Drug Interactions between liraglutide and lixisenatide

MONITOR: Glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists can delay gastric emptying, which may impact the absorption of concomitantly administered oral medications. Mild to moderate decreases in plasma concentrations of coadministered drugs have been demonstrated in pharmacokinetic studies for some GLP-1 receptor agonists (e.g., exenatide, lixisenatide), but not others. According to the prescribing information, liraglutide did not affect the absorption of several orally administered drugs to any clinically significant extent, including acetaminophen, atorvastatin, digoxin, griseofulvin, lisinopril, and an oral contraceptive containing ethinyl estradiol-levonorgestrel. Likewise, no clinically relevant effect on absorption was observed for concomitantly administered oral drugs studied with albiglutide (digoxin, ethinyl estradiol-norethindrone, simvastatin, warfarin), dulaglutide (acetaminophen, atorvastatin, digoxin, ethinyl estradiol-norelgestromin, lisinopril, metformin, metoprolol, sitagliptin, warfarin), or semaglutide (atorvastatin, digoxin, ethinyl estradiol-levonorgestrel, metformin, warfarin). The impact of dual GLP-1 and GIP receptor agonist tirzepatide on gastric emptying was reported to be dose- and time-dependent, with the greatest effect observed after a single 5 mg dose but diminished after subsequent doses. When acetaminophen was administered following a single 5 mg dose of tirzepatide, acetaminophen peak plasma concentration (Cmax) was decreased by 50% and its median time to peak plasma concentration (Tmax) delayed by 1 hour. However, no significant impact on acetaminophen Cmax and Tmax was observed after 4 consecutive weekly doses of tirzepatide (5 mg/5 mg/8 mg/10 mg), and the overall exposure (AUC) of acetaminophen was unaffected. Tirzepatide at lower doses of 0.5 mg and 1.5 mg also had minimal effects on acetaminophen exposure.

MANAGEMENT: Although no specific dosage adjustment of concomitant medications is generally recommended based on available data, potential clinical impact on some oral medications cannot be ruled out, particularly those with a narrow therapeutic index or low bioavailability, those that depend on threshold concentrations for efficacy (e.g., antibiotics), and those that require rapid gastrointestinal absorption (e.g., hypnotics, analgesics). Pharmacologic response to concomitantly administered oral medications should be monitored more closely following initiation, dose adjustment, or discontinuation of a GLP-1 receptor agonist or a dual GLP-1 and GIP receptor agonist.

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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.

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The recommended maximum number of medicines in the 'incretin-based therapies' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'incretin-based therapies' category:

• liraglutide
• lixisenatide

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.