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.

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. 2 Incompatibilities Not applicable. 4 Special precautions for storage This medicinal product does not require any special storage conditions.

5 Nature and contents of container OPA/Al/PVC/Al blisters. OPA/Al/PVC/Al calendar blisters. OPA/Al/PVC/Al perforated unit dose blisters. OPA/Al/PVC/Al perforated unit dose calendar blisters. Pack sizes: oPA/Al/PVC/Al blisters: boxes containing 7, 14, 21, 28, 42 hard capsules.

oPA/Al/PVC/Al calendar blisters: boxes containing 7, 14, 21, 28 and 42 capsules in 1, 2, 3, 4 and 6 calendar blisters of 7 hard capsules each. oPA/Al/PVC/Al perforated unit dose blisters :boxes containing 7 x 1, 14 x 1, 21 x 1, 28 x 1 hard capsules.

oPA/Al/PVC/Al perforated unit dose calendar blisters :boxes containing 7 x 1, 14 x 1, 21 x 1, 28 x 1 hard capsules. Not all pack sizes may be marketed. 6 Special precautions for disposal and other handling Capsules should not be opened or crushed.

If powder from lenalidomide makes contact with the skin, the skin should be washed immediately and thoroughly with soap and water. If lenalidomide makes contact with the mucous membranes, they should be thoroughly flushed with water.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7 MARKETING AUTHORISATION HOLDER Sandoz Limited Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR United Kingdom 8 MARKETING AUTHORISATION NUMBER(S) PL 04416/1526 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 31/03/2023 10 DATE OF REVISION OF THE TEXT 19/06/2024

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.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard) or search for MHRA Yellow Card in Google play or Apple App store. 9 Overdose There is no specific experience in the management of lenalidomide overdose in patients, although in dose- ranging studies some patients were exposed to up to 150 mg, and in single-dose studies, some patients were exposed to up to 400 mg.

The dose limiting toxicity in these studies was essentially haematological. In the event of overdose, supportive care is advised. 1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants.

ATC code:

L04AX04. Mechanism of action Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins 1 (Roc1).

In haematopoietic cells, lenalidomide binds to cereblon recruits substrate proteins Aiolos and Ikaros lymphoid transcriptional factors, leading to their ubiquitination and subsequent degradation resulting in direct cytotoxic and immunomodulatory effects.

Specifically, lenalidomide inhibits proliferation and enhances apoptosis of certain haematopoietic tumour cells (including MM plasma tumour cells, follicular lymphoma tumour cells and those with deletions of chromosome 5), enhances T cell- and Natural Killer (NK) cell-mediated immunity and increases the number of NK, T and NK T cells.

In MDS Del (5q), lenalidomide selectively inhibits the abnormal clone by increasing the apoptosis of Del (5q) cells. The combination of lenalidomide and rituximab increases ADCC and direct tumour apoptosis in follicular lymphoma cells.

The lenalidomide mechanism of action also includes additional activities such as anti- angiogenic and pro-erythropoietic properties. , TNF-α and IL 6) by monocytes. Clinical efficacy and safety Lenalidomide efficacy and safety have been evaluated in six phase 3 studies in newly diagnosed multiple myeloma, two phase 3 studies in relapsed refractory multiple myeloma, one phase 3 study and one phase 2 study in myelodysplastic syndromes and one phase 2 study in mantle cell lymphoma and one phase 3 and one phase 3b study in iNHL as described below.

Newly diagnosed multiple myeloma • Lenalidomide maintenance in patients who have undergone ASCT The efficacy and safety of lenalidomide maintenance was assessed in two phase 3 multicentre, randomised, double-blind 2-arm, parallel group, placebo-controlled studies: CALGB 100104 and IFM 2005-02 CALGB 100104 Patients between 18 and 70 years of age with active MM requiring treatment and without prior progression after initial treatment were eligible.

Patients were randomised 1:1 within 90-100 days after ASCT to receive either lenalidomide or placebo maintenance. The maintenance dose was 10 mg once daily on days 1-28 of repeated 28-day cycles (increased up to 15 mg once daily after 3 months in the absence of dose-limiting toxicity), and treatment was continued until disease progression.

The primary efficacy endpoint in the study was progression free survival (PFS) from randomisation to the date of progression or death, whichever occurred first; the study was not powered for the overall survival endpoint. In total 460 patients were randomised: 231 patients to Lenalidomide and 229 patients to placebo.

The […]

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.