MAVENCLAD 10mg tablets medication leaflet

MAVENCLAD 10 mg tablets

Each tablet contains 10 mg of cladribine.

Each tablet contains 64 mg sorbitol.

For the full list of excipients, see section 6.1.

Tablet

White, round, biconvex tablets of 8.5 mm diameter, engraved with 'C' on one side and '10' on the otherside.

MAVENCLAD is indicated for the treatment of adult patients with highly active relapsing multiplesclerosis (MS) as defined by clinical or imaging features (see section 5.1).

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 as1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one atthe beginning of the first month and one at the beginning of the second month of the respectivetreatment year. If medically necessary (e.g. for recovery of lymphocytes), the treatment course inyear 2 can be delayed for up to 6 months. Each treatment week consists of 4 or 5 days on which apatient receives 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight.

For details, see Tables 1 and 2 below.

Following completion of the 2 treatment courses, no further cladribine treatment is required in years 3and 4 (see section 5.1). 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,

* 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 oflymphocytes. If this recovery takes more than 6 months, the patient should not receive cladribinetablets anymore.

Distribution of dose

The distribution of the total dose over the 2 years of treatment is provided in Table 1. For some weightranges the number of tablets may vary from one treatment week to the next. Use of oral cladribine inpatients weighing less than 40 kg has not been investigated.

Table 1 Dose of cladribine per treatment week by patient weight in each treatment year

Weight range Dose in mg (number of tablets) per treatment weekkg Treatment week 1 Treatment week 240 to < 50 40 mg (4 tablets) 40 mg (4 tablets)50 to < 60 50 mg (5 tablets) 50 mg (5 tablets)60 to < 70 60 mg (6 tablets) 60 mg (6 tablets)70 to < 80 70 mg (7 tablets) 70 mg (7 tablets)80 to < 90 80 mg (8 tablets) 70 mg (7 tablets)90 to < 100 90 mg (9 tablets) 80 mg (8 tablets)100 to < 110 100 mg (10 tablets) 90 mg (9 tablets)110 and above 100 mg (10 tablets) 100 mg (10 tablets)

Table 2 shows how the total number of tablets per treatment week is distributed over the individualdays. It is recommended that the daily cladribine doses in each treatment week be taken at intervals of24 hours at approximately the same time each day. If a daily dose consists of two tablets, both tabletsare taken together as a single dose.

Table 2 Number of tablets per week day

Total number of tabletsper week Day 1 Day 2 Day 3 Day 4 Day 54 1 1 1 1 05 1 1 1 1 16 2 1 1 1 17 2 2 1 1 18 2 2 2 1 19 2 2 2 2 110 2 2 2 2 2

A missed dose must be taken as soon as remembered on the same day according to the treatmentschedule.

A missed dose must not be taken together with the next scheduled dose on the following day. In thecase of a missed dose, the patient must take the missed dose on the following day, and extend thenumber of days in that treatment week. If two consecutive doses are missed, the same rule applies, andthe number of days in the treatment week is extended by two days.

Concomitant use of other oral medicinal products

It is recommended that administration of any other oral medicinal product be separated from that of

MAVENCLAD by at least 3 hours during the limited number of days of cladribine administration (seesection 4.5).

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 isconsidered necessary (see section 5.2).

Safety and efficacy in patients with moderate or severe renal impairment have not been established.

Therefore, cladribine is contraindicated in these patients (see section 4.3).

No studies have been conducted in patients with hepatic impairment.

No dose adjustment is required in patients with mild hepatic impairment because the importance ofhepatic function for the elimination of cladribine is considered negligible (see section 5.2).

In absence of data, the use of cladribine is not recommended in patients with moderate or severehepatic impairment (Child-Pugh score >6).

Caution is recommended when cladribine is used in elderly patients, taking into account the potentialgreater frequency of decreased hepatic or renal function, concomitant diseases and other medicinaltherapies.

The safety and efficacy of MAVENCLAD in children below the age of 18 years have not beenestablished. No data are available.

MAVENCLAD is for oral use. The tablets must be taken with water, and swallowed without chewing.

The tablets can be taken independent of food intake.

As the tablets are uncoated, they must be swallowed immediately once removed from the blister andnot be left exposed on surfaces or handled for any period of time longer than that required for dosing.

If a tablet is left on a surface, or if a broken or fragmented tablet is released from the blister, the areamust be thoroughly washed.

