Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

This medicinal product contains hydroxypropylbetadex, which may be available for complex formation with other medicinal products, potentially leading to an increase in bioavailability of such a product (especially medicinal products with low solubility). Therefore, it is recommended that administration of any other oral medicinal product be separated from that of MAVENCLAD by at least 3 hours during the limited number of days of cladribine administration.


Immunosuppressive medicinal products

Initiation of cladribine treatment is contraindicated in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy with, e.g., methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids because of a risk of additive effects on the immune system (see section 4.3).

Acute short-term therapy with systemic corticosteroids can be administered during cladribine treatment.

Other disease-modifying medicinal products

The use of cladribine with interferon beta results in an increased risk of lymphopenia. Safety and efficacy of cladribine in combination with other disease-modifying treatments for MS have not been established. Concomitant treatment is not recommended.

Haematotoxic medicinal products

Because of the cladribine-induced reduction in lymphocyte count, additive haematological adverse reactions may be expected if cladribine is administered prior to or concomitantly with other substances that affect the haematological profile (e.g. carbamazepine). Careful monitoring of haematological parameters is recommended in such cases.

Live or live attenuated vaccines

Treatment should not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccines because of a risk of active vaccine infection. Vaccination with live or attenuated live vaccines should be avoided during and after cladribine treatment as long as the patient's white blood cell counts are not within normal limits.

Potent ENT1, CNT3 and BCRP transporter inhibitors

At the level of cladribine absorption, the only conceivable interaction pathway of clinical relevance appears to be the breast cancer resistance protein (BCRP or ABCG2). Inhibition of BCRP in the gastrointestinal tract may increase the oral bioavailability and systemic exposure of cladribine. Known BCRP inhibitors, which may alter the pharmacokinetics of BCRP substrates by 20% in vivo, include eltrombopag.

In vitro studies indicate that cladribine is a substrate of the equilibrative nucleoside (ENT1) and concentrative nucleoside (CNT3) transport proteins. Accordingly, the bioavailability, intracellular distribution and renal elimination of cladribine may theoretically be altered by potent ENT1 and CNT3 transporter inhibitors such as dilazep, nifedipine, nimodipine, cilostazol, sulindac or reserpine.
However, net effects in terms of potential cladribine exposure alterations are difficult to predict.

Although the clinical relevance of such interactions is unknown, it is recommended that co- administration of potent ENT1, CNT3 or BCRP inhibitors be avoided during the 4- to 5-day cladribine treatment. If this is not possible, selection of alternative concomitant medicinal products with no, or minimal ENT1, CNT3 or BCRP transporter inhibiting properties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of medicinal products containing these compounds, separation in the timing of administration and careful patient monitoring is recommended.

Potent BCRP and P-gp transporter inducers

The effects of potent inducers of the efflux transporters BCRP and P-glycoprotein (P-gp) on the bioavailability and disposition of cladribine have not been formally studied. A possible decrease in cladribine exposure should be considered if potent BCRP (e.g. corticosteroids) or P-gp (e.g.
rifampicin, St. John's Wort) transporter inducers are co-administered.
Hormonal contraceptives

Co-administration of cladribine with oral hormonal contraceptives (ethinylestradiol and levonorgestrel) showed no clinically relevant pharmacokinetic interaction with cladribine. Therefore, concomitant use of cladribine is not expected to decrease the efficacy of hormonal contraceptives (see section 4.6).