- Approval Id
- 703efef887562ec8
- Drug Approval Emc Name
- Cladribine Merck 10 mg tablets
- Drug Name
- Cladribine Merck 10 mg tablets
- Company Address
- Merck Serono Ltd, 5 New Square, Bedfont Lakes Business Park, Feltham, Middlesex, TW14 8HA, UK
- Company Telephone
- +44 (0)208 818 7200
- Company Fax
- +44 (0)208 818 7274
- Company Medical Info Direct Line
- +44 (0)208 818 7373
- Company Medical Info Email
- [email protected]
- Company Medical Info Fax
- +44 (0)208 818 7274
- Atc Code
- L04AA40
- Legal Category
- Prescription only medicine
- Authorisation Holder
- 7. Marketing authorisation holder Merck Serono Limited 5 New Square Bedfont Lakes Business Park Feltham Middlesex TW14 8HA UK
- Authorisation Number
- 8. Marketing authorisation number(s) PLGB 11648/0272
- Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 01/01/2021 Date of latest renewal: 29/09/2023
- Instruction Authorisation Holder
- 7. Marketing authorisation holder Merck Serono Limited 5 New Square Bedfont Lakes Business Park Feltham Middlesex TW14 8HA UK
- Instruction Authorisation Number
- 8. Marketing authorisation number(s) PLGB 11648/0272
- Instruction Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 01/01/2021 Date of latest renewal: 29/09/2023
- Instruction Composition
- 2. Qualitative and quantitative composition Each tablet contains 10 mg of cladribine. Excipients with known effect Each tablet contains 64 mg sorbitol. For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- 3. Pharmaceutical form Tablet White, round, biconvex tablets of 8.5 mm diameter, engraved with 'C' on one side and '10' on the other side.
- Instruction Clinical Particulars
- 4. Clinical particulars 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
- Instruction Pharmacology
- 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA40 Mechanism of action Cladribine is a nucleoside analogue of deoxyadenosine. A chlorine substitution in the purine ring protects cladribine from degradation by adenosine deaminase, increasing the intracellular residence time of the cladribine prodrug. Subsequent phosphorylation of cladribine to its active triphosphate form, 2‑chlorodeoxyadenosine triphosphate (Cd‑ATP), is particularly efficiently achieved in lymphocytes, due to their constitutively high deoxycytidine kinase (DCK) and relatively low 5'‑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 ratio other bone marrow derived cells are less affected than lymphocytes. DCK is the rate limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to selective depletion 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 synthesis via inhibition of ribonucleotide reductase and competes with deoxyadenosine triphosphate for incorporation into DNA by DNA polymerases. In resting cells cladribine causes DNA single-strand breaks, rapid nicotinamide adenine dinucleotide consumption, ATP depletion and cell death. There is evidence that cladribine can also cause direct caspase-dependent and ‑independent apoptosis via the release 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, including autoreactive T and B cells play a key role. The mechanism by which cladribine exerts its therapeutic effects in MS is not fully elucidated but its predominant effect on B and T lymphocytes is thought to interrupt the cascade of immune events central to MS. Variations in the expression levels of DCK and 5'‑NTases between immune cell subtypes may explain differences in immune cell sensitivity to cladribine. Because of these expression levels, cells of the innate immune system are less affected than cells of the adaptive immune system. Pharmacodynamic effects Cladribine has been shown to exert long-lasting effects by preferentially targeting lymphocytes and the autoimmune processes involved in the pathophysiology of MS. Across studies, the largest proportion of patients with grade 3 or 4 lymphopenia (<500 to 200 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 haematological effect. Across clinical studies, data with the proposed cumulative dose of 3.5 mg/kg body weight show a gradual improvement in the median lymphocyte counts back to the normal range at week 84 from the first dose of cladribine (approximately 30 weeks after the last dose of cladribine). The lymphocyte counts of more than 75% of patients returned to the normal range by week 144 from the first dose of cladribine (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 a temporarily decreased CD4 to CD8 ratio. Cladribine reduces CD19+ B cells and CD16+/CD56+ natural killer cells, which also recover faster than CD4+ T cells. Clinical efficacy and safety 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 objectives were 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 measured by 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 and 5 of the first year and a second treatment course at weeks 1 and 5 of the second year. Patients randomised to the 5.25 mg/kg cumulative dose received additional treatment at weeks 9 and 13 of the first year. The majority of patients in the placebo (87.0%) and the cladribine 3.5 mg/kg (91.9%) and 5.25 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 and to have a Kurtzke Expanded Disability Status Scale (EDSS) from range 0 to 5.5 including MRI lesions consistent with MS.. In the overall study population, the median age was 39 years (range 18 to 65), and the female to male ratio was approximately 2:1. The mean duration of MS prior to study enrolment was 8.7 years, and the median baseline neurological disability based on EDSS score across all treatment groups was 3.0 (range 0 to
- Instruction Pharmaceutical Particulars
- 6. Pharmaceutical particulars 6.1 List of excipients Hydroxypropylbetadex (2‑hydroxypropyl-ß‑cyclodextrin) Sorbitol Magnesium stearate 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Oriented polyamide (OPA)/aluminium (Al)/polyvinyl chloride (PVC) – aluminium (Al) blister sealed in 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. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
2. Qualitative and quantitative composition Each tablet contains 10 mg of cladribine. Excipients with known effect Each tablet contains 64 mg sorbitol. For the full list of excipients, see section 6.1.
