Mavenclad

/ Merck Serono LTD, Israel

Treatment must be initiated and supervised by a physician experienced in the treatment of MS.
The recommended cumulative dose is 3.5 mg/kg body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. If medically necessary (e.g. for recovery of lymphocytes), the treatment course in year 2 can be delayed for up to 6 months. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight. See prescribing information for full details.
Following completion of the 2 treatment courses, no further cladribine treatment is required in years 3 and 4. Re-initiation of therapy after year 4 has not been studied.
Criteria for initiating and continuing therapy:
Lymphocyte counts must be normal before initiating treatment in year 1, and at least 800 cells/mm³ before initiating treatment in year 2.
If necessary, the treatment course in year 2 can be delayed for up to 6 months to allow for recovery of lymphocytes. If this recovery takes more than 6 months, the patient should not receive cladribine tablets anymore.
Concomitant use of other oral medicinal products: It is recommended that cladribine administration be separated from any other oral medicinal product by at least 3 hours during the limited number of days of cladribine administration. See prescribing information for full details.
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. Safety and efficacy in patients with moderate or severe renal impairment have not been established. Therefore, cladribine is contraindicated in these patients. See prescribing information for full details.
Hepatic impairment: No studies have been conducted in patients with hepatic impairment. Although the importance of hepatic function for the elimination of cladribine is considered negligible, 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).
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.
Paediatric population: The safety and efficacy in children below the age of 18 years have not been established. No data are available.
See prescribing information for full details.

Treatment of adult patients with highly active relapsing multiple sclerosis (MS) as defined by clinical or imaging features. See prescribing information for full details.

Hypersensitivity to the active substance or to any of the excipients listed in the prescribing information.
Infection with human immunodeficiency virus (HIV).
Active chronic infection (tuberculosis or hepatitis).
Initiation of cladribine treatment in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy.
Active malignancy.
Moderate or severe renal impairment (creatinine clearance <60 mL/min).
Pregnancy and breast-feeding.
See prescribing information for full details.

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. Lymphocyte counts must be determined before initiating treatment in year 1,before initiating treatment in year 2, and 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 prescribing information for full details.
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. 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 cladribine 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 cladribine treatment 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.
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 cladribine 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.
This medicinal product is contraindicated in MS patients with active malignancies. 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 cladribine. Before initiation, 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 cladribine 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.
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.
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.
When switching from another MS medicinal product, a baseline MRI should be performed.
Hepatic impairment: Although the importance of hepatic function for the elimination of cladribine is considered negligible, in the absence of data, use of cladribine is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh score >6).
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.
See prescribing information for full details.

Very common: Lymphopenia.
Common: Oral herpes, dermatomal herpes zoster, decrease in neutrophil count, rash, alopecia, hypersensitivity including pruritus, urticaria, rash and rare cases of angio-oedema.
See prescribing information for full details.

This medicinal product contains hydroxypropylbetadex, which may be available for complex formation with other medicinal products, potentially leading to an increase in bioavailability of such a product (especially medicinal products with low solubility). Therefore, it is recommended that the products’administration be separated from any other oral medicinal product by at least 3 hours during the limited number of days of cladribine administration.
Immunosuppressive medicinal products:
Initiation of cladribine treatment is contraindicated in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy with, e.g., methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids because of a risk of additive effects on the immune system.
Acute short-term therapy with systemic corticosteroids can be administered during cladribine treatment.
Other disease-modifying medicinal products:
The use of cladribine with interferon beta results in an increased risk of lymphopenia. Safety and efficacy of cladribine in combination with other disease-modifying treatments for MS have not been established. Concomitant treatment is not recommended.
Haematotoxic medicinal products:
Because of the cladribine-induced reduction in lymphocyte count, additive haematological adverse reactions may be expected if cladribine is administered prior to or concomitantly with other substances that affect the haematological profile (e.g. carbamazepine). Careful monitoring of haematological parameters is recommended in such cases.
Live or live attenuated vaccines:
Treatment should not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccines because of a risk of active vaccine infection. Vaccination with live or attenuated live vaccines should be avoided during and after cladribine treatment as long as the patient’s white blood cell counts are not within normal limits.
Potent ENT1, CNT3 and BCRP transporter inhibitors:
At the level of cladribine absorption, the only conceivable interaction pathway of clinical relevance appears to be the breast cancer resistance protein (BCRP or ABCG2). Inhibition of BCRP in the gastrointestinal tract may increase the oral bioavailability and systemic exposure of cladribine. Known BCRP inhibitors, which may alter the pharmacokinetics of BCRP substrates by 20% in vivo, include eltrombopag.
In vitro studies indicate that cladribine is a substrate of the equilibrative nucleoside (ENT1) and concentrative nucleoside (CNT3) transport proteins. Accordingly, the bioavailability, intracellular distribution and renal elimination of cladribine may theoretically be altered by potent ENT1 and CNT3 transporter inhibitors such as dilazep, nifedipine, nimodipine, cilostazol, sulindac or reserpine. However, net effects in terms of potential cladribine exposure alterations are difficult to predict.
Although the clinical relevance of such interactions is unknown, it is recommended that co-administration of potent ENT1, CNT3 or BCRP inhibitors be avoided during the 4- to 5-day cladribine treatment. If this is not possible, selection of alternative concomitant medicinal products with no, or minimal ENT1, CNT3 or BCRP transporter inhibiting properties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of medicinal products containing these compounds, separation in the timing of administration and careful patient monitoring is recommended.
Potent BCRP and P-gp transporter inducers:
The effects of potent inducers of the efflux transporters BCRP and P-glycoprotein (P-gp) on the bioavailability and disposition of cladribine have not been formally studied. A possible decrease in cladribine exposure should be considered if potent BCRP (e.g. corticosteroids) or P-gp (e.g. rifampicin, St. John’s Wort) transporter inducers are co-administered.
Hormonal contraceptives:
It is currently unknown whether cladribine may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should add a barrier method during cladribine treatment and for at least 4 weeks after the last dose in each treatment year.

Contraception in males and females:
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.
In women of childbearing potential, pregnancy must be excluded before the initiation of cladribine in year 1 and year 2, and prevented by use of effective contraception during cladribine treatment and for at least 6 months after the last dose. Women using systemically acting hormonal contraceptives should add a barrier method during cladribine treatment and for at least 4 weeks after the last dose in each treatment year. Women who become pregnant under therapy with cladribine should discontinue treatment.
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.
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.
Cladribine is contraindicated in pregnant women.
Breast-feeding:
Limited data from case reports have shown that cladribine is excreted in human milk. The quantity is not yet well established. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding is contraindicated during treatment with cladribine and for 1 week after the last dose.
Fertility:
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.

There is limited experience with overdose of oral cladribine. Lymphopenia is known to be dose-dependent.
Particularly close monitoring of haematological parameters is recommended in patients who have been exposed to an overdose of cladribine.
There is no known specific antidote to an overdose of cladribine. Treatment consists of careful observation and initiation of appropriate supportive measures. Discontinuation of cladribine may need to be considered. Because of the rapid and extensive intracellular and tissue distribution, haemodialysis is unlikely to eliminate cladribine to a significant extent.

Store below 25°C.
Store in the original package in order to protect from moisture.