The patient's hands must be dry when handling the tablets and washed thoroughly afterwards.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Infection with human immunodeficiency virus (HIV).

Active chronic infection (tuberculosis or hepatitis).

Initiation of cladribine treatment in immunocompromised patients, including patients currentlyreceiving immunosuppressive or myelosuppressive therapy (see section 4.5).

Active malignancy.

Moderate or severe renal impairment (creatinine clearance <60 mL/min) (see section 5.2).

Pregnancy and breast-feeding (see section 4.6).

Haematological monitoring

Cladribine's mode of action is closely linked to a reduction in lymphocyte count. The effect onlymphocyte 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 orconcomitantly 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 below500 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.

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 beenobserved with MAVENCLAD treatment. HIV infection, active tuberculosis and active hepatitis mustbe excluded before initiation of cladribine (see section 4.3).

Latent infections may be activated, including tuberculosis or hepatitis. Therefore, screening for latentinfections, in particular tuberculosis and hepatitis B and C, must be performed prior to initiation oftherapy in year 1 and year 2. Initiation of MAVENCLAD should be delayed until the infection hasbeen adequately treated.

A delay in initiation of cladribine should also be considered in patients with an acute infection untilthe infection is fully controlled.

Particular attention is recommended for patients who have no history of exposure to varicella zostervirus. Vaccination of antibody-negative patients is recommended prior to initiation of cladribinetherapy. Initiation of treatment with MAVENCLAD should be postponed for 4 to 6 weeks to allow forthe full effect of vaccination to occur.

The incidence of herpes zoster was increased in patients on cladribine. If lymphocyte counts dropbelow 200 cells/mm³, anti-herpes prophylaxis according to local standard practice should beconsidered 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 andsymptoms 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 MAVENCLADmay be considered until proper resolution of the infection.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported for parenteralcladribine 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 resonanceimaging (MRI) should be performed before initiating cladribine tablets treatment (usually within3 months).

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

MAVENCLAD is contraindicated in MS patients with active malignancies (see section 4.3). Anindividual benefit-risk evaluation should be performed before initiating treatment in patients with priormalignancy. Patients treated with cladribine should be advised to follow standard cancer screeningguidelines.

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 liverinjury with other drugs or underlying liver disorders should be taken. Patients should have their serumaminotransferase, alkaline phosphatase, and total bilirubin levels assessed prior to initiation of therapyin year 1 and year 2. During treatment, liver enzyme and bilirubin monitoring should be obtainedbased on clinical signs and symptoms.

If a patient develops clinical signs, unexplained liver enzyme elevations or symptoms suggestive ofhepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, orjaundice and/or dark urine), serum transaminases and total bilirubin should be measured promptly.

Treatment with MAVENCLAD should be interrupted or discontinued, as appropriate.

Before initiation of treatment both in year 1 and year 2, women of childbearing potential and maleswho could potentially father a child should be counselled regarding the potential for serious risk to thefoetus and the need for effective contraception (see section 4.6).

Women of childbearing potential must prevent pregnancy by use of effective contraception duringcladribine 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 cladribinetreatment and for at least 6 months after the last dose.

Blood transfusions

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

Switching to and from cladribine treatment

In patients who have previously been treated with immunomodulatory or immunosuppressivemedicinal products the mode of action and duration of effect of the other medicinal product should beconsidered prior to initiation of treatment. A potential additive effect on the immune system shouldalso 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 (seesubsection 'Infections' above).

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 administered products containing sorbitol (or fructose) anddietary 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 othermedicinal products for oral use administered concomitantly.

This medicinal product contains hydroxypropylbetadex, which may be available for complexformation with other medicinal products, potentially leading to an increase in bioavailability of such aproduct (especially medicinal products with low solubility). Therefore, it is recommended thatadministration of any other oral medicinal product be separated from that of MAVENCLAD by atleast 3 hours during the limited number of days of cladribine administration.

Initiation of cladribine treatment is contraindicated in immunocompromised patients, includingpatients currently receiving immunosuppressive or myelosuppressive therapy with, e.g., methotrexate,cyclophosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids because of a risk ofadditive effects on the immune system (see section 4.3).

Acute short-term therapy with systemic corticosteroids can be administered during cladribinetreatment.

Other disease-modifying medicinal products

The use of cladribine with interferon beta results in an increased risk of lymphopenia. Safety andefficacy of cladribine in combination with other disease-modifying treatments for MS have not beenestablished. Concomitant treatment is not recommended.

