Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.
Concomitant use of temsirolimus with sunitinib

The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, gout/cellulitis requiring hospitalisation) were observed in 2 out of 3 patients treated in the first cohort of a Phase 1 study at doses of temsirolimus 15 mg intravenous per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest) (see section 4.4).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors and/or calcium channel blockers 
An increased incidence of angioneurotic oedema- (including delayed reactions occurring two months following initiation of therapy) has been observed in patients who received temsirolimus or other mTOR inhibitors in combination with an ACE inhibitor (e.g. ramipril) and/or a calcium channel blocker (e.g. amlodipine) (see sections 4.4 and 4.8).

Agents inducing CYP3A metabolism

Co-administration of temsirolimus with rifampicin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus maximum concentration (Cmax) and area under the concentration vs. time curve(AUC) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56%, compared to temsirolimus treatment alone. Therefore, concomitant treatment with agents that have CYP3A4/5 induction potential should be avoided (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, and St. John’s wort) (see section 4.4).

Agents inhibiting CYP3A metabolism

Co-administration of temsirolimus 5 mg with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and AUCsum (temsirolimus + sirolimus) increased 2.3-fold compared to temsirolimus alone. The effect on the unbound concentrations of sirolimus has not been determined, but is expected to be larger than the effect on whole-blood concentrations due to the saturable binding to red blood cells. The effect may also be more pronounced at a 25 mg dose. Therefore, substances that are potent inhibitors of CYP3A4 activity (e.g. nelfinavir, ritonavir, itraconazole, ketoconazole, voriconazole, nefazodone) increase sirolimus blood concentrations. Concomitant treatment of temsirolimus with these agents should be avoided (see section 4.4).

Concomitant treatment with moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, clarithromycin, erythromycin, aprepitant, amiodarone) should only be administered with caution in patients receiving 25 mg and should be avoided in patients receiving temsirolimus doses higher than 25 mg.

Cannabidiol (P-gp inhibitor)

There have been reports of increased blood levels of other mTOR inhibitors during concomitant use with cannabidiol. Co-administration of cannabidiol with another orally administered mTOR inhibitor in a healthy volunteer study led to an increase in exposure to the mTOR inhibitor of approximately 2.5- fold for both Cmax and AUC, due to inhibition of intestinal P-gp efflux by cannabidiol.
Temsirolimus was demonstrated to be a substrate for P-gp in vitro. Caution should be used when cannabidiol and temsirolimus are co-administered, closely monitoring for side effects and adjusting the temsirolimus dose as needed (see sections 4.2 and 4 4).

Interaction with medicinal products metabolised by CYP2D6 or CYP3A4/5 
In 23 healthy subjects the concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of temsirolimus was co-administered.In 36 patients with MCL, including 4 poor metabolisers, the effect of CYP2D6 inhibition after administration of single doses of 175 mg and 75 mg temsirolimus was investigated. Population PK analysis based on sparse sampling indicated no clinically significant interaction effect on AUC and Cmax of the CYP2D6 substrate desipramine. No clinically significant effect is anticipated when temsirolimus is co-administered with agents that are metabolised by CYP2D6.


The effect of a 175 or 75 mg temsirolimus dose on CYP3A4/5 substrates has not been studied.
However, in vitro studies in human liver microsomes followed by physiologically-based pharmacokinetic modelling indicate that the blood concentrations achieved after a 175 mg dose of temsirolimus most likely leads to relevant inhibition of CYP3A4/5 (see section 5.2). Therefore, caution is advised during concomitant administration of temsirolimus at a dose of 175 mg with medicinal products that are metabolised predominantly via CYP3A4/5 and that have a narrow therapeutic index.

Interactions with medicinal products that are P-glycoprotein substrates 
In an in vitro study, temsirolimus inhibited the transport of P-glycoprotein (P-gp) substrates with an IC50 value of 2 µM. In vivo, the effect of P-gp inhibition has not been investigated in a clinical drug- drug interaction study ;however,, recent preliminary data from a Phase 1 study of combined lenalidomide (dose of 25 mg) and temsirolimus (dose of 20 mg) seem to support the in vitro findings and suggest an increased risk of adverse events. Therefore, when temsirolimus is co-administered with medicinal products which are P-gp substrates (e.g. digoxin, vincristine, colchicine, dabigatran, lenalidomide, and paclitaxel) close monitoring for adverse events related to the co-administered medicinal products should be observed.

Amphiphilic agents

Temsirolimus has been associated with phospholipidosis in rats. Phospholipidosis has not been observed in mice or monkeys treated with temsirolimus, nor has it been documented in patients treated with temsirolimus. Although phospholipidosis has not been shown to be a risk for patients administered temsirolimus, it is possible that combined administration of temsirolimus with other amphiphilic agents such as amiodarone or statins could result in an increased risk of amphiphilic pulmonary toxicity.