LENALIDOMIDE SANDOZ

2. 5 x ULN or AST > ULN) and indicate that mild hepatic impairment does not influence lenalidomide clearance (exposure in plasma). There are no data available for patients with moderate to severe hepatic impairment. Other intrinsic factors Population pharmacokinetic analyses indicate that body weight (33- 135 kg), gender, race and type of haematological malignancy (MM, MDS or MCL) do not have a clinically relevant effect on lenalidomide clearance in adult patients.

5 and up to 4 mg/kg/day. Findings from this study indicate that lenalidomide produced external malformations including non-patent anus and malformations of upper and lower extremities (bent, shortened, malformed, malrotated and/or absent part of the extremities, oligo and/or polydactyly) in the offspring of female monkeys who received the active substance during pregnancy.

Various visceral effects (discoloration, red foci at different organs, small colourless mass above atrio- ventricular valve, small gall bladder, malformed diaphragm) were also observed in single foetuses. Lenalidomide has a potential for acute toxicity; minimum lethal doses after oral administration were > 2000 mg/kg/day in rodents.

Repeated oral administration of 75, 150 and 300 mg/kg/day to rats for up to 26 weeks produced a reversible treatment- related increase 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.

Summary of the safety profile Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with lenalidomide maintenance A conservative approach was applied to determine the adverse reactions from CALGB 100104. The adverse reactions described in Table 1 included events reported post-HDM/ASCT as well as events from the maintenance treatment period.

A second analysis that identified events that occurred after the start of maintenance treatment suggests that the frequencies described in Table 1 may be higher than actually observed during the maintenance treatment period. In IFM 2005-02, the adverse reactions were from the maintenance treatment period only.

5%). 8%]). 0%). 5%). 0%). Multiple myeloma: patients with at least one prior therapy In two phase 3 placebo-controlled studies, 353 patients with multiple myeloma were exposed to the lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination.

4). 2%). 1). In the phase II, all 148 patients were on lenalidomide treatment. In the phase 3 study, 69 patients were on lenalidomide 5 mg, 69 patients on lenalidomide 10 mg and 67 patients were on placebo during the double-blind phase of the study.

Most adverse reactions tended to occur during the first 16 weeks of therapy with lenalidomide. 4). 7%). Mantle cell lymphoma The overall safety profile of lenalidomide in patients with mantle cell […]

4 Thyroid disorders). Tumour flare reaction and tumour lysis syndrome In study MCL-002, approximately 10% of lenalidomide-treated patients experienced TFR compared to 0% in the control arm. The majority of the events occurred in cycle 1, all were assessed as treatment-related, and the majority of the reports were Grade 1 or 2.

Patients with high MIPI at diagnosis or bulky disease (at least one lesion that is ≥ 7 cm in the longest diameter) at baseline may be at risk of TFR. In study MCL-002, TLS was reported for one patient in each of the two treatment arms.

In the supportive study MCL-001, approximately 10% of subjects experienced TFR; all report were Grade 1 or 2 in severity and all were assessed as treatment-related. The majority of the events occurred in cycle 1. 4). 7%) patients in the placebo/rituximab arm.

Most TFRs (18 out of 19) reported in the lenalidomide/rituximab arm occurred during first two cycles of treatment. One FL patient in the lenalidomide/rituximab arm experienced a Grade 3 TFR event versus no patients in the placebo/rituximab arm.

0%) of FL patients experienced TFR; (3 reports were Grade 1 and 4 reports were Grade 2 severity); while 1 report was considered serious. 4%) in the lenalidomide/rituximab arm and no FL patients in the placebo/rituximab arm; neither patient had a Grade 3 or 4 event.

6%) in study NHL- 008. This single event was identified as a serious, Grade 3 adverse reaction. For study NHL-007 no patients had to discontinue lenalidomide/rituximab therapy due to TFR or TLS. Gastrointestinal disorders Gastrointestinal perforations have been reported during treatment with lenalidomide.

Gastrointestinal perforations may lead to septic complications and may be associated with fatal outcome. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

1. Women who are pregnant. 6). 7 Effects on ability to drive and use machines Lenalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have been reported with the use of lenalidomide.

Therefore, caution is recommended when driving or operating machines.