Mavenclad Drug Interactions

If any other oral medicines are taken concomitantly, administration must be separated from that of MAVENCLAD by at least 3 hours during the limited number of days of cladribine administration. This is because hydroxypropylbetadex released from MAVENCLAD may lead to complex formation with other agents (especially medicines with low solubility), which could cause an increase in bioavailability of such a product.
Haematotoxic, Immunosuppressive and Immunomodulating Agents: Use of MAVENCLAD in immunocompromised patients, including patients receiving immunosuppressive or myelosuppressive therapy with, e.g. cyclosporin, methotrexate, mitoxantrone, azathioprine, natalizumab, or chronic use of corticosteroids is contraindicated because of a risk of additive effects on immune status (refer to Contraindications). Acute short-term therapy with corticosteroids can be administered if clearly necessary.
Safety and efficacy of MAVENCLAD in combination with other disease-modifying treatments for MS has not been assessed. Concomitant treatment is not recommended.
Because of the cladribine-induced reduction in lymphocyte count, additive haematological adverse effects may be expected if MAVENCLAD is administered concomitantly with other agents that affect the haematological profile (e.g. carbamazepine, non-steroidal anti-inflammatory drugs). Careful monitoring of haematological parameters is recommended in such cases.
In a clinical study, when beta-interferon was used in combination with cladribine, a more pronounced effect in the reduction of lymphocyte count was observed. This needs to be considered when beta-interferon is used after cladribine.
Live or Live Attenuated Vaccines: MAVENCLAD therapy and individual treatment courses must not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccines because of a risk of active vaccine infection. Also patients must not be vaccinated with live or attenuated live vaccines during a MAVENCLAD treatment course and also not after the last dose of MAVENCLAD, as long as the patient's white blood cell counts are not within normal limits.
Potent ENT1, CNT3 and ABCG2 transporter inhibitors: At the level of cladribine absorption, the only conceivable interaction pathway of clinical relevance appears to be ATP-binding cassette sub-family G member 2 (ABCG2). Inhibition of ABCG2 in the gastrointestinal tract may increase the oral bioavailability and systemic exposure of cladribine. Known ABCG2 inhibitors, which may alter the pharmacokinetics of ABCG2 substance by 20% in vivo, include eltrombopag.
Based on in vitro data suggesting inhibition of ENT1, CNT3 or ABCG2 transport proteins, the bioavailability, intracellular distribution and renal elimination of cladribine may theoretically be altered by medicinal products containing potent ENT1, CNT3 and ABCG2 transporter inhibitors, such as dipyridamole, dilazep, nifedipine, nimodipine, cilostazol, sulindac, reserpine or eltrombopag. The net effects in terms of potential cladribine exposure alterations are difficult to predict and hence, the clinical relevance of these findings is unknown.
It is recommended that co-administration of these products be avoided during the 4 to 5 day MAVENCLAD treatment. If this is not possible, selection of alternative concomitant medicinal products with no, or minimal ENT1, CNT3 or ABCG2 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 by several hours, and careful patient monitoring is recommended.
Potent ABCG2 and P-gp transporter inducers: The effects of potent inducers of the efflux transporters ABCG2 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 ABCG2 (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 (ethinyl estradiol 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 (refer to Use in Pregnancy & Lactation).
Other: In vitro studies suggest that cladribine efflux is not or only minimally P-gp related. Clinically relevant interactions with inhibitors of P-gp are not expected.
In vitro data indicated that cladribine could be degraded at acidic pH. However, drug interaction studies in vivo showed that the bioavailability of MAVENCLAD 10 mg tablet was not changed when co-administered with pantoprazole and the bioavailability of cladribine oral solution was not enhanced when co-administered with omeprazole.
Cladribine showed no significant potential to act as inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Inhibition of one of these enzymes, or genetic polymorphism (e.g. in CYP2D6, CYP2C9 or CYP2C19) is not expected to result in clinically significant effects on MAVENCLAD pharmacokinetics.
Cladribine has no inductive effect on CYP1A2, CYP2B6 and CYP3A4 enzymes.