Haematotoxic medicinal products

Because of the cladribine-induced reduction in lymphocyte count, additive haematological adversereactions may be expected if cladribine is administered prior to or concomitantly with other substancesthat affect the haematological profile (e.g. carbamazepine). Careful monitoring of haematologicalparameters 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 livevaccines because of a risk of active vaccine infection. Vaccination with live or attenuated live vaccinesshould be avoided during and after cladribine treatment as long as the patient's white blood cell countsare not within normal limits.

Potent ENT1, CNT3 and BCRP transporter inhibitors

At the level of cladribine absorption, the only conceivable interaction pathway of clinical relevanceappears to be the breast cancer resistance protein (BCRP or ABCG2). Inhibition of BCRP in thegastrointestinal 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, includeeltrombopag.

In vitro studies indicate that cladribine is a substrate of the equilibrative nucleoside (ENT1) andconcentrative nucleoside (CNT3) transport proteins. Accordingly, the bioavailability, intracellulardistribution and renal elimination of cladribine may theoretically be altered by potent ENT1 and CNT3transporter 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 cladribinetreatment. If this is not possible, selection of alternative concomitant medicinal products with no, orminimal ENT1, CNT3 or BCRP transporter inhibiting properties should be considered. If this is notpossible, dose reduction to the minimum mandatory dose of medicinal products containing thesecompounds, 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 thebioavailability and disposition of cladribine have not been formally studied. A possible decrease incladribine 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.

Co-administration of cladribine with oral hormonal contraceptives (ethinylestradiol andlevonorgestrel) showed no clinically relevant pharmacokinetic interaction with cladribine. Therefore,concomitant use of cladribine is not expected to decrease the efficacy of hormonal contraceptives (seesection 4.6).

Before initiation of treatment both in year 1 and year 2, women of childbearing potential and maleswho could potentially father a child should be counselled regarding the potential for serious risk to thefoetus and the need for effective contraception.

In women of childbearing potential, pregnancy must be excluded before the initiation of

MAVENCLAD in year 1 and year 2, and prevented by use of effective contraception during cladribinetreatment and for at least 6 months after the last dose. Women who become pregnant under therapywith MAVENCLAD should discontinue treatment.

As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could beexpected (see section 5.3). Therefore, male patients must take precautions to prevent pregnancy oftheir partner during cladribine treatment and for at least 6 months after the last dose.

Based on human experience with other substances inhibiting DNA synthesis, cladribine could causecongenital malformations when administered during pregnancy. Studies in animals have shownreproductive toxicity (see section 5.3).

MAVENCLAD is contraindicated in pregnant women (see section 4.3).

Limited data from case reports have shown that cladribine is excreted in human milk. The quantity isnot yet well established. Because of the potential for serious adverse reactions in breast-fed infants,breast-feeding is contraindicated during treatment with MAVENCLAD and for 1 week after the lastdose (see section 4.3).

In mice, there were no effects on fertility or the reproductive function of offspring. However, testiculareffects were observed in mice and monkeys (see section 5.3).

As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could beexpected. Therefore, male patients must take precautions to prevent pregnancy of their partner duringcladribine treatment and for at least 6 months after the last dose (see above).

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

The most clinically relevant adverse reactions are lymphopenia (25.6%) and herpes zoster (3.0%). Theincidence of herpes zoster was higher during the period of grade 3 or 4 lymphopenia (<500 to200 cells/mm³ or <200 cells/mm³) compared to the time when the patients were not experiencinggrade 3 or 4 lymphopenia (see section 4.4).

Adverse reactions described in the list below are derived from pooled data from clinical studies in MSin which oral cladribine was used as monotherapy at a cumulative dose of 3.5 mg/kg. The safetydatabase 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).

Common: Oral herpes, dermatomal herpes zoster.

Very rare: Tuberculosis (see section 4.4).

Very common: Lymphopenia.

Common: Decrease in neutrophil count.

Common: Hypersensitivity* including pruritus, urticaria, rash and rare cases of angio-oedema.

Uncommon: Liver Injury*.

Common: Rash, alopecia.