## Pharmaceutical Form
3. Pharmaceutical form Tablet White, round, biconvex tablets of 8.5 mm diameter, engraved with 'C' on one side and '10' on the other side.
## Clinical Particulars
4. Clinical particulars 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
## Pharmacological Properties
5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA40 Mechanism of action Cladribine is a nucleoside analogue of deoxyadenosine. A chlorine substitution in the purine ring protects cladribine from degradation by adenosine deaminase, increasing the intracellular residence time of the cladribine prodrug. Subsequent phosphorylation of cladribine to its active triphosphate form, 2‑chlorodeoxyadenosine triphosphate (Cd‑ATP), is particularly efficiently achieved in lymphocytes, due to their constitutively high deoxycytidine kinase (DCK) and relatively low 5'‑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 ratio other bone marrow derived cells are less affected than lymphocytes. DCK is the rate limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to selective depletion 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 synthesis via inhibition of ribonucleotide reductase and competes with deoxyadenosine triphosphate for incorporation into DNA by DNA polymerases. In resting cells cladribine causes DNA single-strand breaks, rapid nicotinamide adenine dinucleotide consumption, ATP depletion and cell death. There is evidence that cladribine can also cause direct caspase-dependent and ‑independent apoptosis via the release 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, including autoreactive T and B cells play a key role. The mechanism by which cladribine exerts its therapeutic effects in MS is not fully elucidated but its predominant effect on B and T lymphocytes is thought to interrupt the cascade of immune events central to MS. Variations in the expression levels of DCK and 5'‑NTases between immune cell subtypes may explain differences in immune cell sensitivity to cladribine. Because of these expression levels, cells of the innate immune system are less affected than cells of the adaptive immune system. Pharmacodynamic effects Cladribine has been shown to exert long-lasting effects by preferentially targeting lymphocytes and the autoimmune processes involved in the pathophysiology of MS. Across studies, the largest proportion of patients with grade 3 or 4 lymphopenia (<500 to 200 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 haematological effect. Across clinical studies, data with the proposed cumulative dose of 3.5 mg/kg body weight show a gradual improvement in the median lymphocyte counts back to the normal range at week 84 from the first dose of cladribine (approximately 30 weeks after the last dose of cladribine). The lymphocyte counts of more than 75% of patients returned to the normal range by week 144 from the first dose of cladribine (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 a temporarily decreased CD4 to CD8 ratio. Cladribine reduces CD19+ B cells and CD16+/CD56+ natural killer cells, which also recover faster than CD4+ T cells. Clinical efficacy and safety 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 objectives were 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 measured by 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 and 5 of the first year and a second treatment course at weeks 1 and 5 of the second year. Patients randomised to the 5.25 mg/kg cumulative dose received additional treatment at weeks 9 and 13 of the first year. The majority of patients in the placebo (87.0%) and the cladribine 3.5 mg/kg (91.9%) and 5.25 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 and to have a Kurtzke Expanded Disability Status Scale (EDSS) from range 0 to 5.5 including MRI lesions consistent with MS.. In the overall study population, the median age was 39 years (range 18 to 65), and the female to male ratio was approximately 2:1. The mean duration of MS prior to study enrolment was 8.7 years, and the median baseline neurological disability based on EDSS score across all treatment groups was 3.0 (range 0 to
## Pharmaceutical Particulars
6. Pharmaceutical particulars 6.1 List of excipients Hydroxypropylbetadex (2‑hydroxypropyl-ß‑cyclodextrin) Sorbitol Magnesium stearate 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage Store in the original package in order to protect from moisture. 6.5 Nature and contents of container Oriented polyamide (OPA)/aluminium (Al)/polyvinyl chloride (PVC) – aluminium (Al) blister sealed in 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. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Company Detail Path
- /organization/msd-international-gmbh-puerto-rico-branch-llc
