study in mice, the highest dose used was 10 mg/kg, which was seen to be genotoxic in the mouse micronucleus study (equivalent to approximately 16-fold the expected human exposure in AUC in patients taking the maximum daily dose of 20 mg cladribine). No increased incidence of lymphoproliferative disorders or other tumour types (apart from Harderian gland tumours, predominantly adenomas) was seen in mice. Harderian gland tumours are not considered to be of clinical relevance, as humans do not have comparable anatomical structures.
• In the short-term carcinogenicity study in Tg rasH2 mice, no cladribine-related increase in incidence of lymphoproliferative disorders or other tumour types was seen at any dose tested up to 30 mg/kg per day (equivalent to approximately 25-fold the expected human exposure in AUC in 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 increased incidence 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 did not 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 of offspring, cladribine was shown to be embryolethal when administered to pregnant mice, and the compound was teratogenic in mice (also following treatment of the males only) and rabbits. The observed embryolethal and teratogenic effects are consistent with the pharmacologic mechanisms of cladribine. In a male mouse fertility study, malformed foetuses with agenesis of portions of appendage(s) distal the humerus and/or femur were seen. The incidence of affected mouse foetuses in this study was in the same range of spontaneous incidence of amelia and phocomelia in this strain of mice. However, considering cladribine genotoxicity, male-mediated effects related to potential genetic alteration of differentiating sperm cells cannot be excluded.
Cladribine did not affect the fertility of male mice, but observed testicular effects were reduced testicular weights and increased numbers of non-motile sperm. Testicular degeneration and reversible decrease 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.
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
3 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.
7. Marketing authorisation holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands
8. Marketing authorisation number(s)
EU/1/17/1212/001
EU/1/17/121 |
