Current treatment options for relapsed/refractory multiple myeloma in practice

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1 Current treatment options for relapsed/refractory multiple myeloma in practice Professor Marίa-Victoria Mateos University Hospital of Salamanca, Salamanca, Spain Please note that discussion throughout this presentation focuses on the experience of the speaker and may not always be relevant to the UK-specific multiple myeloma treatment landscape. This educational meeting was organised and fully funded by Takeda UK Ltd. Takeda medicines were discussed during this meeting. Please see end of presentation for prescribing Information. Zinc code: UK/IXA/1805/0040a Date of preparation: July 2018

2 Disclosures Dr Mateos has received honoraria from participation in lectures and advisory boards from: AbbVie Amgen Celgene Janssen Takeda

3 Content overview Goals for treatment of RRMM patients Treatment pathways in RRMM Due to time limitation, this presentation will focus upon therapies with a Revlimid dexamethasone (Rd) backbone, specifically: (lenalidomide)- KYPROLIS (carfilzomib)-lenalidomide-dexamethasone (KRd) DARZALEX (daratumumab)-lenalidomide-dexamethasone (DRd) NINLARO (ixazomib)-lenalidomide-dexamethasone (NRd) EMPLICITI TM (elotuzumab)-lenalidomide-dexamethasone (ERd) FARYDAK (panobinostat) and IMNOVID (pomalidomide) will also briefly be touched upon Patient factors influencing treatment decision-making and treatment sequencing Resource implications of hospital-administered treatments KRd, carfilzomib-lenalidomide-dexamethasone; DRd, daratumumab-lenalidomide-dexamethasone; NRd, NINLARO-lenalidomide-dexamethasone; ERd, elotuzumab-lenalidomide-dexamethasone; Rd, lenalidomide-dexamethasone; RRMM, relapsed/refractory multiple myeloma.

4 M protein Tumour cell diversity and clonal evolution drive MM relapse ASYMPTOMATIC SYMPTOMATIC 1 Active myeloma Relapse Relapsed refractory Relapse MGUS or smouldering myeloma Remission Time 2 MGUS, monoclonal gammopathy of unknown significance; MM, multiple myeloma. 1. Durie BGM. Concise review of the disease and treatment options. Multiple myeloma, cancer of the bone marrow. International Myeloma Foundation, Available at: (accessed January 2018); 2. Manier S et al. Nat Rev Clin Oncol 2017;14:

5 Increased duration of treatment has been associated with improved disease control and patient outcomes to < Many Phase III trials are investigating treatment until disease progression or unacceptable toxicity with novel triplet regimens in RRMM patients 1 4 DOT in 2LT (months) 5 10 to <11 9 to <10 8 to < Increased DOT demonstrated an OS benefit in RRMM patients, including those treated with PI and/or IMiD based regimens 5 7 to < Percentage increase in 1-year OS relative to DOT in 2LT (%) 2LT, second line-treatment; DOT, duration of treatment; IMiD, immunomodulatory drug; OS, overall survival; PI, proteasome inhibitor; RRMM, relapsed/refractory multiple myeloma; 1. Moreau P et al. N Engl J Med 2016;374: ; 2. Stewart K et al. N Engl J Med 2015;372: ; 3. Lonial S et al. N Engl J Med 2015;373: ; 4. Dimopoulos MA et al. N Engl J Med 2016;375: ; 5. Hari P et al. Clin Lymphoma Myeloma Leuk 2018;18:

6 Treatment intentions derived from evidence from RCTs may not reflect what is possible in real-life practice Clinical trials suggest that patients benefit from treatment at later stages, however, in reality, few patients reach fourth and fifth lines of treatment CI, confidence interval; L, line of therapy; m, months; RCT, randomised clinical trials. Yong K et al. Br J Haematol 2016;175: Understanding the reasons for discontinuation of treatment can provide an insight into patient outcomes and treatment decisions

7 Main objectives for the treatment of RRMM patients Induces deep, long-lasting responses Well-tolerated Minimal impact on patient lifestyle and healthcare resources RRMM, relapsed/refractory multiple myeloma.

8 Factors influencing treatment decision: making the right choice for RRMM patients Type of relapse Efficacy and toxicity of previous therapies Factors to consider Further options RRMM, relapsed/refractory multiple myeloma.

