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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 Interactions).
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 Dosage & Administration and Infections as follows.
Infections: Cladribine can reduce the body's immune defence and may increase the likelihood of infections. HIV infection, active tuberculosis and active hepatitis must be excluded before initiation of cladribine (see Contraindications).
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 Adverse Reactions).
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 Adverse Reactions).
MAVENCLAD is contraindicated in MS patients with active malignancies (see Contraindications). 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 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, including 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 Use in Pregnancy & Lactation).
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 Interactions).
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 with (see Interactions).
When switching from another MS medicinal product, a baseline MRI should be performed (see Infections as previously mentioned).
Sorbitol: The additive effect of concomitantly administered 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 administered concomitantly.
Effects on ability to drive and use machines: MAVENCLAD has no or negligible influence on the ability to drive and use machines.
Renal impairment: No dedicated studies have been conducted in patients with renal impairment.
In patients with mild renal impairment (creatinine clearance 60 to 89 mL/min), no dose adjustment is considered necessary (see Pharmacology: Pharmacokinetics under Actions).
Safety and efficacy in patients with moderate or severe renal impairment have not been established. Therefore, cladribine is contraindicated in these patients (see Pharmacology under Actions).
Hepatic impairment: Although the importance of hepatic function for the elimination of cladribine is considered negligible (see Pharmacology: Pharmacokinetics under Actions), in the absence of data, no dose adjustment is required in patients with mild hepatic impairment. The use of cladribine is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh score >6) (see Dosage & Administration).
Use in the Elderly: Caution is recommended when cladribine is used in elderly patients, taking into account the potential greater frequency of decreased hepatic or renal function, concomitant diseases, and other medicinal therapies.
