Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on lomitapide and other forms of interaction Table 2:      Interactions between Lojuxta and other medicinal products and other forms of interaction
Medicinal products       Effects on lomitapide levels  Recommendation concerning co-administration with Lojuxta



Inhibitors of CYP3A4   Strong and moderate inhibitors      Strong and moderate inhibitors When lomitapide 60 mg was           Use of strong or moderate inhibitors of co-administered with                CYP3A4 is contraindicated with ketoconazole 200 mg twice           Lojuxta. If treatment with antifungal daily, a strong inhibitor of        azoles (e.g., itraconazole, ketoconazole, CYP3A4, lomitapide AUC              fluconazole, voriconazole,
increased approximately 27-fold     posaconazole); the antiarrhythmic and Cmax increased                  dronedarone; macrolide antibiotics (e.g., approximately 15-fold.              erythromycin, clarithromycin); ketolide antibiotics (e.g., telithromycin); HIV
Interactions between moderate       protease inhibitors; the calcium channel CYP3A4 inhibitors and               blockers diltiazem and verapamil is lomitapide have not been            unavoidable, therapy with Lojuxta studied.                            should be suspended during the course of treatment (see sections 4.3 and 4.4).
Moderate CYP3A4 inhibitors are predicted to have a substantial     Grapefruit juice is a moderate inhibitor impact on lomitapide’s              of CYP3A4 and is expected to pharmacokinetics. Concomitant       substantially increase exposure to use of moderate CYP3A4              lomitapide. Patients taking Lojuxta inhibitors are expected to          should avoid consumption of grapefruit increase lomitapide exposure by     juice.
4-10 fold based on the results of the study with the strong
CYP3A4 inhibitor ketoconazole and on historical data for the model CYP3A4 probe midazolam.



Medicinal products     Effects on lomitapide levels        Recommendation concerning co-administration with Lojuxta



Weak inhibitors                      Weak inhibitors
Weak CYP3A4 inhibitors are        When administered with atorvastatin, the expected to increase the exposure dose of Lojuxta should either be taken of lomitapide when taken          12 hours apart or be decreased by half (see simultaneously.                   section 4.2). The dose of Lojuxta should be taken 12 hours apart from any other
When lomitapide 20 mg was concomitant weak CYP3A4 inhibitors.
co-administered simultaneously
Examples of weak CYP3A4 inhibitors with atorvastatin, a weak include: alprazolam, amiodarone,
CYP3A4 inhibitor, lomitapide amlodipine, atorvastatin, azithromycin,
AUC and Cmax increased bicalutamide, cilostazol, cimetidine,
approximately 2-fold. When the ciclosporin, clotrimazole, fluoxetine,
dose of lomitapide was taken fluvoxamine, fosaprepitant, ginkgo,
12 hours apart from atorvastatin,
goldenseal, isoniazid, ivacaftor,
no clinically meaningful increase lacidipine, lapatinib, linagliptin, nilotinib,
in lomitapide exposure was oestrogen-containing oral observed.
contraceptives, pazopanib, peppermint
When lomitapide 20 mg was co- oil, propiverine, ranitidine, ranolazine, administered simultaneously or     roxithromycin, Seville oranges,
12 hours apart with ethinyl        tacrolimus, ticagrelor and tolvaptan. This estradiol/norgestimate, a weak     list is not intended to be comprehensive CYP3A4 inhibitor, no clinically and prescribers should check the meaningful increase in             prescribing information of medicinal lomitapide exposure was            products to be co-administered with observed.                          Lojuxta for potential CYP3A4 mediated interactions.

The effect of administration of more than one weak CYP3A4 inhibitor has not been tested, but the effect on the exposure of lomitapide is expected to be greater than for co-administration of the individual inhibitors with lomitapide.

