4.1. Therapeutic indications

Cladribine Merck is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease as defined by clinical or imaging features.

4.2. Posology and method of administration

Treatment must be initiated and supervised by a physician experienced in the treatment of MS.

Posology

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. For details, see Tables 1 and 2 below.

Following completion of the 2 treatment courses, no further cladribine treatment is required in years 3 and 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 of lymphocytes. If this recovery takes more than 6 months, the patient should not receive cladribine tablets anymore.

Distribution of dose

The distribution of the total dose over the 2 years of treatment is provided in Table 1. For some weight ranges the number of tablets may vary from one treatment week to the next. Use of oral cladribine in patients 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 week

kg

Treatment week 1

Treatment week 2

40 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 individual days. It is recommended that the daily cladribine doses in each treatment week be taken at intervals of 24 hours at approximately the same time each day. If a daily dose consists of two tablets, both tablets are taken together as a single dose.

Table 2 Number of tablets per week day

Total number of tablets per week

Day 1

Day 2

Day 3

Day 4

Day 5

4

1

1

1

1

0

5

1

1

1

1

1

6

2

1

1

1

1

7

2

2

1

1

1

8

2

2

2

1

1

9

2

2

2

2

1

10

2

2

2

2

2

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

A missed dose must not be taken together with the next scheduled dose on the following day. In the case of a missed dose, the patient must take the missed dose on the following day, and extend the number of days in that treatment week. If two consecutive doses are missed, the same rule applies, and the 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 Cladribine Merck by at least 3 hours during the limited number of days of cladribine administration (see section 4.5).

Special populations

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 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).

Hepatic impairment

No studies have been conducted in patients with hepatic impairment.

No dose adjustment is required in patients with mild hepatic impairment because the importance of hepatic 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 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 of Cladribine Merck in children below the age of 18 years have not been established. No data are available.

Method of administration

Cladribine Merck 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 and not 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 area must be thoroughly washed.

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

4.3. Contraindications

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 currently receiving 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).

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 Cladribine Merck 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 Cladribine Merck 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 Cladribine Merck 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 Cladribine Merck 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).

Cladribine Merck 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 Cladribine Merck.

Before initiating Cladribine Merck 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 Merck 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 3 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 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.

4.5. Interaction with other medicinal products and other forms of interaction

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 administration of any other oral medicinal product be separated from that of Cladribine Merck 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 (see section 4.3).

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

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

4.6. Fertility, pregnancy and lactation

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 Merck 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 who become pregnant under therapy with Cladribine Merck should discontinue treatment.

As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected (see section 5.3). Therefore, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 3 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 (see section 5.3).

Cladribine Merck is contraindicated in pregnant women (see section 4.3).

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 Merck and for 1 week after the last dose (see section 4.3).

Fertility

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

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 3 months after the last dose (see above).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

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

Infections and infestations

Common:

Oral herpes, dermatomal herpes zoster.

Very rare:

Tuberculosis (see section 4.4).

Blood and lymphatic system disorders

Very common:

Lymphopenia.

Common:

Decrease in neutrophil count.

Immune system disorders

Common:

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

Hepatobiliary disorders

Uncommon:

Liver Injury*.

Skin and subcutaneous tissue disorders

Common:

Rash, alopecia.

Description of selected adverse reactions

Lymphopenia

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

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

Malignancies

In clinical studies and long-term follow-up 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 3,414 patient-years [0.29 events per 100 patient-years]) compared to patients who received placebo (3 events in 2,022 patient-years [0.15 events per 100 patient-years]) (see section 4.4).

Hypersensitivity

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 in 0.3% of cladribine-treated patients and in no patients who received placebo. Hypersensitivity events led to treatment discontinuation in 0.4% of cladribine-treated patients and in 0.3% patients who received placebo.

Liver Injury

During post-marketing experience, uncommon events of liver injury, including serious cases and cases leading to discontinuation of treatment, were reported in temporal association with Cladribine Merck.

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 / or symptomatic 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 (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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 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 Merck 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.