Lymphopenia

In clinical studies, 20% to 25% of the patients treated with a cumulative dose of cladribine 3.5 mg/kgover 2 years as monotherapy developed transient grade 3 or 4 lymphopenia. Grade 4 lymphopenia wasseen in less than 1% of the patients. The largest proportion of patients with grade 3 or 4 lymphopeniawas seen 2 months after the first cladribine dose in each year (4.0% and 11.3% of patients withgrade 3 lymphopenia in year 1 and year 2, 0% and 0.4% of patients with grade 4 lymphopenia inyear 1 and year 2). It is expected that most patients recover to either normal lymphocyte counts orgrade 1 lymphopenia within 9 months.

To decrease the risk for severe lymphopenia, lymphocyte counts must be determined before, duringand after cladribine treatment (see section 4.4) and strict criteria for initiating and continuingcladribine treatment must be followed (see section 4.2).

In clinical studies and long-term follow-up of patients treated with a cumulative dose of 3.5 mg/kgoral 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 whoreceived placebo (3 events in 2,022 patient-years [0.15 events per 100 patient-years]) (see section 4.4).

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 in0.3% of cladribine-treated patients and in no patients who received placebo. Hypersensitivity eventsled to treatment discontinuation in 0.4% of cladribine-treated patients and in 0.3% patients whoreceived placebo.

Liver Injury

During post-marketing experience, uncommon events of liver injury, including serious cases and casesleading 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/orsymptomatic 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 (seesection 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited experience with overdose of oral cladribine. Lymphopenia is known to be dose-dependent (see sections 4.4 and 4.8).

Particularly close monitoring of haematological parameters is recommended in patients who have beenexposed to an overdose of cladribine.

There is no known specific antidote to an overdose of cladribine. Treatment consists of carefulobservation and initiation of appropriate supportive measures. Discontinuation of MAVENCLAD mayneed to be considered. Because of the rapid and extensive intracellular and tissue distribution,haemodialysis is unlikely to eliminate cladribine to a significant extent.

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants,

ATC code: L04AA40

Cladribine is a nucleoside analogue of deoxyadenosine. A chlorine substitution in the purine ringprotects cladribine from degradation by adenosine deaminase, increasing the intracellular residencetime of the cladribine prodrug. Subsequent phosphorylation of cladribine to its active triphosphateform, 2-chlorodeoxyadenosine triphosphate (Cd-ATP), is particularly efficiently achieved inlymphocytes, due to their constitutively high deoxycytidine kinase (DCK) and relatively low5'-nucleotidase (5'-NTase) levels. A high DCK to 5'-NTase ratio favours the accumulation of Cd-ATP,making lymphocytes particularly susceptible to cell death. As a result of a lower DCK/5'-NTase ratioother bone marrow derived cells are less affected than lymphocytes. DCK is the rate limiting enzymefor conversion of the cladribine prodrug into its active triphosphate form, leading to selectivedepletion of dividing and non-dividing T and B cells.

The primary apoptosis-inducing mechanism of action of Cd-ATP has direct and indirect actions on

DNA synthesis and mitochondrial function. In dividing cells, Cd-ATP interferes with DNA synthesisvia inhibition of ribonucleotide reductase and competes with deoxyadenosine triphosphate forincorporation into DNA by DNA polymerases. In resting cells cladribine causes DNA single-strandbreaks, rapid nicotinamide adenine dinucleotide consumption, ATP depletion and cell death. There isevidence that cladribine can also cause direct caspase-dependent and -independent apoptosis via therelease of cytochrome c and apoptosis-inducing factor into the cytosol of non-dividing cells.

MS pathology involves a complex chain of events in which different immune cell types, includingautoreactive T and B cells play a key role. The mechanism by which cladribine exerts its therapeuticeffects in MS is not fully elucidated but its predominant effect on B and T lymphocytes is thought tointerrupt the cascade of immune events central to MS.

Variations in the expression levels of DCK and 5'-NTases between immune cell subtypes may explaindifferences in immune cell sensitivity to cladribine. Because of these expression levels, cells of theinnate immune system are less affected than cells of the adaptive immune system.

Cladribine has been shown to exert long-lasting effects by preferentially targeting lymphocytes andthe autoimmune processes involved in the pathophysiology of MS.

Across studies, the largest proportion of patients with grade 3 or 4 lymphopenia (<500 to200 cells/mm³ or <200 cells/mm³) was seen 2 months after the first cladribine dose in each year,indicating a time gap between cladribine plasma concentrations and the maximum haematologicaleffect.

