Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Summary of the safety profile

The most clinically relevant adverse 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*.
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 treatment must be followed (see section 4.2).

Malignancies

In clinical studies and long-term follow-up of patients treated with a cumulative dose of 3.5 mg/kg oral cladribine, events of malignancies were observed more frequently in cladribine-treated patients (10 events in 3,414 patient-years [0.29 events per 100 patient-years]) compared to patients who received placebo (3 events in 2,022 patient-years [0.15 events per 100 patient-years]) (see section 4.4).

Hypersensitivity

In clinical studies of patients treated with a cumulative dose of 3.5 mg/kg oral cladribine, hypersensitivity events were observed more frequently in cladribine-treated patients (11.8%) compared to patients who received placebo (8.4%). Serious hypersensitivity events were observed in 0.3% of cladribine-treated patients and in no patients who received placebo. Hypersensitivity events led to treatment discontinuation in 0.4% of cladribine-treated patients and in 0.3% patients who received placebo.

Liver Injury

During post-marketing experience, uncommon events of liver injury, including serious cases and cases leading to discontinuation of treatment, were reported in temporal association with MAVENCLAD.
Transient elevations of serum transaminases were usually greater than 5-fold the upper limit of normal (ULN). Isolated cases of transient serum transaminase elevations up to 40-fold the ULN and / or symptomatic hepatitis with transient elevation of bilirubin and jaundice have been observed.
Time to onset varied, with most cases occurring within 8 weeks after the first treatment course (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/