5.3 Preclinical safety data

 Multiple dose romiplostim toxicology studies were conducted in rats for 4 weeks and in monkeys for up to 6 months. In general, effects observed during these studies were related to the thrombopoietic activity of romiplostim and were similar regardless of study duration. Injection site reactions were also related to romiplostim administration. Myelofibrosis has been observed in the bone marrow of rats at all tested dose levels. In these studies, myelofibrosis was not observed in animals after a 4-week post-treatment recovery period, indicating reversibility.

In 1-month rat and monkey toxicology studies, a mild decrease in red blood cell count, haematocrit and haemoglobin was observed. There was also a stimulatory effect on leukocyte production, as peripheral blood counts for neutrophils, lymphocytes, monocytes, and eosinophils were mildly increased. In the longer duration chronic monkey study, there was no effect on the erythroid and leukocytic lineages when romiplostim was administered for 6 months where the administration of romiplostim was decreased from thrice weekly to once weekly. Additionally, in the phase 3 pivotal studies, romiplostim did not affect the red blood cell and white blood cells lineages relative to placebo treated subjects.

Due to the formation of neutralising antibodies pharmacodynamic effects of romiplostim in rats were often decreasing at prolonged duration of administration. Toxicokinetic studies showed no interaction of the antibodies with the measured concentrations. Although high doses were tested in the animal studies, due to differences between the laboratory species and humans with regard to the sensitivity for the pharmacodynamic effect of romiplostim and the effect of neutralising antibodies, safety margins cannot be reliably estimated.

Carcinogenesis: The carcinogenic potential of romiplostim has not been eva luated. Therefore, the risk of potential carcinogenicity of romiplostim in humans remains unknown.

Reproductive toxicology: In all developmental studies neutralising antibodies were formed, which may have inhibited romiplostim effects. In embryo-foetal development studies in mice and rats, reductions in maternal body weight were found only in mice. In mice there was evidence of increased post-implantation loss. In a prenatal and postnatal development study in rats an increase of the duration of gestation and a slight increase in the incidence of peri-natal pup mortality was found. Romiplostim is known to cross the placental barrier in rats and may be transmitted from the mother to the developing foetus and stimulate foetal platelet production. Romiplostim had no observed effect on the fertility of rats.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

 Mannitol (E421)

Sucrose

L-histidine

Hydrochloric acid (for pH adjustment)

Polysorbate 20

6.2 Incompatibilities

 In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.

6.3 Shelf life

 3 years.

After reconstitution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C and for 24 hours at 2°C – 8°C, when protected from light and kept in the original vial.

From a microbiological point of view, the product should be used immediately. If not use