rease in kidney pelvis mineralisation in all 3 doses, most notably in females. The no observed adverse effect level (NOAEL) was considered to be less than 75 mg/kg/day, and is approximately 25-fold greater than the human daily exposure based on AUC exposure. Repeated oral administration of 4 and 6 mg/kg/day to monkeys for up to 20 weeks produced mortality and significant toxicity (marked weight loss, reduced red and white blood cell and platelet counts, multiple organ haemorrhage, gastrointestinal tract inflammation, lymphoid, and bone marrow atrophy). Repeated oral administration of 1 and 2 mg/kg/day to monkeys for up to 1 year produced reversible changes in bone marrow cellularity, a slight decrease in myeloid:erythroid cell ratio and thymic atrophy. Mild suppression of white blood cell count was observed at 1 mg/kg/day corresponding to approximately the same human dose based on AUC comparisons.
In vitro (bacterial mutation, human lymphocytes, mouse lymphoma, Syrian Hamster Embryo cell transformation) and in vivo (rat micronucleus) mutagenicity studies revealed no drug related effects at either the gene or chromosomal level. Carcinogenicity studies with lenalidomide have not been conducted.
Developmental toxicity studies were previously conducted in rabbits. In these studies, rabbits were administered 3, 10 and 20 mg/kg/day orally. An absence of the intermediate lobe of the lung was observed at 10 and 20 mg/kg/day with dose dependence and displaced kidneys were observed at 20 mg/kg/day. Although it was observed at maternotoxic levels they may be attributable to a direct effect. Soft tissue and skeletal variations in the foetuses were also observed at 10 and 20 mg/kg/day.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Revlimid 5 mg hard capsules:
Capsule contents: Lactose, anhydrous
Cellulose, microcrystalline
Croscarmellose sodium
Magnesium stearate
Capsule shell:
Gelatin
Titanium dioxide (E171)
Printing ink:
Shellac
Propylene glycol
Black iron oxide (E172)
Potassium hydroxide
Revlimid 10 mg hard capsules:
Capsule contents:
Lactose, anhydrous
Cellulose, microcrystalline
Croscarmellose sodium
Magnesium stearate
Capsule shell:
Gelatin
Titanium dioxide (E171)
Indigo carmine (E132)
Yellow iron oxide (E172)
Printing ink:
Shellac
Propylene glycol
Black iron oxide (E172)
Potassium hydroxide
Revlimid 15 mg hard capsules:
Capsule contents:
Lactose, anhydrous
Cellulose, microcrystalline
Croscarmellose sodium
Magnesium stearate
Capsule shell:
Gelatin
Titanium dioxide (E171)
Indigo carmine (E132)
Printing ink:
Shellac
Propylene glycol
Black iron oxide (E172)
Potassium hydroxide
Revlimid 25 mg hard capsules:
Capsule contents:
Lactose, anhydrous
Cellulose, microcrystalline
Croscarmellose sodium
Magnesium stearate
Capsule shell:
Gelatin
Titanium dioxide (E171)
Printing ink:
Shellac
Propylene glycol
Black iron oxide (E172)
Potassium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf li