Across clinical studies, data with the proposed cumulative dose of 3.5 mg/kg body weight show agradual improvement in the median lymphocyte counts back to the normal range at week 84 from thefirst dose of cladribine (approximately 30 weeks after the last dose of cladribine). The lymphocytecounts of more than 75% of patients returned to the normal range by week 144 from the first dose ofcladribine (approximately 90 weeks after the last dose of cladribine).

Treatment with oral cladribine leads to rapid reductions in circulating CD4+ and CD8+ T cells. CD8+

T cells have a less pronounced decrease and a faster recovery than CD4+ T cells, resulting in atemporarily decreased CD4 to CD8 ratio. Cladribine reduces CD19+ B cells and CD16+/CD56+natural killer cells, which also recover faster than CD4+ T cells.

Relapsing-remitting MS

Efficacy and safety of oral cladribine were evaluated in a randomised, double-blind, placebo-controlled clinical study (CLARITY) in 1,326 patients with relapsing-remitting MS. Study objectiveswere to evaluate the efficacy of cladribine versus placebo in reducing the annualised relapse rate(ARR) (primary endpoint), slowing disability progression and decreasing active lesions as measuredby MRI.

Patients received either placebo (n = 437), or a cumulative dose of cladribine of 3.5 mg/kg (n = 433)or 5.25 mg/kg body weight (n = 456) over the 96-week (2-year) study period in 2 treatment courses.

Patients randomised to the 3.5 mg/kg cumulative dose received a first treatment course at weeks 1 and5 of the first year and a second treatment course at weeks 1 and 5 of the second year. Patientsrandomised to the 5.25 mg/kg cumulative dose received additional treatment at weeks 9 and 13 of thefirst year. The majority of patients in the placebo (87.0%) and the cladribine 3.5 mg/kg (91.9%) and5.25 mg/kg (89.0%) treatment groups completed the full 96 weeks of the study.

Patients were required to have at least 1 relapse in the previous 12 months. In the overall studypopulation, the median age was 39 years (range 18 to 65), and the female to male ratio wasapproximately 2:1. The mean duration of MS prior to study enrolment was 8.7 years, and the medianbaseline neurological disability based on Kurtzke Expanded Disability Status Scale (EDSS) scoreacross all treatment groups was 3.0 (range 0 to 6.0). Over two thirds of the study patients weretreatment-naive for MS disease-modifying drugs (DMDs). The remaining patients were pre-treatedwith either interferon beta-1a, interferon beta-1b, glatiramer acetate or natalizumab.

Patients with relapsing-remitting MS receiving cladribine 3.5 mg/kg showed statistically significantlyimprovements in the annualised relapse rate, proportion of patients relapse-free over 96 weeks,proportion of patients free of sustained disability over 96 weeks and time to 3-month EDSSprogression compared to patients on placebo (see Table 3).

Table 3 Clinical outcomes in the CLARITY study (96 weeks)

Placebo Cladribine cumulative dose

Parameter (n = 437) 3.5 mg/kg 5.25 mg/kg(n = 433) (n = 456)

Annualised relapse rate (95% CI) 0.33 (0.29, 0.38) 0.14* (0.12, 0.17) 0.15* (0.12, 0.17)

Relative reduction (cladribine vs.placebo) 57.6% 54.5%

Proportion of patients relapse-freeover 96 weeks 60.9% 79.7% 78.9%

Time to 3-month EDSS progression,10th percentile (months) 10.8 13.6 13.6

Hazard ratio (95% CI) 0.67 (0.48, 0.93) 0.69 (0.49, 0.96)p = 0.018 p = 0.026

* p <0.001 compared to placebo

In addition, the cladribine 3.5 mg/kg treatment group was statistically significantly superior to placebowith regard to number and relative reduction of T1 Gd+ lesions, active T2 lesions and combinedunique lesions as demonstrated in brain MRI over the entire 96 weeks of the study. Patients takingcladribine compared to the placebo treatment group had 86% relative reduction in the mean number of

T1 Gd+ lesions (adjusted mean number for cladribine 3.5 mg/kg, and placebo groups were 0.12 and0.91, respectively), 73% relative reduction in the mean number of active T2 lesions (adjusted meannumber for cladribine 3.5 mg/kg, and placebo groups were 0.38 and 1.43, respectively) and 74%relative reduction in the mean number of combined unique lesions per patient per scan (adjusted meannumber for cladribine 3.5 mg/kg, and placebo groups were 0.43 and 1.72, respectively) (p <0.001across all 3 MRI outcomes).

