NINLARO has received a conditional marketing authorisation in Europe

NINLARO® (ixazomib) in combination with lenalidomide and dexamethasone (NRd) Patient Case Studies
NINLARO has received a conditional marketing authorisation in Europe Prescribing information and adverse event reporting is available on the final 2 slides. Zinc code: UK/IXA/1808/0063a(1) Date of preparation: April 2019

NINLARO (ixazomib) – now recommended by NICE via the CDF1
NINLARO with lenalidomide and dexamethasone is recommended for use within the Cancer Drugs Fund as an option for treating multiple myeloma in adults if they have already had 2 or 3 previous lines of therapy and the conditions of the managed access agreement for NINLARO are followed1 NINLARO is also available to appropriate patients in Wales and Northern Ireland2 CDF, Cancer Drugs Fund; NICE, National Institute for Health and Care Excellence. 1. NICE Final Appraisal Determination – ixazomib for relapsed or refractory multiple myeloma. Issue date: December Available at: (accessed April 2019); 2. New Treatments Fund as found at (accessed April 2019).

NRd patient case studies
Dr Aris Chaidos – 50 year old male Management of diarrhoea and rash Dr Matthew Jenner – 58 year old male Management of thrombocytopenia Dr Sally Moore – 69 year old female Management of diarrhoea, cytopenias, infections Dr Karthik Ramasamy – 69 year old male Management of rash Dr Pratap Neelakantan – 75 year old male Management of neutropenia, rash and mouth ulcers NR, NINLARO-lenalidomide. NRd, NINLARO-lenalidomide-dexamethasone; VGPR, very good partial response.

This patient case was provided by: Dr Aris Chaidos
Consultant Haematologist, Hammersmith Hospital, London, UK Prescribing information is available from your Takeda representative.

Presentation and diagnosis
50 year old male Unremarkable medical history Presented with fatigue and symptomatic anaemia Hb 96 g/L; creatinine 86 µmol/L; Ca 2.1 mmol/L; IgAκ PP 38 g/L; FLC κ: 1840 mg/L; κ:λ ratio 766; β2M 2.1 mg/L; albumin 33 g/L; ISS 2; skeletal survey: no lytic lesions FISH: hyperdiploid only February 2011: diagnosed with IgAκ MM; ISS 2 BMA: 66% plasma cells β2M, beta-2 microglobulin; BMA, bone marrow aspirate; FISH, fluorescent in situ hybridisation; FLC, free light chain; Hb, haemoglobin; IgA, immunoglobulin A; ISS, International Staging System; MM, multiple myeloma.

Induction treatment February 2011: Induction June 2011: SD
September 2011: Second line March 2012: PR CTd ×4 (thalidomide dose up to 200 mg) PP 34 g/L FLC κ: 927 mg/L κ:λ ratio 662 Vd ×8 PP 4 g/L FLC κ: 14.1 mg/L κ:λ ratio 3.46 CTd, cyclophosphamide-thalidomide-dexamethasone; FLC, free light chains; PP, paraprotein; PR, partial response; SD, stable disease; Vd; bortezomib-dexamethasone .

ASCT June 2012: ASCT September 2012: VGPR
Diagnosis SD PR VGPR CTd x4 Vd x8 Mel 200 Melphalan mg/m2 followed by ASCT Trace levels of PP in immunofixation only FLC κ: 6.4 mg/L κ:λ ratio 0.94 BM: PC 3% PP g/L Months from diagnosis ASCT, autologous stem cell transplant; BM, bone marrow; CTd, cyclophosphamide-thalidomide-dexamethasone; FLC, free light chain; Hb, haemoglobin; Mel 200; melphalan 200 mg/m2; PC, plasma cell; PP, paraprotein; PR, partial response; SD, stable disease; Vd, bortezomib-dexamethasone; VGPR, very good partial response.

