Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Laboratoires Delbert, 49 Rue Rouelle, 75015 Paris, France
Pharmacotherapeutic group: Immunostimulants, other immunostimulants
ATC code: L03AX14
Ceplene/IL-2 is an immunotherapy which aims to induce immune-mediated destruction of residual myeloid leukaemic cells and thereby to prevent relapse of leukaemia. The role of Ceplene is to protect lymphocytes, in particular NK cells and T cells, which are responsible for the immune-mediated destruction of residual leukaemic cells. The role of IL-2 is to promote the functions of NK cells and T cells by activating the anti-leukaemic properties of these cells and by expanding these cell populations by inducing cell cycle proliferation.
The mechanism by which Ceplene improves the anti-leukaemic function of lymphocytes in AML is not completely established; it is considered to be by inhibition of reactive oxygen species (ROS or ‘oxygen free radicals’), which are synthesised by monocytes/macrophages and granulocytes. ROS are known to limit the anti-leukaemic effects of lymphocyte activators such as IL-2, by triggering dysfunction and death by apoptosis in NK cells and T cells. Ceplene inhibits NAPDH oxidase which initiates the formation and release of ROS from phagocytes. By inhibiting oxidase function and reducing ROS production, Ceplene protects IL-2-activated NK cells and T cells from oxygen free radical-induced inhibition and apoptosis. The concomitant administration of Ceplene and IL-2 therefore aims to optimise the anti-leukaemic functions of NK cells and T cells.
There have been 2 clinical studies to evaluate the use of Ceplene in the maintenance of remission in adult AML patients. Study AML-1 was exploratory, enrolling 39 AML patients in remission to determine the dose and feasibility of Ceplene administered together with IL-2. Results of this pilot study were used to design and implement a multi-national phase 3 trial. The randomised phase 3 trial (0201) compared Ceplene+IL-2 treatment to no treatment in 261 patients in first remission (CR1) and in another 59 patients in subsequent remission after relapse (CR>1). For CR1 patients, the median duration of leukaemia-free survival increased from 291 days (9.7 months) to 450 days (15 months) after Ceplene/IL-2 versus no maintenance treatment (ITT, p=0.01. n=261). The number of CR1 patients remaining leukaemia-free for 3 years was 40% after Ceplene+IL-2 versus 26% in patients not receiving this treatment (p=0.01).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
Ceplene is indicated for use in adults. There are no data available on pharmacodynamic properties in children below 18 years of age.
Histamine is rapidly absorbed after subcutaneous injection. Maximum plasma concentration is reached approximately 10 minutes after end of subcutaneous infusion. Histamine concentrations and PK were highly variable across studies, as well as within the normal volunteer and patient groups.
Patients showed a higher degree of variability with respect to systemic exposure as compared to healthy subjects. Overall systemic exposure of Ceplene was greater in patients versus healthy subjects. However, this difference was not statistically significant. It is not known whether histamine crosses the placenta.
Histamine is eliminated by metabolism in kidney, liver and other tissues. The main enzymes involved in the metabolism of histamine are HNMT (histamine-N-methyltransferase) and DAO (diamine oxidase). The metabolites are mainly excreted in urine. The mean half-life was 0.75 to 1.5 hours in patients.
There are no significant effects of age or weight on the pharmacokinetic properties of histamine. Clearance of Ceplene is almost twice as high in females resulting in considerably lower systemic exposure than in males.
The pharmacokinetics of histamine are similar in healthy volunteers with normal renal function compared to volunteers with mild, moderate, or severe renal impairment. In subjects with severe renal impairment, there were decreases in systolic and diastolic blood pressure at plasma histamine concentrations which caused no appreciable decrease in blood pressure in other subjects. Thus, subjects with severe renal impairment may be more sensitive to the blood pressure lowering effects of exogenously administered histamine than subjects with normal renal function or subjects with mild or moderate renal impairment. Although the degree of renal impairment has little effect on the PK disposition of histamine, caution should be used in the administration of histamine to patients with severe renal impairment.
A study was performed to measure the PK of histamine in normal volunteers compared to patients with mild, moderate, and severe hepatic impairment. There were no clinically significant differences in safety parameters or in pharmacodynamics. Plasma histamine concentrations were highly variable and were considerably higher in the groups of patients with moderate or severe hepatic impairment (medians 10 and 5 times the normal volunteers respectively). Patients with all degrees of hepatic impairment may have tachycardia or hypotension for 30-60 minutes after Ceplene+IL-2 administration.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated-dose toxicity, local tolerance and genotoxicity. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use. No carcinogenicity studies have been performed on Ceplene.
Histamine dihydrochloride was not teratogenic in rats or rabbits at doses resulting in several hundredfold greater systemic exposures than the clinical exposure. In female rats dosed before mating to gestation day 7, slightly reduced numbers of implantations and viable foetuses were found, but without any dose-response and within the range of historical control data. In the peri-post natal development study, high doses of histamine dihydrochloride caused maternal toxicity, and the offspring showed toxicity during lactation (fewer live pups at day 21 compared to lactation at day 4) but not after weaning.
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