Post-hoc analysis of time to 6-month confirmed EDSS progression resulted in a 47% reduction of therisk of disability progression in the cladribine 3.5 mg/kg compared to placebo (hazard ratio = 0.53,95% CI [0.36, 0.79], p <0.05); in the placebo group the 10th percentile was reached at 245 days, andnot reached at all during the study period in the cladribine 3.5 mg/kg group.

As shown in Table 3 above, higher cumulative doses did not add any clinically meaningful benefit, butwere associated with a higher incidence in ≥grade 3 lymphopenia (44.9% in the 5.25 mg/kg group vs.25.6% in the 3.5 mg/kg group).

Patients who had completed the CLARITY study could be enrolled in CLARITY Extension. In thisextension study, 806 patients received either placebo or a cumulative dose of cladribine 3.5 mg/kg (ina regimen similar to that used in CLARITY) over the 96-week study period. The primary objective ofthis study was safety, while efficacy endpoints were exploratory.

The magnitude of the effect in reducing the frequency of relapses and slowing disability progression inpatients receiving the 3.5 mg/kg dose over 2 years was maintained in years 3 and 4 (see section 4.2).

Efficacy in patients with high disease activity

Post-hoc subgroup efficacy analyses have been conducted in patients with high disease activity treatedwith oral cladribine at the recommended 3.5 mg/kg cumulative dose. These included

* patients with 1 relapse in the previous year and at least 1 T1 Gd+ lesion or 9 or more T2 lesions,while on therapy with other DMDs,

* patients with 2 or more relapses in the previous year, whether on DMD treatment or not.

In the analyses of the CLARITY data, a consistent treatment effect on relapses was observed with theannualised relapse rate ranging from 0.16 to 0.18 in the cladribine groups and 0.47 to 0.50 in theplacebo group (p <0.0001). Compared to the overall population, a greater effect was observed in timeto 6-month sustained disability where cladribine reduced the risk of disability progression by 82%(hazard ratio = 0.18, 95% CI [0.07, 0.47]). For placebo the 10th percentile for disability progressionwas reached between 16 and 23 weeks, while for the cladribine groups it was not reached during theentire study.

Secondary progressive MS with relapses

A supportive study in patients treated with cladribine as an add-on to interferon beta vs. placebo +interferon beta also included a limited number of patients with secondary progressive MS(26 patients). In these patients, treatment with cladribine 3.5 mg/kg resulted in a reduction of theannualised relapse rate compared to placebo (0.03 versus 0.30, risk ratio: 0.11, p <0.05). There was nodifference in annualised relapse rate between patients with relapsing-remitting MS and patients withsecondary progressive MS with relapses. An effect on disability progression could not be shown ineither subgroup.

Patients with secondary progressive MS were excluded in the CLARITY study. However, a post-hocanalysis of a mixed cohort including CLARITY and ONWARD patients, defined by a baseline EDSSscore of ≥3.5 as a proxy for secondary progressive MS, showed a similar reduction in annualisedrelapse rate compared to patients with an EDSS score below 3.

The European Medicines Agency has waived the obligation to submit the results of studies with

MAVENCLAD in all subsets of the paediatric population in multiple sclerosis (see section 4.2 forinformation on paediatric use).

Cladribine is a prodrug that has to be phosphorylated intracellularly to become biologically active.

Cladribine pharmacokinetics were studied following oral and intravenous administration in MSpatients and patients with malignancies, and in in vitro systems.

Following oral administration, cladribine is rapidly absorbed. Administration of 10 mg cladribineresulted in a cladribine mean Cmax in the range of 22 to 29 ng/mL and corresponding mean AUC in therange of 80 to 101 ng*h/mL (arithmetic means from various studies).

When oral cladribine was given in fasted state, median Tmax was 0.5 h (range 0.5 to 1.5 h). Whenadministered with a high-fat meal, cladribine absorption was delayed (median Tmax 1.5 h, range 1 to3 h) and Cmax was reduced by 29% (based on geometric mean), while AUC was unchanged. Thebioavailability of 10 mg oral cladribine was approximately 40%.

The volume of distribution is large, indicating extensive tissue distribution and intracellular uptake.

Studies revealed a mean volume of distribution of cladribine in the range of 480 to 490 L. The plasmaprotein binding of cladribine is 20%, and independent of plasma concentration.

