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Therapy is to be initiated and supervised by neurologists. Neurologists must discuss the risks and benefits of therapy with the patient in particular with respect to infections and haematological monitoring. The long term safety of MAVENCLAD has not been assessed. There is no conclusive evidence of an increase in the incidence of malignancies.
Haematological Monitoring: The mode of action of MAVENCLAD 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 the limits of normal.
Lymphocyte counts must be determined: before initiating MAVENCLAD in year 1, before initiating MAVENCLAD 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.
Monitoring of other haematological parameters can be considered at the discretion of the physician.
For treatment decisions based on the patient's lymphocyte count, refer to Dosage & Administration and Infections as follows.
Infections: MAVENCLAD 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 (refer to Contraindications).
Latent infections may be activated, including tuberculosis, viral hepatitis or herpes zoster infections. 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 (refer to Dosage & Administration).
In clinical trials, a fatal case of hepatitis B was observed, but was not considered related to cladribine. Three cases of reactivation of latent tuberculosis, including one fatal case, were observed before implementation of the pre-screening for infections as recommended previously. For most common infections, incidence rates were similar between patients receiving cladribine and those receiving placebo, except for herpes zoster.
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 MAVENCLAD. Initiation of treatment with MAVENCLAD must 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 (refer to Adverse Reactions).
Patients with lymphocyte counts below 500 cells/mm3 should be actively monitored carefully for signs and symptoms suggestive of infections, in particular herpes zoster. If such signs and symptoms occur, treatment for the infection should be initiated as clinically indicated. Interruption or delay of MAVENCLAD may be considered until full resolution of the infection.
In the clinical trial data base of cladribine in MS (1,976 patients, 8,650 patient years) no case of progressive multifocal leukoencephalopathy (PML) has been reported. However, a baseline magnetic resonance imaging (MRI) should be considered before initiating MAVENCLAD (usually within 3 months). This is particularly recommended if patients are switched from other MS agents that have a risk of PML.
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.
Malignancies: In clinical studies and long-term follow-up (mean [±SD] duration: 194 ± 111 weeks) 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 3414 patient-years [0.29 events per 100 patient-years]) compared to patients who received placebo (3 events in 2022 patient-years [0.15 events per 100 patient-years]).
MAVENCLAD has not been studied in MS patients with prior or current malignancies (with the exception of in situ basal or squamous cell skin cancer surgically removed without recurrence for at least five years). Therefore, in MS patients with active malignancy, the use of MAVENCLAD is contraindicated (refer to Contraindications). As with other immunomodulating therapies, caution should be exercised when initiating MAVENCLAD in patients with prior malignancy. It is currently not known whether oral cladribine confers a higher risk for developing malignancies. Observation over longer treatment periods is required before any effect on the development of malignancies can be determined. Patients treated with MAVENCLAD 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, especially in patients with a medical history of abnormal liver tests. Patients should have their serum aminotransferase, alkaline phosphatase, and total bilirubin levels assessed prior to initiation of therapy in year 1 and year 2 (see Precautions).
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), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with MAVENCLAD as appropriate.
Switching to and from MAVENCLAD treatment: In patients who have previously been treated with immunomodulating or immunosuppressive therapies, the mode of action and duration of effect of the other product should be considered prior to initiation of MAVENCLAD (refer to Dosage & Administration). A potential additive effect on the immune system should also be considered when such products are used after treatment with MAVENCLAD (refer to Haematotoxic, Immunosuppressive and Immunomodulating Agents under Interactions).
When switching from an MS agent with a risk of PML, a baseline MRI is recommended (refer to Infections as previously mentioned).
Renal Impairment: No dedicated studies have been conducted in patients with renal impairment (refer to Contraindications).
The safety profile in patients with mild renal impairment (creatinine clearance 60-89 mL/min) was shown to be similar to that in patients with normal renal function; no dosage adjustment is considered necessary.
In patients with moderate or severe renal impairment (creatinine clearance < 60 mL/min), a decrease in cladribine clearance can be predicted (refer to Pharmacology: Pharmacokinetics under Actions). Safety and efficacy in patients with moderate or severe renal impairment have not been established. Therefore, MAVENCLAD is contraindicated in these patients (refer to Contraindications).
Hepatic Impairment: No dedicated studies have been conducted in patients with hepatic impairment.
Although the importance of hepatic function for the elimination of cladribine is considered negligible (refer to Pharmacology: Pharmacokinetics under Actions), in the absence of data, use of MAVENCLAD is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh score > 6).
Liver function: Serum aminotransferase, alkaline phosphatase, and total bilirubin levels should be obtained prior to initiation of therapy in year 1 and year 2.
Fructose Intolerance: MAVENCLAD contains 64.04 mg sorbitol per tablet. Its use is not recommended in patients with fructose intolerance.
Effects on ability to drive and use machines: No studies on the effect of MAVENCLAD on the ability to drive or handle machines have been performed.
Use in Children: Safety and effectiveness of MAVENCLAD in paediatric MS patients are not known. MAVENCLAD is not recommended in patients below the age of 18 years.
Use in the Elderly: Clinical studies with MAVENCLAD did not include patients over 65 years of age to determine whether they respond differently from younger patients.
Caution is recommended when MAVENCLAD is used in elderly patients, taking into account the potential greater frequency of decreased hepatic or renal function, concomitant diseases, and other medicinal therapy.