9 Treatment pathways are complex and vary based on individual treatment history 1 Yes Eligible for ASCT No First line Induction (VTd/VCd/PAd/VRd), HD melphalan, ASCT and lenalidomide maintenance First option (VMP/Rd*/VRd*) Second option (MPT/VCd) Other (CTd/MP/bendaP) Prior IMiD-based induction Prior V-based induction Second line Doublets (Kd*/Vd*) or Triplets (DVd/PanoVd/EVd/VCd) Rd* or Triplets (DRd*/KRd*/NRd*/ERd*) Third line Pom+d backbone (+C/V/D/E/N) Daratumumab (mono or combination therapy) Clinical trial This pathway is based on the ESMO guidelines and does not reflect NICE recommendations. Treatment recommendations vary internationally *low-dose dexamethasone. A, doxorubicin; ASCT, autologous stem cell transplant; benda, bendamustine; C, cyclophosphamide; D, daratumumab; d, dexamethasone; Da, attenuated dexamethasone; E, elotuzumab; K, carfilzomib; HD, high-dose; IMiD, immunomodulatory drug; M, melphalan; MM, multiple myeloma; mono, monotherapy; N, NINLARO; P, prednisone; PAd, bortezomib-doxorubicin-dexamethasone; Pano, panobinostat; Pom, pomalidomide; R, lenalidomide; T, thalidomide; V, bortezomib. 1. Moreau P et al. Ann Oncol 2017;28:iv52 iv61.

10 ASPIRE: KRd vs Rd (N=792) Median PFS, mo: 26.3 vs 17.6 [KRd vs Rd] HR: 0.69 (95% CI ; p=0.0001) Median follow-up: 67 months 1 ORR: 87% vs 67%; CR: 32% vs 9% [KRd vs Rd] 1 21% reduction in risk of progression or death with KRd vs Rd 1 Adverse event 2*, % KRd (n=392) Rd (n=389) Treatment discontinuation Median OS, mo: 48.3 vs 40.4 [KRd vs Rd] HR: 0.79 (95% CI ; p=0.0045) Serious AEs Grade 3 AEs Grade 3 4 AEs of specific interest Dyspnoea Acute renal failure Cardiac failure Ischaemic heart disease Hypertension Fatal AEs *At median follow-up 32.3 months in study population. AE, adverse event; CI, confidence interval; CR, complete resonse; HR, hazard ratio; KRd, carfilzomib-lenalidomide-dexamethasone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide-dexamethasone. 1. Stewart K et al. Blood 2017;130:743; 2. Stewart K et al. N Engl J Med 2015;372:

11 ELOQUENT-2: ERd vs Rd (N=646) Median PFS, mo: 19.4 vs 14.9 [ERd vs Rd]* HR: 0.71 (95% CI ; p=0.0004) Median follow-up: 46 months2 29% reduction in the risk of progression or death for ERd vs Rd1 50% reduction in the PFS rate at 4 years (21% vs 14%) in favour of ERd1 Adverse event3, % ERd (n=321) Rd (n=325) Treatment discontinuation Serious AEs Neutropenia Lymphocytopenia Cardiac disorders 4 6 Renal disorders 4 4 Fatal AEs 2 2 Grade 3 4 AEs of special interest Median OS, mo: 48.3 vs 39.6 [ERd vs Rd] HR: 0.78 (95% CI ) *All randomised patients; Data cut-off Oct 18, 2016; At median follow-up 24.5 months. CI, confidence interval; ERd, elotuzumab-lenalidomide-dexamethasone; HR, hazard ratio; NR, not reported; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide-dexamethasone; SPM, secondary primary malignancy. 1. Lonial S et al. J Clin Oncol 2017;35:8028; 2. Dimopoulos MA et al. Haematologica 2017;102:167; 3. Lonial S et al. N Engl J Med 2015;373:

12 Probability of PFS TOURMALINE-MM1: NRd vs placebo-rd (N=722) Median PFS, mo: 20.6 vs 14.7 [NRd vs Rd] HR: 0.74 (95% CI ; p=0.01) Adverse event, % NRd (n=361) Placebo-Rd (n=359) Treatment discontinuation Serious AEs Grade 3 AE Grade 3 4 AEs of special interest Thrombocytopenia NRd Placebo-Rd Number of events: NRd 129; placebo-rd Time from randomisation (months) Median follow-up: 15 months 26% relative reduction in the risk of progression or death with NRd vs Rd ORR: 78% vs 72%; CR: 12% vs 7% [NRd vs Rd] Peripheral neuropathy 2 2 Hypertension 3 1 Heart failure <3 <2 Myocardial infarction <1 <2 Acute renal failure <3 4 AE, adverse event; CR, complete response; CI, confidence interval; HR, hazard ratio; NRd, NINLARO-lenalidomide-dexamethasone; ORR, overall response rate; PFS, progression-free survival; Rd, lenalidomidedexamethasone. Moreau P et al. N Engl J Med 2016;374:

13 POLLUX: DRd vs Rd (N=569) Median PFS, mo: NR vs 17.5 [DRd vs Rd]* HR: 0.41 (95% CI ; p<0.0001) Adverse event 2 *, % DRd (n=286) Rd (n=283) Treatment discontinuations Serious AEs Grade 3 4 AEs of special interest Neutropenia Thrombocytopenia Infection Pneumonia Diarrhoea Fatigue Nausea Deep vein thrombosis Median follow-up: 32.9 months 1 56% reduction in risk of progression or death for DRd vs Rd 1 ORR: 93% vs 76%; CR: 55% vs 23% [DRd vs Rd] 1 *At median follow-up 13.5 months., any grade. CI, confidence interval; CR, complete response; DRd, daratumumab-lenalidomide-dexamethasone; HR, hazard ratio; NR, not reached; ORR, overall response rate; PFS, progression-free survival; Rd, lenalidomide-dexamethasone. 1. Dimopoulos MA et al. Blood 2017;130;739; 2. Dimopoulos MA et al. N Engl J Med 2016;375:

14 Treatment pathways are complex and vary based on individual treatment history 1 Yes Eligible for ASCT No First line Induction (VTd/VCd/PAd/VRd), HD melphalan, ASCT and lenalidomide maintenance First option (VMP/Rd*/VRd*) Second option (MPT/VCd) Other (CTd/MP/bendaP) Prior IMiD-based induction Prior V-based induction Second line Doublets (Kd*/Vd*) or Triplets (DVd/PanoVd/EVd/VCd) Rd* or Triplets (DRd*/KRd*/NRd*/ERd*) Third line Pom+d backbone (+C/V/D/E/N) Daratumumab (mono or combination therapy) Clinical trial This pathway is based on the ESMO guidelines and does not reflect NICE recommendations. Treatment recommendations vary internationally *low-dose dexamethasone. A, doxorubicin; ASCT, autologous stem cell transplant; benda, bendamustine; C, cyclophosphamide; D, daratumumab; d, dexamethasone; Da, attenuated dexamethasone; E, elotuzumab; K, carfilzomib; HD, high-dose; IMiD, immunomodulatory drug; M, melphalan; MM, multiple myeloma; mono, monotherapy; N, NINLARO; P, prednisone; PAd, bortezomib-doxorubicin-dexamethasone; Pano, panobinostat; Pom, pomalidomide; R, lenalidomide; T, thalidomide; V, bortezomib. 1. Moreau P et al. Ann Oncol 2017;28:iv52 iv61.

15 Patient-based factors are highly influential in treatment decisionmaking Frailty Disease morbidity Risk assessment Treatment history Lifestyle Age Refractory disease ISS Previous therapies Patient preference Performance status Renal impairment Cytogenetics Travel / infusion time Disability Bone disease Comorbidities Quality of life ISS, International Staging System. Clegg A et al. Lancet 2013;381: ; Handforth C et al. Ann Oncol 2015;26: ; Chen X et al. Clin Interv Aging 2014;9: ; Palumbo A et al. Blood 2015;125: ; Jhaveri D et al. Haematologica 2016;101(S1):1 881 (Abstract E1312); Sonneveld P et al. Leukemia 2013;27: ; Faiman BM et al. Clin J Oncol Nurs 2011;15 Suppl:66 76; Miceli TS et al. Clin J Oncol Nurs 2011;15:9 23; Greipp PR et al. J Clin Oncol 2005;23: ; Binder M et al. Haematologica 2016;101(S1):P665; Merz M et al. Haematologica 2016;101(S1):P650; Chng WJ et al. Leukemia 2016;30: ; Chung TH et al. PLoS One 2013;20:e66361; Ramsenthaler C et al. BMC Cancer 2016;16:427; Williams LA et al. J Clin Oncol 2016;34:e18127; Tatarczuch M, Ramasamy K et al. Haematologica 2017;102(S2):E1457.

