Patients with a history of seizures may be at greater risk.

MANAGEMENT: Clinical monitoring for signs of CNS stimulation such as tremors, involuntary muscle movements, hallucinations, or seizures is recommended if fluoroquinolone antibiotics are prescribed in combination with NSAIDs.