Drug Interactions between lixisenatide and Methadone Diskets

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of methadone. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of methadone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 8 study subjects stabilized on methadone maintenance treatment, ingestion of regular strength grapefruit juice (200 mL one-half hour before and 200 mL simultaneously with the daily methadone dose) for five days resulted in an approximately 17% mean increase in methadone peak plasma concentration (Cmax) and systemic exposure (AUC) and a 14% mean decrease in apparent clearance for both the R(+) and S(-) enantiomers. Grapefruit juice did not affect the time to peak level (Tmax), terminal half-life, or apparent volume of distribution of methadone. No signs or symptoms of methadone toxicity or changes in intensity of withdrawal symptoms were reported in the study. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In addition, high dosages (particularly above 200 mg/day) and high serum levels of methadone have been associated with QT interval prolongation and torsade de pointes arrhythmia.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with methadone. Any history of alcohol or illicit drug use should be considered when prescribing methadone, and therapy initiated at a lower dosage if necessary. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. In addition, patients treated with oral methadone should preferably avoid or limit the consumption of grapefruit juice, particularly during the induction of maintenance treatment. Given the interindividual variability in the pharmacokinetics of methadone, a significant interaction with grapefruit juice in certain patients cannot be ruled out. Patients should be advised to seek immediate 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.

ADJUST DOSING INTERVAL: Lixisenatide slows gastric emptying, which may impact the absorption of concomitantly administered oral medications. The interaction has been studied with various medications, which demonstrated primarily an effect on the rate rather than the overall extent of absorption.

Acetaminophen: When acetaminophen 1000 mg was administered 1 hour and 4 hours after lixisenatide 10 mcg injection, acetaminophen peak plasma concentration (Cmax) was decreased by 29% and 31%, respectively; and median time to peak plasma concentration (Tmax) was delayed by 2 hours and 1.75 hours, respectively. The Cmax and Tmax of acetaminophen were not significantly altered when acetaminophen was given one hour before lixisenatide injection, and systemic exposure (AUC) was not affected whether administered before or after lixisenatide administration. Based on these results, no dose adjustment for acetaminophen is required; however, it may be advisable to take acetaminophen at least one hour before lixisenatide if a rapid onset of action is required.

Oral Contraceptives: When an oral contraceptive containing ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg was administered 1 hour and 4 hours after lixisenatide 10 mcg injection, ethinyl estradiol Cmax was decreased by 52% and 39%, respectively, while levonorgestrel Cmax was decreased by 46% and 20%, respectively. Median Tmax values were delayed by 1 to 3 hours, but overall exposure (AUC) and mean terminal half-life (T1/2) of ethinyl estradiol and levonorgestrel were not significantly altered. Administration of the oral contraceptive 1 hour before or 11 hours after lixisenatide had no effect on any of the measured pharmacokinetic parameters of either ethinyl estradiol or levonorgestrel. Based on these results, no dose adjustment for oral contraceptives is required; however, some authorities recommend that oral contraceptives be administered at least 1 hour before or 11 hours after lixisenatide.

Atorvastatin: When atorvastatin 40 mg and lixisenatide 20 mcg were coadministered in the morning for 6 days, atorvastatin Cmax was decreased by 31% and Tmax was delayed by 3.25 hours, but AUC was not affected. When atorvastatin was administered in the evening and lixisenatide in the morning, the AUC and Cmax of atorvastatin were increased by 27% and 66%, respectively, but there was no change in Tmax. Based on these results, no dose adjustment for atorvastatin is required; however, some authorities recommend that atorvastatin be administered at least 1 hour before lixisenatide.

Warfarin: When warfarin 25 mg was coadministered with repeated dosing of lixisenatide 20 mcg, warfarin Cmax was decreased by 19% and Tmax was delayed by 7 hours, but there were no effects on AUC or International Normalized Ratio (INR). Based on these results, no dose adjustment for warfarin is required; however, closer monitoring of INR may be appropriate following initiation or discontinuation of lixisenatide treatment.

Digoxin: When digoxin 0.25 mg and lixisenatide 20 mcg were coadministered at steady state, digoxin Cmax was decreased by 26% and Tmax was delayed by 1.5 hours, but AUC was not affected. Based on these results, no dose adjustment for digoxin is required.

Ramipril: When ramipril 5 mg and lixisenatide 20 mcg were coadministered for 6 days, ramipril Cmax was decreased by 63% and AUC was increased by 21%, while Cmax and AUC of the active metabolite (ramiprilat) were not affected. The Tmax values of ramipril and ramiprilat were delayed by approximately 2.5 hours. Based on these results, no dose adjustment for ramipril is required.

MANAGEMENT: Caution is advised during concomitant use of lixisenatide with oral medications that have a narrow therapeutic index or that require careful clinical monitoring. These medications should be administered on a consistent schedule relative to lixisenatide, and blood levels and/or pharmacologic effects should be closely monitored. In addition, if they are to be administered with food, patients should be advised to take them with a meal or snack when lixisenatide is not administered. Oral medications that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, or medications for which a delay in effect is undesirable, such as acetaminophen, should be administered at least 1 hour before lixisenatide. Gastro-resistant formulations containing substances sensitive to stomach degradation should be administered 1 hour before or 4 hours after lixisenatide. Patients taking oral contraceptives should be advised to take them at least 1 hour before or 11 hours after lixisenatide.