16 Treatment sequencing Type of relapse Indolent/biochemical relapse vs aggressive relapse All combinations are feasible in both situations Patient age All combinations are effective and well tolerated by elderly patients Number and type of prior lines All studies were conducted in lenalidomide-naïve or sensitive patients and we are now seeing more lenalidomide-refractory patients Professor Mateos personal opinion.

17 ASPIRE: PFS by prior lines of therapy 1 previous line of therapy 2 previous lines of therapy Please note Rd is only reimbursed in the UK in patients who have received two or more prior lines of therapy KRd (n=184) Rd (n=157) Progression/death, n (%) 91 (49.5) 88 (56.1) Median PFS, months % CI, months HR (95% CI) ( ) p-value KRd (n=212) Rd (n=239) Progression/death, n (%) 116 (54.7) 136 (56.9) Median PFS, months % CI, months HR (95% CI) ( ) p-value CI, confidence interval; HR, hazard ratio; KRd, carfilzomib with lenalidomide and dexamethasone; PFS, progression-free survival; Rd, lenalidomide and dexamethasone. Dimopoulos MA, et al. Blood Cancer Journal 2017;7:e554.

18 TOURMALINE-MM1: PFS by prior lines of therapy 1 previous line of therapy 2 3 previous lines of therapy Please note Rd is only reimbursed in the UK in patients who have received two or more prior lines of therapy NRd (n=213) Rd (n=212) NRd (n=149) Rd (n=148) Median PFS, months HR (95% CI) ( ) p-value Median PFS, months NE 12.9 HR (95% CI) ( ) p-value CI, confidence interval; HR, hazard ratio; NE, not estimable; NRd, NINLARO-lenalidomide-dexamethasone; PFS, progression-free survival; Rd, lenalidomide-dexamethasone. Mateos MV et al. Haematologica 2017;102:

19 POLLUX: PFS by prior lines of therapy DRd improved PFS vs Rd regardless of the number of prior lines of therapy Median PFS, mo: NR vs 19.6 [DRd vs Rd] HR: 0.41 (95% CI ; p<0.0001) Median PFS, mo: NR vs 11.9 [DRd vs Rd] HR: 0.38 (95% CI ; p<0.0001) Please note Rd is only reimbursed in the UK in patients who have received two or more prior lines of therapy Median PFS, mo: 29.3 vs 19.5 [DRd vs Rd] HR: 0.47 (95% CI ; p<0.0001) Median PFS, mo: NR vs 17.5 [DRd vs Rd] HR: 0.42 (95% CI ; p<0.0001) CI, confidence interval; DRd, daratumumab-lenalidomide-dexamethasone; HR, hazard ratio; Rd, lenalidomide-dexamethasone. Moreau P et al. Blood 2017;130:1883.

20 Treatment sequencing Type of relapse Indolent/biochemical relapse vs aggressive relapse All combinations are feasible in both situations Patient age All combinations are effective and well tolerated by elderly patients Number and type of prior lines All studies were conducted in lenalidomide-naïve or sensitive patients and we are seeing now more patients lenalidomide-refractory Cytogenetic abnormalities Combination of PIs and IMiDs is the optimal choice IMiD, immunomodulatory drug; PI, proteasome inhibitor. Professor Mateos personal opinion.

21 ASPIRE: PFS by cytogenetic risk status at baseline High-risk* Standard-risk KRd (n=48) Rd (n=52) Median PFS, months HR (95% CI) 0.70 ( ) KRd (n=147) Rd (n=170) Median PFS, months HR (95% CI) 0.66 ( ) *High-risk as defined by IMWG criteria. CI, confidence interval; HR, hazard ratio; IMWG, International Myeloma Working Group; KRd, carfilzomib-lenalidomide-dexamethasone; PFS, progression-free survival; Rd, lenalidomide-dexamethasone. Avet-Loiseau H, et al. Blood 2016;128:

22 TOURMALINE-MM1: NRd extends PFS irrespective of the patients cytogenetic risk profiles Patients with del(17p) alone or in combination with t(4;14) and/or t(14;16) Median PFS, mo: 21.4 vs 9.7 [NRd vs Rd] HR: (95% CI ; p=0.162) High-risk* Standard-risk Patients with t(4;14) alone High-risk (n=137) NRd (n=75) Placebo-Rd (n=62) Standard-risk (n=415) NRd (n=199) Placebo-Rd (n=216) Number of events Median PFS, mos HR (95% CI) ( ) ( ) p-value Median PFS, mo: 18.5 vs 12.0 [NRd vs Rd] HR: (95% CI ; p=0.3553) *High-risk as defined by IMWG criteria. CI, confidence interval; HR, hazard ratio; IMWG, International Myeloma Working Group;NRd, NINLARO-lenalidomide-dexamethasone; PFS, progression-free survival; Rd, lenalidomide-dexamethasone. Richardson P et al. J Clin Oncol 2016;34:8018.