The distribution of cladribine across biological membranes is facilitated by various transport proteins,including ENT1, CNT3 and BCRP.

In vitro studies indicate that cladribine efflux is only minimally P-gp related. Clinically relevantinteractions with inhibitors of P-gp are not expected. The potential consequences of P-gp induction onthe bioavailability of cladribine have not been formally studied.

In vitro studies showed negligible transporter-mediated uptake of cladribine into human hepatocytes.

Cladribine has the potential to penetrate the blood brain barrier. A small study in cancer patients hasshown a cerebrospinal fluid/plasma concentration ratio of approximately 0.25.

Cladribine and/or its phosphorylated metabolites are substantially accumulated and retained in humanlymphocytes. In vitro, intra- versus extracellular accumulation ratios were found to be around 30 to 40already 1 hour after cladribine exposure.

The metabolism of cladribine was studied in MS patients following the administration of a single10-mg tablet and a single 3-mg intravenous dose. Following both oral and intravenous administration,the parent compound cladribine was the main component present in plasma and urine. The metabolite2-chloroadenine was a minor metabolite both in plasma and in urine, e.g. accounting only for ≤ 3% ofplasma parent drug exposure after oral administration. Only traces of other metabolites could be foundin plasma and in urine.

In hepatic in vitro systems, negligible metabolism of cladribine was observed (at least 90% wasunchanged cladribine).

Cladribine is not a relevant substrate to cytochrome P450 enzymes and does not show significantpotential to act as inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1and CYP3A4. Inhibition of these enzymes or genetic polymorphisms (e.g. CYP2D6, CYP2C9 or

CYP2C19) are not expected to result in clinically significant effects on cladribine pharmacokinetics orexposure. Cladribine has no clinically meaningful inductive effect on CYP1A2, CYP2B6 and

CYP3A4 enzymes.

After entering the target cells, cladribine is phosphorylated to cladribine monophosphate (Cd-AMP)by DCK (and also by deoxyguanosine kinase in the mitochondria). Cd-AMP is further phosphorylatedto cladribine diphosphate (Cd-ADP) and cladribine triphosphate (Cd-ATP). The dephosphorylationand deactivation of Cd-AMP is catalysed by cytoplasmic 5'-NTase. In a study of the intracellularpharmacokinetics of Cd-AMP and Cd-ATP in patients with chronic myelogenous leukaemia, thelevels of Cd-ATP were approximately half of the Cd-AMP levels.

Intracellular half-life of Cd-AMP was 15 h. Intracellular half-life of Cd-ATP was 10 h.

Based on pooled population pharmacokinetic data from various studies, the median values forelimination were 22.2 L/h for renal clearance and 23.4 L/h for non-renal clearance. Renal clearanceexceeded the glomerular filtration rate, indicating active renal tubular secretion of cladribine.

The non-renal part of the elimination of cladribine (approximately 50%) consists of negligible hepaticmetabolism and of extensive intracellular distribution and trapping of the active cladribine principle(Cd-ATP) within the targeted intracellular compartment (i.e. the lymphocytes) and subsequentelimination of intracellular Cd-ATP according to the life-cycle and elimination pathways of thesecells.

The estimated terminal half-life for a typical patient from the population pharmacokinetic analysis isapproximately 1 day. This however does not result in any drug accumulation after once daily dosing asthis half-life only accounts for a small portion of the AUC.

Dose and time dependence

After oral administration of cladribine across a dose range from 3 to 20 mg, Cmax and AUC increasedin a dose-proportional fashion, suggesting that absorption is not affected by rate- or capacity-limitedprocesses up to a 20 mg oral dose.

No significant accumulation of cladribine concentration in plasma has been observed after repeateddosing. There is no indication that cladribine pharmacokinetics might change in a time-dependentfashion after repeated administration.

No studies have been conducted to evaluate the pharmacokinetics of cladribine in elderly or inpaediatric MS patients, or in subjects with renal or hepatic impairment.

A population kinetic analysis did not show any effect of age (range 18 to 65 years) or gender oncladribine pharmacokinetics.

Renal clearance of cladribine was shown to be dependent on creatinine clearance. Based on apopulation pharmacokinetic analysis including patients with normal renal function and with mild renalimpairment, total clearance in patients with mild renal impairment (CLCR = 60 mL/min) is expected todecrease moderately, leading to an increase in exposure of 25%.

The role of hepatic function for the elimination of cladribine is considered negligible.

An interaction study in MS patients showed that the bioavailability of 10 mg oral cladribine was notaltered when co-administered with pantoprazole.

Non-clinical safety pharmacological and toxicological assessment of cladribine in animal modelsrelevant for the safety assessment of cladribine did not yield significant findings other than thosepredicted by the pharmacologic mechanism of cladribine. The primary target organs identified in therepeat-dose toxicology studies by parenteral routes (intravenous or subcutaneous) up to 1-yearduration in mice and monkeys were the lymphoid and haematopoietic system. Other target organsafter longer administration (14 cycles) of cladribine to monkeys by subcutaneous route were thekidneys (karyomegaly of renal tubular epithelium), adrenals (cortex atrophy and decreasedvacuolation), gastrointestinal tract (mucosa atrophy) and testes. Effects on the kidneys were also seenin mice.

Cladribine is incorporated into DNA strands and inhibits DNA synthesis and repair. Cladribine did notinduce gene mutation in bacteria or mammalian cells, but it was clastogenic causing chromosomaldamage in mammalian cells in vitro at a concentration which was 17-fold above the expected clinical

Cmax. In vivo clastogenicity in mice was detected at 10 mg/kg, which was the lowest dose tested.

The carcinogenic potential of cladribine was assessed in a long-term 22-month study withsubcutaneous administration in mice and in a short-term 26-week study by oral route in transgenicmice.

* In the long-term carcinogenicity study in mice, the highest dose used was 10 mg/kg, which wasseen to be genotoxic in the mouse micronucleus study (equivalent to approximately 16-fold theexpected human exposure in AUC in patients taking the maximum daily dose of 20 mgcladribine). No increased incidence of lymphoproliferative disorders or other tumour types(apart from Harderian gland tumours, predominantly adenomas) was seen in mice. Harderiangland tumours are not considered to be of clinical relevance, as humans do not have comparableanatomical structures.

* In the short-term carcinogenicity study in Tg rasH2 mice, no cladribine-related increase inincidence of lymphoproliferative disorders or other tumour types was seen at any dose tested upto 30 mg/kg per day (equivalent to approximately 25-fold the expected human exposure in AUCin patients taking the maximum daily dose of 20 mg cladribine).

Cladribine was also assessed in a 1-year monkey study by the subcutaneous route. No increasedincidence in lymphoproliferative disorders and no tumours were seen in this study.

Although cladribine may have a potential for genotoxicity, long-term data in mice and monkeys didnot provide any evidence of a relevant increased carcinogenicity risk in humans.

Reproduction toxicity

While there were no effects on female fertility, reproductive function or general performance ofoffspring, cladribine was shown to be embryolethal when administered to pregnant mice, and thecompound was teratogenic in mice (also following treatment of the males only) and rabbits. Theobserved embryolethal and teratogenic effects are consistent with the pharmacologic mechanisms ofcladribine. In a male mouse fertility study, malformed foetuses with agenesis of portions ofappendage(s) distal the humerus and/or femur were seen. The incidence of affected mouse foetuses inthis study was in the same range of spontaneous incidence of amelia and phocomelia in this strain ofmice. However, considering cladribine genotoxicity, male-mediated effects related to potential geneticalteration of differentiating sperm cells cannot be excluded.

Cladribine did not affect the fertility of male mice, but observed testicular effects were reducedtesticular weights and increased numbers of non-motile sperm. Testicular degeneration and reversibledecrease in spermatozoa with rapid progressive motility were also seen in the monkey. Histologically,testicular degeneration was only seen in one male monkey in a 1-year subcutaneous toxicity study.

Hydroxypropylbetadex (2-hydroxypropyl-ß-cyclodextrin)

Sorbitol

Magnesium stearate

Not applicable.

4 years.

Store in the original package in order to protect from moisture.

Oriented polyamide (OPA)/aluminium (Al)/polyvinyl chloride (PVC) - aluminium (Al) blister sealedin a cardboard wallet and fixed in a child-resistant outer carton.

Pack sizes of 1, 4, 5, 6, 7 or 8 tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Merck Europe B.V.

Gustav Mahlerplein 1021082 MA Amsterdam

The Netherlands

EU/1/17/1212/001

EU/1/17/1212/002

EU/1/17/1212/003

EU/1/17/1212/004

EU/1/17/1212/005

EU/1/17/1212/006

Date of first authorisation: 22 August 2017

Date of latest renewal: 25 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.