Treatment at first relapse
PFS post-ASCT: 30 months January 2015: Progression June 2015: First relapse June 2015: Third line January 2016: Second relapse Asymptomatic disease progression in January 2015 with PP 8 g/L PP 14 g/L FLC κ: 340 mg/L κ:λ ratio 9.96 BM: PC 60% Started on CRd PP 16 g/L FLC κ: 405 mg/L κ:λ ratio 37.2 BM:PC 30% ASCT, autologous stem cell transplant; BM, bone marrow; CRd, carfilzomib-lenalidomide-dexamethasone; CTd, cyclophosphamide-thalidomide-dexamethasone; FLC, free light chain; Hb, haemoglobin; PC, plasma cell; PFS, progression free survival; PP, paraprotein; PR, partial response; SD, stable disease; Vd, bortezomib-dexamethasone; VGPR, very good partial response.

Treatment at relapse with CRd
Diagnosis CTd ×4 Vd ×8 PR SD VGPR PP g/L Months from diagnosis PD Mel 200 Relapse CRd ×9 CRd, cyclophosphamide-lenalidomide-dexamethasone; CTd, cyclophosphamide-thalidomide-dexamethasone; Mel 200, melphalan 200 mg/m2; PD, progressive disease; PP. paraprotein; PR, partial response; SD, stable disease; Vd, bortezomib-dexamethasone; VGPR, very good partial response.

Treatment with NINLARO
Third treatment February 2016 Received 24 cycles of NRd* and achieved VGPR July 2016: trace levels of PP (immunofixation); FLC κ: 42.3 mg/L; κ:λ ratio 4.65 September 2016: dexamethasone stopped due to intolerance± Grade 1 diarrhoea (with lenalidomide) and Grade 1 skin rash developed January 2018: trace levels of PP (immunofixation); FLC κ: 72.2 mg/L; FLC λ: 26.6 mg/L; κ:λ ratio 2.71 *Please note this patient accessed NINLARO (ixazomib) via a named patient programme. NINLARO (ixazomib) with lenalidomide and dexamethasone (Rd) is recommended for use within the Cancer Drugs Fund (CDF) as an option for treating multiple myeloma (MM) in adults if they have already had 2 or 3 previous lines of therapy and the conditions of the managed access agreement for ixazomib are followed7 ±This was the clinician’s approach and not that recommended by the NINLARO® (ixazomib) Summary of Product Characteristics. Ca, calcium; Cr, creatinine; Hb, haemoglobin; IgM, immunoglobulin M; NRd, NINLARO-lenalidomide-dexamethasone; K, potassium; PP, paraprotein; VGPR, very good partial response; WCC, white cell count;

Dose modification for AE management*: rash1–3
Gastrointestinal toxicities (Grade 3 or 4)** Rash (Grade 2 or 3) Platelets <30,000/mm3 or Neutrophils <500/mm3 PN (Grade 1 with pain to Grade 3) Withhold… NINLARO Lenalidomide for first occurrence; NINLARO and lenalidomide thereafter NINLARO and lenalidomide Grade ≤1 gastrointestinal toxicities or at patient’s baseline Until… Grade ≤1 rash Platelets ≥30,000/mm3 or Neutrophils ≥500/mm3 Grade ≤1 PN without pain or at patient’s baseline If attributable to ixazomib, resume at the next lower dose Then resume treatment… Resume lenalidomide at the next lower dose† Resume lenalidomide at the next lower dose and resume ixazomib at the most recent dose† For grade 1 with pain or Grade 2 without pain, resume ixazomib at the most recent dose. For Grade 2 with pain or Grade 3, resume ixazomib at the next lower dose Discontinue treatment regimen if the patient experiences Grade 4 rash or PN1 For full dose modification recommendations, please refer to the NINLARO and lenalidomide Summaries of Product Characteristics1,3 *Mid-cycle blood analysis and/or adverse events; **Or other non-haematological toxicities that are not rash or PN; †For additional occurrences, alternate dose modification of lenalidomide and ixazomib. AE, adverse event; PN, peripheral neuropathy. 1. NINLARO (ixazomib capsules) Summary of Product Characteristics. Available at (Accessed August 2018); 2. Moreau P et al. N Engl J Med 2016;374:1621–1634; 3. REVLIMID 25 mg Summary of Product Characteristics. Available at (Accessed August 2018).

Dose modification for AE management*: diarrhoea1–3

AE management Grade 1 rash developed in cycle 1
Maximum 2–3 episodes per day Dose reduction to 15 mg lenalidomide and addition of loperamide diarrhoea resolved Grade 1 skin rash developed Treated with topical steroids and resolved *This was the clinician’s approach and not that recommended by the NINLARO Summary of Product Characteristics GCSF, granulocyte colony-stimulating factor; NRd, NINLARO-lenalidomide-dexamethasone; VTE, venous thromboembolism.

Treatment at relapse with CRd
Diagnosis CTd ×4 Vd ×8 PR SD VGPR PP g/L Months from diagnosis PD Mel 200 Relapse CRd ×9 24× NRd Dex stopped* Len 15 mg Sept 2016 *This was the clinician’s approach and not that recommended by the NINLARO® (ixazomib) Summary of Product Characteristics. CRd, carfilzomib-lenalidomide-dexamethasone; CTd, cyclophosphamide-thalidomide-dexamethasone; Dex, dexamethasone; NRd, NINLARO-lenalidomide-dexamethasone;; Len; lenalidomide; PD, progressive disease; PP, paraprotein; PR, partial response; SD, stable disease; Vd, bortezomib-dexamethasone; VGPR, very good partial response.

Case study: key learnings
NRd is an effective triplet combination regimen, including PI and IMiD NRd is effective in patients with high-risk disease This oral regimen was well-tolerated and is suitable for prolonged treatment Successful treatment relies on effective management of haematological and non- haematological toxicity Appropriate dose modifications should be made to minimise toxicity NRd, NINLARO-lenalidomide-dexamethasone; IMiD, immunomodulatory drug; PI, proteasome inhibitor.

This patient case was provided by: Dr Matthew Jenner
Consultant Haematologist, University Hospital Southampton, Southampton, UK Prescribing information is available from your Takeda representative.

58 year old Presented with fatigue, back pain and vertebral collapse (T11) IgG 31 g/L; Hb 125 g/L; albumin 30 g/L; β2M 2.9 mg/L June 2010: diagnosed with IgG lambda MM ISS 2 BMA: 70% plasma cells β2M, beta-2 microglobulin; BMA, bone marrow aspirate; Hb, haemoglobin; IgG, immunoglobulin G; ISS, International Staging System; MM, multiple myeloma.

Treatment March 2011: Initial treatment January 2012: First relapse
March 2012: Second treatment September 2013: Second relapse CTd ×6  PR ASCT  VGPR Serological progression October 2011: PP 14 g/L Clinical progression January 2012: PP 21 g/L; Hb 120 g/L BMA: 46% FISH: t(4;14) 100%; del(17p) 30%; chr 1 failed Myeloma X trial PAd ×4  PP 4.3 g/L HD melphalan and second ASCT  PP 1.4 g/L PP peak 29 g/L IgG 71.6 g/L; Hb g/L BMA: heavy PC infiltration FISH: t(4;14) 100%; del(17p) 87%; gain 1q21 80% (clonal evolution) ASCT, autologous stem cell transplant; BMA, bone marrow aspirate; chr, chromosome; CTd, cyclophosphamide-thalidomide-dexamethasone; FISH, fluorescent in situ hybridisation; Hb, haemoglobin; HD, high dose; IgG, immunoglobulin G; PAd, bortezomib-doxorubicin-dexamethasone; PC, plasma cell; PP, paraprotein; PR, partial response; VGPR, very good partial response.

Third treatment October 2013 Started NRd on TOURMALINE-MM1 trial Received 26 cycles of NRd Reached PP nadir 9 g/L Experienced decrease in platelets but levels did not fall below 30,000/mm3 NRd, NINLARO-lenalidomide-dexamethasone; PP, paraprotein.

Dose modification for AE management*: thrombocytopenia1–3

IgG lambda paraprotein, blood
Patient bloods IgG lambda paraprotein, blood Thrombocytopenia NRd CTd x6 First ASCT PAd x4 Second ASCT IgG (g/L) Scanned monoclonal component (g/L) NRd g/L Platelets x 109/L ASCT, autologous stem cell transplant; CTd, cyclophosphamide-thalidomide-dexamethasone; IgG, immunoglobulin G; NRd, NINLARO-lenalidomide-dexamethasone; PAd, bortezomib-doxorubicin-dexamethasone.

NRd is generally well tolerated with manageable side effects vs
NRd is generally well tolerated with manageable side effects vs. placebo-Rd AEs after median follow-up of 23 months NRd (n=361), % Placebo-Rd (n=359), % Preferred terms All grades Grade 3 Grade 4 Diarrhoea 45 6 39 3 Constipation 35 <1 26 Nausea 29 2 22 Fatigue 4 28 Vomiting 23 1 12 Rash* 36 5 Back pain 24 17 Upper respiratory tract infection 19 Thrombocytopenia* 31 7 16 Peripheral neuropathies* 27 Peripheral oedema 20 Thromboembolism*¶ 8 11 Neutropenia* 33 18 *Represents multiple MedDRA preferred terms. ¶In addition, grade 5 arrhythmia was reported in two patients in the NINLARO group and in three patients in the placebo group; grade 5 thromboembolism was reported in one patient in each group; grade 5 hypotension was reported in one patient in the NINLARO group; grade 5 heart failure was reported in one patient in the NINLARO group and in three patients in the placebo group; and grade 5 myocardial infarction was reported in one patient in the NINLARO group and in two patients in the placebo group. AE, adverse event; NRd, NINLARO-lenalidomide-dexamethasone; Rd, lenalidomide-dexamethasone. Moreau P et al. N Engl J Med 2016;374:1621–1634.

Key learnings Rationale for continuous treatment, especially in high-risk myeloma Role of FISH in newly diagnosed and relapsed myeloma NINLARO is generally well-tolerated with manageable side effects FISH, fluorescent in situ hybridisation.

This patient case was provided by: Dr Sally Moore
Consultant haematologist, Royal United Hospital Bath, Bath, UK Prescribing information is available from your Takeda representative.

69 year old lady PMH: well controlled asthma FH: breast cancer Presented November 16 with mandibular plasmacytoma with nerve root impingement PET-CT at diagnosis revealed cauda equina at L2–4 Treated with radiotherapy for both November 16: BMT 100% plasma cells; FISH: gain of 1q, t(14;16) IgG lambda paraprotein 33 g/L Hb 76 g/L BMT, bone marrow transplantation; FH, family history; FISH, fluorescent in situ hybridisation; Hb, haemoglobin; IgG, immunoglobulin G; PET-CT, positron emission tomography computed tomography; PP, paraprotein.

Patient bloods Full blood count U&E’s and LFT’s
ALP, alkaline phosphatase; ALT, alanine aminotransferase; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; EPI-CKD, Epidemiology Collaboration chronic kidney disease equation; LFT, liver function test; PO4, phosphate; U&E, urea and electrolytes.

Investigation PET-CT at diagnosis MRI at diagnosis
MRI, magnetic resonance imaging; PET-CT, positron emission tomography.

Treatment Nov 2016: Initial treatment Nov 2017: First relapse
Nov 2017: Second treatment December 2017: Second relapse VTd ×5  VGPR PP: 33 g/L to <1 g/L No side effects June 2017: HDM and stem cell return d=0 Declined d100 post-BM PP: 23 g/L Re-occurrence of jaw pain and new back pain No new cord compromise on MRI Commenced Cd No response Paraprotein rise to 32 g/L following cycle 1 BM, bone marrow; Cd, cyclophosphamide-dexamethasone; HDM, high-dose melphalan; MRI, magnetic resonance imaging; PP, paraprotein; VGPR, very good partial response; VTd, bortezomib-thalidomide-dexamethasone.

Third treatment December 2017 Started NRd Grade 1 rash, Grade 3 thrombocytopenia and Grade 4 neutropenia developed in cycle 1 Grade 1 diarrhoea developed in cycle 2 Ca, calcium; Cr, creatinine; Hb, haemoglobin; IgM, immunoglobulin M; NRd, NINLARO-lenalidomide-dexamethasone; K, potassium; PP, paraprotein; WCC, white cell count;

Dose modification for AE management*: neutropenia/thrombocytopenia1–3

AE management Grade 1 rash, Grade 3 thrombocytopenia and Grade 4 neutropenia developed in cycle 1 Presumed allopurinol for the management of rash; allopurinol was discontinued and rash resolved Twice-weekly supportive GCSF was prescribed for the management of thrombocytopenia and neutropenia* VTE prophylaxis was withheld Diarrhoea developed in cycle 2 Treated with loperamide and resolved Cycle 3: Neutropenia resolved – GCSF stopped. Platelet count improved. Aspirin started as VTE prophylaxis VGPR to NRd (paraprotein from 32g/l to 2g/l) Progressed after 6 cycles *This was the clinician’s approach and not that recommended by the NINLARO Summary of Product Characteristics. VGPR, very good partial response; GCSF, granulocyte colony-stimulating factor; NRd, NINLARO-lenalidomide-dexamethasone; VTE, venous thromboembolism.

Key learnings Baseline cytopenias can improve with successful treatment and disease control. Dose reductions are not always needed. Active management of low blood counts (GCSF) can safely avoid dose reductions Common side effects are often due to supportive medication rather than the regimen itself NRd can successfully exert disease control, even in high risk disease GCSF, granulocyte colony-stimulating factor; NRd, NINLARO-lenalidomide-dexamethasone.

This patient case was provided by: Dr Karthik Ramasamy
Consultant Haematologist, Oxford University Hospitals, Oxford, UK Prescribing information is available from your Takeda representative.

69 year old male Type 2 diabetes mellitus Right and partial left nephrectomy for RCC Presented with fatigue, anaemia and hypercalcemia Raised paraprotein levels June 2013: diagnosed with IgM kappa MM IgM, immunoglobulin M; MM, multiple myeloma; RCC, renal cell carcinoma.

Treatment June 2013: Initial treatment June 2015: First relapse
June 2015: Second treatment February 2016: Second relapse CTd ×5  VGPR HDM followed by ASCT Biochemical rise in PP Hypercalcaemia MM FISH – hyperdiploidy WB MRI showed no EMD VCd ×6  PR Developed posterior circulator stoke leading to visual field loss during cycle 1 Developed grade 2 neuropathy Biochemical rise in PP MM FISH – hyperdiploidy ASCT, autologous stem cell transplant; CTd, cyclophosphamide-thalidomide-dexamethasone; EMD, extramedullary disease; FISH, fluorescent in situ hybridisation; HDM, high-dose melphalan; IgM, immunoglobulin M; MRI, magnetic resonance imaging; PP, paraprotein; PR, partial response; VCd, bortezomib-cyclophosphamide-dexamethasone; VGPR, very good partial response; WB, whole body.

Third treatment April 2016 Started NRd Bloods pre starting treatment: Hb 111 g/L, platelets 177, WCC 3.69, neutrophils 2.82 Urea 6.3, Cr 97, Ca 2.61, IgM 20.27, K 66.34, kappa:lambda ratio 12.24 PP – unable to quantify due to position in beta region (subsequently Hevylite assay is used to help monitor) Rash grade 3 developed in first cycle on day 10 Ca, calcium; Cr, creatinine; Hb, haemoglobin; IgM, immunoglobulin M; NRd, NINLARO-lenalidomide-dexamethasone; K, potassium; PP, paraprotein; WCC, white cell count;

AE management* Rash grade 3 developed in first cycle on day 10
Discontinued all agents until the end of the cycle, rash fully cleared with low-dose dexamethasone continuously Restarted with 5 mg lenalidomide during cycle 2 and increased to 10 mg for cycles 3 and 4 Rash reappeared and lenalidomide cut back to 5 mg URTI grade 2 developed during cycle 8 and 12 2 week temporary discontinuation of NRd temporarily prior to cycle 9 and for a further 6 weeks prior to cycle 13 *This was the clinician’s approach and not that recommended by the NINLARO® (ixazomib) Summary of Product Characteristics. Please note that 4 mg NINLARO is indicated in combination with 25 mg lenalidomide and 40 mg dexamethasone. AE, adverse event; URTI, upper respiratory tract infection.

URTI – Tx discontinuation URTI – Tx discontinuation
Patient bloods URTI – Tx discontinuation NRd started NRd started URTI – Tx discontinuation NRd, NINLARO-lenalidomide-dexamethasone; Tx, treatment.

Special populations: renal impairment
No cardiac, renal, or respiratory safety signals were associated with the use of NINLARO1 No dose adjustment of NINLARO is required for patients with mild or moderate renal impairment (creatinine clearance ≥30 mL/min)2 The reduced dose of 3 mg is recommended in patients with severe renal impairment (creatinine clearance <30 mL/min) or ESRD requiring dialysis2 NINLARO is not dialysable and, therefore, can be administered without regard to the timing of dialysis2 ESRD, end-stage renal disease. 1. Moreau P et al. N Engl J Med 2016;374:1621–1634; 2. NINLARO® (ixazomib capsules) Summary of Product Characteristics. Available at (accessed November 2017).

Key learnings A good partial response is achievable with third-line treatment with NRd NRd is suitable for patients with renal impairment and dose not require dose modification for those with mild to moderate impairment NRd, NINLARO-lenalidomide-dexamethasone.

This patient case was provided by: Dr Pratap Neelakantan
Consultant Haematologist, Royal Berkshire NHS Foundation Trust, Reading, UK Prescribing information is available from your Takeda representative.

75 year old TB ISS 3 No poor risk FISH Paraprotein only on immunofixation; kappa LC 556 Mild anaemia December 2015: diagnosed with plasmacytoma Extensive skeletal disease with C3 infiltration FISH, fluorescent in situ hybridisation; ISS, International Staging System; LC, light chain; TB, tuberculosis; MM, multiple myeloma; RCC, renal cell carcinoma.

Treatment January 2016: Initial treatment February 2016:
Adverse events March 2016: Second treatment June 2016: First relapse Randomised on MM XI trial to KCRd Completed one 28- day cycle End of cycle 1: admitted to the ICU with chest sepsis and respiratory failure secondary to carfilzomib CT: cirrhosis thought to be pre-existing Paraprotein: 4 g/L VCd ×6 Completed 3 cycles Very little response Rib lesions still painful, poor QoL Kappa LC (increased from at presentation) Significant pain and swelling on the left side of the chest PET to evaluate disease CT, computed tomography; ICU, Intensive Care Unit; KCRd, carfilzomib-cyclophosphamide-lenalidomide-dexamethasone; LC, light chain; MM, multiple myeloma; PET, positron emission tomography; QoL, quality of life; VCd, bortezomib-cyclophosphamide-dexamethasone.

PET post-bortezomib treatment
PET investigation PET at diagnosis PET post-bortezomib treatment PET, positron emission tomography.

Third treatment June 2016 Started NRd: NINLARO 4 mg days 1, 8 and 15; lenalidomide 25 mg days 1–21; dexamethasone 20 mg days 1, 8, 15 and 22* Significant clinical improvement in 1 month; left chest pain disappeared Patient developed neutropenia after cycle 1 NRd was continued for 9 cycles and achieved CR Developed extensive rashes and mouth ulcers *This was the clinician’s approach and not that recommended by the NINLARO® (ixazomib) Summary of Product Characteristics. Please note that 4 mg NINLARO is indicated in combination with 25 mg lenalidomide and 40 mg dexamethasone. CR, complete response; NRd, NINLARO-lenalidomide-dexamethasone; SmPC, Summary of Product Characteristics.

PET post-bortezomib treatment
PET investigation PET post-bortezomib treatment PET post-6 cycles of NRd NRd, NINLARO-lenalidomide-dexamethasone; PET, positron emission tomography.

Dose modification for AE management*: neutropenia1–3

AE management* Neutropenia developed during cycle 1
Neutropenia was thought to be lenalidomide related Lenalidomide dose was reduced to 15 mg from cycle 2* Developed extensive rashes and mouth ulcers Attributed to lenalidomide As the patient was in CR all drugs were stopped for 6–8 weeks Chest pain and swelling returned Patient remained in biochemical CR whilst PET showed progressive disease *This was the clinician’s approach and not that recommended by the NINLARO® (ixazomib) Summary of Product Characteristics. Please note that 4 mg NINLARO is indicated in combination with 25 mg lenalidomide and 40 mg dexamethasone. AE, adverse event; CR, complete response; PET, positron emission tomography.

Quality of life maintained with NINLARO + Rd vs
Quality of life maintained with NINLARO + Rd vs. placebo + Rd: EORTC-QLQ-C30 Quality of life was maintained with the addition of NINLRO to a standard Rd regimen NINLARO-Rd placebo-Rd EORTC-QLQ-C30 Mean global health status score placebo-Rd CI, confidence interval; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30 module; EOT, end of treatment; Rd, lenalidomide-dexamethasone; QoL, quality of life. Moreau P et al. N Engl J Med 2016; 374:1621–1634 (Supplementary Appendix).

Key learnings It is possible to keep elderly patients on NRd without significant toxicities Dose reductions may be required to keep patients on continuous therapy This patient had very aggressive disease, even stopping therapy for 8 weeks led to progressive disease NRd, NINLARO-lenalidomide-dexamethasone.

Abbreviated Prescribing Information: NINLARO® (ixazomib)
Presentation: Ixazomib 2.3 mg, 3 mg and 4 mg hard capsules. Indication: NINLARO in combination with lenalidomide and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Dosage & Administration: Treatment must be initiated and monitored under the supervision of a physician experienced in the management of multiple myeloma. NINLARO should be used in combination with lenalidomide and dexamethasone. For additional information regarding lenalidomide and dexamethasone, refer to their SmPCs. The recommended starting dose of NINLARO is 4 mg (one capsule) administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle at least 1 hour before or at least 2 hours after food. The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 to 21 of a 28-day treatment cycle. The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle. Prior to initiating a new cycle of therapy, absolute neutrophil count should be ≥ 1,000/mm3, platelet count should be ≥ 75,000/mm3, non-haematologic toxicities should, at the physician’s discretion, generally be recovered to patient’s baseline condition or ≤ Grade 1. Treatment should be continued until disease progression or unacceptable toxicity. Treatment with NINLARO in combination with lenalidomide and dexamethasone for longer than 24 cycles should be based on an individual benefit risk assessment, as the data on the tolerability and toxicity beyond 24 cycles are limited. Antiviral prophylaxis should be considered in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation. Thromboprophylaxis is recommended in patients being treated with NINLARO in combination with lenalidomide and dexamethasone, and should be based on an assessment of the patient’s underlying risks and clinical status. Elderly: No dose adjustment is necessary in patients over 65 years of age. Renal impairment: Mild or moderate renal impairment, no dose adjustment is necessary. Reduced 3 mg starting dose recommended in severe renal impairment or end-stage renal disease requiring dialysis. Hepatic impairment: Mild hepatic impairment, no dose adjustment is necessary. Reduced 3 mg starting dose recommended in moderate or severe hepatic impairment. Paediatric population: No data are available. Contraindications: Hypersensitivity to the active substance or to its excipients. Warnings & Precautions: Thrombocytopenia: Thrombocytopenia has been reported with NINLARO with platelet nadirs typically occurring between Days of each 28-day cycle and recovery to baseline by the start of the next cycle. Thrombocytopenia did not result in an increase in haemorrhagic events or platelet transfusions. Platelet counts should be monitored at least monthly during NINLARO treatment. Thrombocytopenia can be managed with dose modifications and platelet transfusions as per standard medical guidelines. Gastrointestinal toxicities: Diarrhoea, constipation, nausea and vomiting have been reported with NINLARO, occasionally requiring use of antiemetic and antidiarrhoeal medicinal products and supportive care. The dose should be adjusted for severe (Grade 3–4) symptoms. Peripheral neuropathy: Peripheral neuropathy has been reported with NINLARO. Patients should be monitored for symptoms of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification. Peripheral oedema: Peripheral oedema has been reported with NINLARO. Patients should be evaluated for underlying causes and provide supportive care, as necessary. The dose of dexamethasone should be adjusted per its SmPC or NINLARO for Grade 3 or 4 symptoms. Cutaneous reactions: Rash has been reported with NINLARO. Rash should be managed with supportive care or with dose modification if Grade 2 or higher. Hepatotoxicity: Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have been uncommonly reported with NINLARO. Hepatic enzymes should be monitored regularly and the dose should be adjusted for Grade 3 or 4 symptoms. Pregnancy: Women should avoid becoming pregnant while being treated with NINLARO. Posterior reversible encephalopathy syndrome (PRES): PRES has occurred in patients receiving NINLARO. In patients developing PRES, discontinue NINLARO. Interactions: Strong cytochrome P450 (CYP) 3A inducers: Co-administration of strong CYP3A inducers with NINLARO is not recommended. Strong CYP3A inhibitors: No dose modification is required for NINLARO with co-administration of strong CYP3A inhibitors. Strong CYP1A2 inhibitors: No dose modification is required for NINLARO with co-administration of strong CYP1A2 inhibitors. Fertility, Pregnancy & Lactation: Women should avoid becoming pregnant while being treated with NINLARO. Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following treatment. Women using oral hormonal contraceptives should additionally use a barrier method of contraception. No data from use in pregnant women. Avoid use during pregnancy. Unknown whether NINLARO/metabolites are excreted in human milk, a risk to newborns/infants cannot be excluded; therefore breast feeding should be discontinued. The effect of NINLARO on fertility in humans has not been studied. Undesirable Effects: (All grades) Very common (≥1/10): Upper respiratory tract infection, thrombocytopenia, neutropenia, peripheral neuropathies, diarrhoea, nausea, vomiting, constipation, rash, back pain and oedema peripheral. Common (≥1/100, <1/10): Herpes zoster. Outside of the Phase 3 study, the following serious adverse reactions were rarely (≥ 1/10,000 to < 1/1,000) reported: acute febrile neutrophilic dermatosis, Stevens- Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumour lysis syndrome and thrombotic thrombocytopenic purpura. Refer to the SmPC for details on full side effect profile and interactions. Pharmaceutical Precautions: Do not store above 30°C. Do not freeze. Store in the original package in order to protect from moisture. PI Date of Preparation: Dec 2016 PI approval code: UK/IXA/1611/0096 Legal category: POM Basic NHS Price: £6336 for 3 capsules. Marketing Authorisation: EU/1/16/1094/001, EU/1/16/1094/002, EU/1/16/1094/003 Further information is available from: Takeda UK Ltd. Building 3, Glory Park, Glory Park Avenue, Wooburn Green, Buckinghamshire, HP10 0DF. Tel: Fax: NINLARO® is a registered trademark of Takeda Pharmaceutical Company Limited. NINLARO has received a conditional marketing authorisation in Europe. A conditional marketing authorisation is granted to a medicinal product that fulfils an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact additional data are still required. The European regulatory agency will review new information on NINLARO at least every year and the summary of product characteristics will be updated as necessary.

Adverse Event Reporting
Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Takeda UK Ltd +44 (0)

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NINLARO has received a conditional marketing authorisation in Europe

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