23 Treatment sequencing Type of relapse Indolent/biochemical relapse vs aggressive relapse All combinations are feasible in both situations Patient age All combinations are effective and well tolerated by elderly patients Number and type of prior lines All studies were conducted in lenalidomide-naïve or sensitive patients and we are now seeing more patients who are lenalidomide-refractory Cytogenetic abnormalities Combination of PIs and IMiDs is the optimal choice Toxicity profile/comorbidities Renal impairment: carfilzomib/ixazomib/elotuzumab/daratumumab and lenalidomide can be used Consider variable adverse events with combination therapies: cardiovascular toxicity/severe COPD/skin sensitivity etc. Patient preferences/lifestyle/visits to the hospital COPD, chronic obstructive pulmonary disease; IMiD, immunomodulatory drug; PI, proteasome inhibitor. Professor Mateos personal opinion.

24 Administration of combination treatments can have lifestyle implications for patients Minimum number of planned hospital visits required for administration/collection of MM treatments over 18 cycles 1 5 * *Patients are treated until progression or unacceptable toxicity. Calculation excludes visits for monitoring. Standard carfilzomib (IV) regimen is 18 cycles; number of administrations of carfilzomib per cycle: cycle 1-12 = 6 doses (2 consecutive doses each week for 3 weeks), cycle = 4 doses (2 consecutive doses during 1 st and 3 rd week). Treatment with carfilzomib + Rd for longer than 18 cycles should be based on an individual benefit-risk assessment, as the data on the tolerability and toxicity of carfilzomib beyond 18 cycles are limited; 2 4 Daratumumab is administered (IV) in, weekly for the first 8 weeks, then once every two weeks throughout weeks 9 24, followed by every 4 weeks from week 25 until disease progression or unacceptable toxicity. Calculation: 18 x 4 =72 weeks in 18 cycles. (1 x 8) + (1 x 16/2) + (1 x 64/2) = 28 doses. 5 MM, multiple myeloma; Rd, lenalidomide-dexamethasone. 1. NINLARO Summary of Product Characteristics; 2. REVLIMID 25 mg Summary of Product Characteristics. 3. Dexamethasone 2 mg Tablets Summary of Product Characteristics; 4. KYPROLIS Summary of Product Characteristics; 5. DARZALEX Summary of Product Characteristics.

25 There are significant resource implications of hospital-administered treatments University Hospital of Salamanca Median time from check-in to administration 63 minutes Median travel time 120 minutes Median travel distance 100 km Patients requiring hospital transport 40% Professor Mateos personal opinion.

26 Experience with treatment regimens can enhance practical guidance and management recommendations Experience in routine clinical practice can identify practical challenges which are not present in the trial setting, thereby helping to optimise treatment in real-world practice Practical learnings from experience with NRd include: Can also be used following indolent or biochemical relapses Use at 1 st relapse in elderly after bortezomib-based combinations Use at 2 nd and 3 rd relapses in patients who received ASCT in the first line The extension of PFS irrespective of cytogenetic profile Opportunities for patients who want to maintain their regular activity Options for patients who do not want to or cannot come to the hospital every week When patients are asked for their preference they usually prefer the oral administration Please note NINLARO is only reimbursed in second and third relapse setting in the UK ASCT, autologous stem cell transplant; PFS, progression-free survival; NRd, NINLARO-lenalidomide-dexamethasone. Professor Mateos personal experience.

27 Conclusions New combinations are emerging for the treatment of RRMM patients In clinical practice, choosing the optimal combination for each patient is a challenge Treatment choice at relapse is influenced by previous lines of therapy and first-line treatments have evolved over the last few years Efficacy together with safety, convenience, QoL etc. have to be considered and discussed with each patient before selecting the combination to use at relapse Opportunities exist to give triplet therapies, including a PI and an IMiD, to progression without increasing the hospital resource burden IMiD, immunomodulatory drug; PI, proteasome inhibitor; QoL, quality of life; RRMM, relapsed/refractory multiple myeloma.

28 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. Please refer to the Summary of Product Characteristics for details on the full side-effect profile and drug interactions of Ninlaro. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Takeda UK Ltd. Tel: