Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction
Lixisenatide is a peptide and is not metabolised by cytochrome P450. In in vitro studies, lixisenatide did not affect the activity of cytochrome P450 isozymes or human transporters tested.

The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally administered medicinal products. Patients receiving medicinal products of either a narrow therapeutic ratio or medicinal products that require careful clinical monitoring should be followed closely, especially at the time of initiation of lixisenatide treatment. These medicinal products should be taken in a standardised way in relation to lixisenatide. If such medicinal products are to be administered with food, patients should be advised to, if possible, take them with a meal when lixisenatide is not administered.

For oral medicinal products that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, patients should be advised to take those medicinal products at least 1 hour before or 4 hours after lixisenatide injection.

Gastro-resistant formulations containing substances sensitive to stomach degradation, should be administered 1 hour before or 4 hours after lixisenatide injection.

Paracetamol

Paracetamol was used as a model medicinal product to evaluate the effect of lixisenatide on gastric emptying. Following administration of a single dose of paracetamol 1000 mg, paracetamol AUC and t1/2 were unchanged whatever the timing of its administration (before or after the lixisenatide injection).
When administered 1 or 4 hours after 10 mcg lixisenatide, Cmax of paracetamol was decreased by   29% and 31% respectively and median tmax was delayed by 2.0 and 1.75 hours respectively. A further delay in tmax and a reduced Cmax of paracetamol have been predicted with the 20 mcg maintenance dose.

No effects on paracetamol Cmax and tmax were observed when paracetamol was administered 1 hour before lixisenatide.

Based on these results, no dose adjustment for paracetamol is required but the delayed tmax observed when paracetamol is administered 1-4 hours after lixisenatide should be taken into account when a rapid onset of action is required for efficacy.

Oral contraceptives

Following administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour before or 11 hours after 10 mcg lixisenatide, the C max, AUC, t1/2 and tmax of ethinylestradiol and levonorgestrel were unchanged.

Administration of the oral contraceptive 1 hour or 4 hours after lixisenatide did not affect AUC and t 1/2 of ethinylestradiol and levonorgestrel, whereas Cmax of ethinylestradiol was decreased by 52% and 39% respectively and Cmax of levonorgestrel was decreased by 46% and 20%, respectively and median tmax was delayed by 1 to 3 hours.

The reduction in Cmax is of limited clinical relevance and no dose adjustment for oral contraceptives is required.


Atorvastatin

When lixisenatide 20 mcg and atorvastatin 40 mg were co-administered in the morning for 6 days, the exposure to atorvastatin was not affected, while Cmax was decreased by 31% and tmax was delayed by 3.25 hours.

No such increase for tmax was observed when atorvastatin was administered in the evening and lixisenatide in the morning but the AUC and Cmax of atorvastatin were increased by 27% and 66% respectively.

These changes are not clinically relevant and therefore, no dose adjustment for atorvastatin is required when co-administered with lixisenatide.

Warfarin and other coumarin derivatives

After concomitant administration of warfarin 25 mg with repeated dosing of lixisenatide 20 mcg, there were no effects on AUC or INR (International Normalised Ratio) while Cmax was reduced by 19% and tmax was delayed by 7 hours.

Based on these results, no dose adjustment for warfarin is required when co-administered with lixisenatide; however, frequent monitoring of INR in patients on warfarin and/or coumarin derivatives is recommended at the time of initiation or ending of lixisenatide treatment.

Digoxin

After concomitant administration of lixisenatide 20 mcg and digoxin 0.25 mg at steady state, the AUC of digoxin was not affected. The tmax of digoxin was delayed by 1.5 hour and the Cmax was reduced by   26%.

Based on these results, no dose adjustment for digoxin is required when co-administered with lixisenatide.

Ramipril

After concomitant administration of lixisenatide 20 mcg and ramipril 5 mg during 6 days, the AUC of ramipril was increased by 21% while the Cmax was decreased by 63%. The AUC and Cmax of the active metabolite (ramiprilat) were not affected. The tmax of ramipril and ramiprilat were delayed by approximately 2.5 hours.

Based on these results, no dose adjustment for ramipril is required when co-administered with lixisenatide.