Mavenclad · 4.3 Contraindications · 1

HOS-097911 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most clinically relevant adverse reactions are lymphopenia (25.6%) and herpes zoster (3.0%). The incidence of herpes zoster was higher during the period of grade 3 or 4 lymphopenia (<500 to 200 cells/mm³ or <200 cells/mm³) compared to the time when the patients were not experiencing grade 3 or 4 lymphopenia (see section 4.4). Tabulated list of adverse reactions Adverse reactions described in the list below are derived from pooled data from clinical studies in MS in which oral cladribine was used as monotherapy at a cumulative dose of 3.5 mg/kg. The safety database from these studies comprises 923 patients. Adverse reactions identified during post- marketing surveillance are indicated by an asterisk [*]. The following definitions apply to the frequency terminology used hereafter: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and frequency not known (cannot be estimated from the available data). Infections and infestations Common: Oral herpes, dermatomal herpes zoster. Very rare: Tuberculosis (see section 4.4). Blood and lymphatic system disorders Very common: Lymphopenia. Common: Decrease in neutrophil count. Immune system disorders Common: Hypersensitivity* including pruritus, urticaria, rash and rare cases of angio-oedema. Hepatobiliary disorders Uncommon: Liver Injury*. 9 Skin and subcutaneous tissue disorders Common: Rash, alopecia. Description of selected adverse reactions Lymphopenia In clinical studies, 20% to 25% of the patients treated with a cumulative dose of cladribine 3.5 mg/kg over 2 years as monotherapy developed transient grade 3 or 4 lymphopenia. Grade 4 lymphopenia was seen in less than 1% of the patients. The largest proportion of patients with grade 3 or 4 lymphopenia was seen 2 months after the first cladribine dose in each year (4.0% and 11.3% of patients with grade 3 lymphopenia in year 1 and year 2, 0% and 0.4% of patients with grade 4 lymphopenia in year 1 and year 2). It is expected that most patients recover to either normal lymphocyte counts or grade 1 lymphopenia within 9 months. To decrease the risk for severe lymphopenia, lymphocyte counts must be determined before, during and after cladribine treatment (see section 4.4) and strict criteria for initiating and continuing cladribine

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HOS-097907 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Infection with human immunodeficiency virus (HIV). Active chronic infection (tuberculosis or hepatitis). Initiation of cladribine treatment in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy (see section 4.5). Active malignancy. Moderate or severe renal impairment (creatinine clearance <60 mL/min) (see section 5.2). Pregnancy and breast-feeding (see section 4.6). 4

HOS-097906 · has-indication-information · PDF-Seite 2

MAVENCLAD is indicated for the treatment of adult patients with highly active relapsing multiple sclerosis (MS) as defined by clinical or imaging features (see section 5.1).

HOS-097909 · has-interaction-information · PDF-Seite 7

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.

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HOS-097910 · has-pregnancy-information · PDF-Seite 8

Contraception in males and females Before initiation of treatment both in year 1 and year 2, women of childbearing potential and males who could potentially father a child should be counselled regarding the potential for serious risk to the foetus and the need for effective contraception. In women of childbearing potential, pregnancy must be excluded before the initiation of MAVENCLAD in year 1 and year 2, and prevented by use of effective contraception during cladribine treatment and for at least 6 months after the last dose. Women who become pregnant under therapy with MAVENCLAD should discontinue treatment. As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected (see section 5.3). Therefore, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 3 months after the last dose. Pregnancy Based on human experience with other substances inhibiting DNA synthesis, cladribine could cause congenital malformations when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). MAVENCLAD is contraindicated in pregnant women (see section 4.3). 8 Breast-feeding Limited data from case reports have shown that cladribine is excreted in human milk. The quantity is not yet well established. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding is contraindicated during treatment with MAVENCLAD and for 1 week after the last dose (see section 4.3). Fertility In mice, there were no effects on fertility or the reproductive function of offspring. However, testicular effects were observed in mice and monkeys (see section 5.3). As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 3 months after the last dose (see above).

HOS-097908 · has-warning-information · PDF-Seite 5

Haematological monitoring Cladribine's mode of action is closely linked to a reduction in lymphocyte count. The effect on lymphocyte count is dose-dependent. Decreases in neutrophil count, red blood cell count, haematocrit, haemoglobin or platelet count compared to baseline values have also been observed in clinical studies, although these parameters usually remain within normal limits. Additive haematological adverse reactions may be expected if cladribine is administered prior to or concomitantly with other substances that affect the haematological profile (see section 4.5). Lymphocyte counts must be determined • before initiating treatment in year 1, • before initiating treatment in year 2, • 2 and 6 months after start of treatment in each treatment year. If the lymphocyte count is below 500 cells/mm³, it should be actively monitored until values increase again. For treatment decisions based on the patient's lymphocyte counts, see section 4.2 and subsection 'Infections' below. Infections Cladribine can reduce the body's immune defence and may increase the likelihood of infections. Serious, severe, and opportunistic infections - including events with fatal outcome - have been observed with MAVENCLAD treatment. HIV infection, active tuberculosis and active hepatitis must be excluded before initiation of cladribine (see section 4.3). Latent infections may be activated, including tuberculosis or hepatitis. Therefore, screening for latent infections, in particular tuberculosis and hepatitis B and C, must be performed prior to initiation of therapy in year 1 and year 2. Initiation of MAVENCLAD should be delayed until the infection has been adequately treated. A delay in initiation of cladribine should also be considered in patients with an acute infection until the infection is fully controlled. Particular attention is recommended for patients who have no history of exposure to varicella zoster virus. Vaccination of antibody-negative patients is recommended prior to initiation of cladribine therapy. Initiation of treatment with MAVENCLAD should be postponed for 4 to 6 weeks to allow for the full effect of vaccination to occur. The incidence of herpes zoster was increased in patients on cladribine. If lymphocyte counts drop below 200 cells/mm³, anti-herpes prophylaxis according to local standard practice should be considered during the time of grade 4 lymphopenia (see section 4.8). Patients with lymphocyte counts below 500 cells/mm³ should

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