Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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 be actively monitored for signs and symptoms suggestive of infections, in particular herpes zoster. If such signs and symptoms occur, anti- infective treatment should be initiated as clinically indicated. Interruption or delay of MAVENCLAD may be considered until proper resolution of the infection.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported for parenteral cladribine in patients treated for hairy cell leukaemia with a different treatment regimen.

Although no case of PML has been reported with cladribine tablets, a baseline magnetic resonance imaging (MRI) should be performed before initiating cladribine tablets treatment (usually within 3 months).

Malignancies

In clinical studies, events of malignancies were observed more frequently in cladribine-treated patients compared to patients who received placebo (see section 4.8).

MAVENCLAD is contraindicated in MS patients with active malignancies (see section 4.3). An individual benefit-risk evaluation should be performed before initiating treatment in patients with prior malignancy. Patients treated with cladribine should be advised to follow standard cancer screening guidelines.

Liver function

Liver injury, including serious cases, has been reported uncommonly in patients treated with MAVENCLAD.
Before initiating MAVENCLAD a comprehensive patient history regarding previous episodes of liver injury with other drugs or underlying liver disorders should be taken. Patients should have their serum aminotransferase, alkaline phosphatase, and total bilirubin levels assessed prior to initiation of therapy in year 1 and year 2. During treatment, liver enzyme and bilirubin monitoring should be obtained based on clinical signs and symptoms.


If a patient develops clinical signs, unexplained liver enzyme elevations or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), serum transaminases and total bilirubin should be measured promptly.
Treatment with MAVENCLAD should be interrupted or discontinued, as appropriate.

Contraception

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 (see section 4.6).

Women of childbearing potential must prevent pregnancy by use of effective contraception during cladribine treatment and for at least 6 months after the last dose (see section 4.5).

Male patients must take precautions to prevent pregnancy of their female partner during cladribine treatment and for at least 6 months after the last dose.

Blood transfusions

In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to prevent transfusion-related graft-versus-host disease. Consultation with a haematologist is advised.

Switching to and from cladribine treatment

In patients who have previously been treated with immunomodulatory or immunosuppressive medicinal products the mode of action and duration of effect of the other medicinal product should be considered prior to initiation of treatment. A potential additive effect on the immune system should also be considered when such medicinal products are used after treatment (see section 4.5).

When switching from another MS medicinal product, a baseline MRI should be performed (see subsection 'Infections' above).

Hepatic impairment

The use of cladribine is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh score >6) (see section 4.2).

Sorbitol

The additive effect of concomitantly administrated products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administrated concomitantly.

Effects on Driving

4.7    Effects on ability to drive and use machines

MAVENCLAD has no or negligible influence on the ability to drive and use machines.