Exercise additional caution if administering more than 1 weak
CYP3A4 inhibitor with Lojuxta.
Inducers of CYP3A4   Medicines that induce CYP3A4         When co-administering CYP3A4 would be expected to increase        inducers (i.e., aminoglutethimide, the rate and extent of               nafcillin, non-nucleoside reverse metabolism of lomitapide.            transcriptase inhibitors, phenobarbital, Consequently, this would reduce      rifampicin, carbamazepine, pioglitazone, the effect of lomitapide. Any        St John’s Wort, glucocorticoids, impact on efficacy is likely to be   modafinil and phenytoin) with Lojuxta, variable.                            the possibility of a drug-drug interaction affecting efficacy should be considered.
It is recommended to increase the frequency of LDL-C assessment during such concomitant use and consider increasing the dose of Lojuxta to ensure maintenance of the desired level of efficacy if the CYP3A4 inducer is intended for chronic use.



Bile acid sequestrants     Lomitapide has not been tested      Because bile acid sequestrants can for interaction with bile acid      interfere with the absorption of oral sequestrants (resins such as        medicines, bile acid sequestrants should colesevelam and                     be taken at least 4 hours before or at least cholestyramine).                    4 hours after Lojuxta.

Effects of lomitapide on other medicinal products

HMG-CoA reductase inhibitors (“Statins”)
Lomitapide increases plasma concentrations of statins. When lomitapide 60 mg was administered to steady state prior to simvastatin 40 mg, simvastatin acid AUC and Cmax increased 68% and 57%, respectively. When lomitapide 60 mg was administered to steady state prior to atorvastatin 20 mg, atorvastatin acid AUC and Cmax increased 52% and 63%, respectively. When lomitapide 60 mg was administered to steady state prior to rosuvastatin 20 mg, rosuvastatin Tmax increased from 1 to 4 hours, AUC was increased 32%, and its Cmax was unchanged. The risk of myopathy with simvastatin is dose related. Use of Lojuxta is contraindicated in patients treated with high doses of simvastatin (>40 mg) (see sections 4.3 and 4.4).

Coumarin anticoagulants
When lomitapide 60 mg was administered to steady state and 6 days following warfarin 10 mg, INR increased 1.26-fold. AUCs for R(+)-warfarin and S(-)-warfarin increased 25% and 30%, respectively.
Cmax for R(+)-warfarin and S(-)-warfarin increased 14% and



15%, respectively. In patients taking coumarins (such as warfarin) and Lojuxta concomitantly, INR should be determined before starting Lojuxta and monitored regularly with dosage of coumarins adjusted as clinically indicated (see section 4.4).

Fenofibrate, niacin and ezetimibe
When lomitapide was administered to steady state prior to micronised fenofibrate 145 mg, extended release niacin 1000 mg, or ezetimibe 10 mg, no clinically significant effects on the exposure of any of these medicinal products were observed. No dose adjustments are required when co-administered with Lojuxta.

Oral contraceptives
When lomitapide 50 mg was administered to steady state along with an oestrogen-based oral contraceptive, no clinically meaningful or statistically significant impact on the pharmacokinetics of the components of the oral contraceptive (ethinyl estradiol and 17-deacetyl norgestimate, the metabolite of norgestimate) was observed. Lomitapide is not expected to directly influence the efficacy of oestrogen based oral contraceptives; however diarrhoea and/or vomiting may reduce hormone absorption. In cases of protracted or severe diarrhoea and/or vomiting lasting more than 2 days, additional contraceptive measures should be used for 7 days after resolution of symptoms.

P-gp substrates
Lomitapide inhibits P-gp in vitro, and may increase the absorption of P-gp substrates.
Coadministration of Lojuxta with P gp substrates (such as aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) may increase the absorption of P gp substrates. Dose reduction of the P gp substrate should be considered when used concomitantly with Lojuxta.

In vitro assessment of drug interactions
Lomitapide inhibits CYP3A4. Lomitapide does not induce CYPs 1A2, 3A4, or 2B6, and does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1. Lomitapide is not a P-gp substrate but does inhibit P-gp. Lomitapide does not inhibit breast cancer resistance protein (BCRP).