ast infusion 11 or 12 weeks later, were almost superimposable and the mean AUC values of the free mifamurtide after the first and last infusion were similar. These data indicate that neither total nor free mifamurtide accumulated during the treatment period.
At 6 hours after injection of radiolabelled liposomes containing 6 mg mifamurtide, radioactivity was found in liver, spleen, nasopharynx, thyroid, and, to a lesser extent, in lung. The liposomes were phagocytosed by cells of the reticuloendothelial system. In 2 of 4 patients with lung metastases, radioactivity was associated with lung metastases. Mean half-life of radiolabelled material was biphasic with an α phase of about 15 minutes and a terminal half-life of approximately 18 hours.
5.3 Preclinical safety data
In sensitive species (rabbit and dog) the highest daily dose of liposomal mifamurtide that did not cause adverse effects was 0.1 mg/kg, corresponding to 1.2 and 2 mg/m2, respectively. The no-adverse-effect level for MEPACT in animals corresponds roughly to the 2 mg/m2 recommend dose for humans.
Data from a six month dog study of daily intravenous injections of up to 0.5 mg/kg (10 mg/m2) MEPACT provide an 8- to 19-fold cumulative exposure safety margin for overt toxicity for the intended clinical dose in humans. Major toxic effects associated with these high daily and cumulative doses of MEPACT were mainly exaggerated pharmacological effects: pyrexia, signs of pronounced inflammatory response manifested as synovitis, bronchopneumonia, pericarditis and inflammatory necrosis of the liver and bone marrow. The following events were also observed: haemorrhage and prolongation of coagulation times, infarcts, morphological changes in the wall of small arteries, oedema and congestion of the central nervous system, minor cardiac effects, and slight hyponatraemia. MEPACT was not mutagenic and did not cause teratogenic effects in rats and rabbits. Embryotoxic effects were observed only at maternal toxic levels.
There were no results from general toxicity studies that suggested harmful effects on male or female reproductive organs. Specific studies addressing reproductive function, perinatal toxicity and carcinogenic potential have not been performed.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)
1,2-Dioleoyl-sn-glycero-3-phospho-L-serine monosodium salt (OOPS)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Unopened vial of powder:
30 months
Reconstituted suspension:
Chemical and physical stability has been demonstrated for 6 hours up to 25ºC.
From a microbiological point of view, immediate use is recommended. If not used immediately, the reconstituted, filtered and diluted solution in-use storage times and conditions prior to use of the reconstituted product are the responsibility of the user and must not be longer than 6 hours at 25ºC. Do not store in a refrigerator and do not freeze the solution.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
50 ml type I glass vial with a grey butyl rubber stoppe |
