er the last dose in each treatment year (see section 4.5). 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 6 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).
Breast-feeding
It is not known whether cladribine is excreted in human milk. 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 6 months after the last dose (see above).
4.7 Effects on ability to drive and use machines
MAVENCLAD has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most clinically relevant adverse reactions reported in MS patients who received cladribine at the recommended cumulative dose of 3.5 mg/kg over 2 years in clinical studies were lymphopenia and herpes zoster. 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).
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.
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)
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.
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 |
