Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI).
There are very limited data from drug interaction studies and on the safety of linezolid when administered to patients on concomitant medications that might put them at risk from MAO inhibition. Therefore, linezolid is not recommended for use in these circumstances unless close observation and monitoring of the recipient is possible (see sections 4.3 and 4.4).

Potential interactions producing elevation of blood pressure
In normotensive healthy volunteers, linezolid enhanced the increases in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Co-administration of linezolid with either pseudoephedrine or phenylpropanolamine resulted in mean increases in systolic blood pressure of the order of 30-40 mmHg, compared with 11-15 mmHg increases with linezolid alone, 14-18 mmHg with either pseudoephedrine or phenylpropanolamine alone and 8-11 mmHg with placebo. Similar studies in hypertensive subjects have not been conducted. It is recommended that doses of drugs with a vasopressive action, including dopaminergic agents, should be carefully titrated to achieve the desired response when co- administered with linezolid.

Potential serotonergic interactions
The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20 mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.

Post marketing experience: there has been one report of a patient experiencing serotonin syndrome-like effects while taking linezolid and Page 9 of 24
dextromethorphan which resolved on discontinuation of both medications.

During clinical use of linezolid with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), cases of serotonin syndrome have been reported. Therefore, while co-administration is contraindicated (see section 4.3), management of patients for whom treatment with linezolid and serotonergic agents is essential, is described in section 4.4.

Use with tyramine-rich foods
No significant pressor response was observed in subjects receiving both linezolid and less than 100 mg tyramine. This suggests that it is only necessary to avoid ingesting excessive amounts of food and beverages with a high tyramine content (e.g. mature cheese, yeast extracts, undistilled alcoholic beverages and fermented soya bean products such as soy sauce).

Drugs metabolised by cytochrome P450
Linezolid is not detectably metabolised by the cytochrome P450 (CYP) enzyme system and it does not inhibit any of the clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, no CYP450-induced drug interactions are expected with linezolid.

Rifampicin
The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers administered linezolid 600 mg twice daily for 2.5 days with and without rifampicin 600 mg once daily for 8 days.
Rifampicin decreased the linezolid Cmax and AUC by a mean 21% [90% CI, 15, 27] and a mean 32% [90% CI, 27, 37], respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin
When warfarin was added to linezolid therapy at steady-state, there was a 10% reduction in mean maximum INR on co-administration with a 5% reduction in AUC INR. There are insufficient data from patients who have received warfarin and linezolid to assess the clinical significance, if any, of these findings.