The TOURMALINE-MM1 study: results and expert insights

Transcription

1 The TOURMALINE-MM1 study: results and expert insights Professor Faith Davies UAMS Myeloma Institute, Arkansas, USA This educational meeting was organised and fully funded by Takeda UK Ltd. Takeda medicines were discussed during this meeting. Prescribing Information is available on final slide The views expressed during this presentation are those of the speaker Zinc code: UK/IXA/1711/0062a. Date of preparation: December 2017

2 TOURMALINE-MM1 study design 1 Phase III global, double-blind, randomised, placebo-controlled study design 1 Primary endpoint: PFS Key secondary endpoints: OS OS in patients with del(17p) Response and progression (IMWG 2011 criteria 2 ) assessed by an IRC blinded to both treatment and investigator assessment Stratification: Prior therapy: 1 vs. 2 or 3 ISS: I or II vs. III Prior PI exposure: yes vs. no *10 mg for patients with creatinine clearance 60 or 50 ml/min, depending on local label/practice. IMWG, International Myeloma Working Group; IRC, independent review committee; ISS, International Staging System; OS, overall survival; PFS, progression-free survival; PI, proteasome inhibitor; RRMM, relapsed/refractory multiple myeloma. 1. Moreau P et al. N Engl J Med 2016;374: ; 2. Rajkumar S et al. Blood 2011;117:

3 Patient eligibility criteria Key inclusion criteria: Confirmed diagnosis of MM Measurable disease by at least one of: Serum protein electrophoresis Urine protein electrophoresis Free light chain assay Received 1 3 prior treatments Relapsed, relapsed and refractory, or primary refractory disease* Creatinine clearance 30 ml/min Key exclusion criteria: Refractory to previous PI-based or lenalidomide-based treatment *Including primary refractory patients (i.e., patients refractory to all prior therapies). Refractory = PD on treatment or within 60 days after last dose of therapy. MM, multiple myeloma; PD, progressive disease; PI, proteasome inhibitor. Moreau P et al. N Engl J Med 2016;374:

4 722 patients enrolled at 147 study centres in 26 countries Demographics Ixazomib-Rd (n=360) Placebo-Rd (n=362) Median age, years Gender, male/female, % 58/42 56/44 Number of prior lines of therapy, % 1* or 3* Prior PI*, % Prior IMiD, % Prior stem cell transplant, % Relapsed, % Refractory, % Relapsed and refractory, % High-risk cytogenetics, % ISS stage I or II*, % ISS stage III*, % Creatinine clearance <60 ml/min *Stratification factor; High-risk cytogenetic abnormalities were detected by fluorescence in situ hybridization (FISH) analysis and were defined as patients with del(17), t(4;14) or t(14;16). IgA, immunoglobulin A; IgG, immunoglobulin G; IMiD, immunomodulatory drug; ISS, International Staging System; PI, proteasome inhibitor; Rd, lenalidomide-dexamethasone. Moreau P et al. N Engl J Med 2016;374:

5 TOURMALINE-MM1: Clinical efficacy

6 First interim analysis: median follow-up of ~15 months Significant 35% improvement was seen in median PFS * with ixazomib-rd vs. placebo-rd Median PFS (primary endpoint): Ixazomib-Rd: 20.6 months Placebo-Rd: 14.7 months Probability of PFS Number of patients at risk: Ixazomib-Rd Placebo-Rd Median follow-up: ~15 months Log-rank test p=0.01 Hazard ratio (95% CI): 0.74 (0.59; 0.94) Number of events: ixazomib-rd 129; placebo-rd 157 Time from randomisation (months) *At first and final PFS analysis. Any subsequent interim analysis of PFS is non-inferential. CI, confidence interval; PFS, progression-free survival; Rd, lenalidomide-dexamethasone. Moreau P et al. N Engl J Med 2016;374:

7 First interim analysis: median follow-up of ~15 months Ixazomib-Rd extends PFS across a broad group of patients vs. placebo-rd 1,2 n Median PFS (months) Variable * Subgroup Ixazomib-Rd Placebo-Rd Ixazomib-Rd Placebo-Rd HR TOURMALINE-MM1 was not powered to assess efficacy in any specific subgroups, and as multiple myeloma 65 is 168 a heterogeneous disease, 14.1 benefit may vary across > subgroups1,2 > All patients ALL Age (years) ISS stage Cytogenetic risk I or II III Standard-risk High-risk Number of prior therapies 1 2 or NE Proteasome inhibitor Exposed Naive NE Prior IMiD therapy Exposed Naive NE Refractory to last prior therapy Yes No NE 20.6 NE Relapsed or refractory Relapsed Refractory Relapsed & Refractory NE NE Baseline CrCl group <50 ml/min 50 ml/min Figure adapted from Moreau P et al and NINLARO Summary of Product Characteristics 2. *TOURMALINE-MM1 was not powered to assess efficacy in any specific subgroups Favours ixazomib-rd Favours placebo-rd CrCL, creatinine clearance; HR, hazard ratio; IMiD, immunomodulatory drug; ISS, International Staging System; NE, not estimable; PFS, progression-free survival; Rd, lenalidomide-dexamethasone. 1. Moreau P et al. N Engl J Med 2016;374: ; 2. NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017.

8 PFS is prolonged with ixazomib-rd vs. placebo-rd regardless of prior therapies Previous therapy Subgroup Median PFS, months Ixazomib-Rd Placebo-Rd HR 95% CI Prior PI Prior bortezomib Prior IMiD Prior lenalidomide Prior therapies Exposed (n=503) ( ) Naïve (n=219) NE ( ) Exposed (n=498) ( ) Naïve (n=224) NE ( ) Exposed (n=397) NE ( ) Naïve (n=325) ( ) Exposed (n=88) NE ( ) Naïve (n=634) ( ) 1 (n=425) ( ) 2 or 3 (n=297) NE ( ) CI, confidence interval; HR, hazard ratio; IMiD, immunomodulatory drugs; NE, not estimable; PFS, progression-free survival; PI, proteasome inhibitor; Rd, lenalidomide-dexamethasone. Mateos MV et al. Haematologica 2017; pii: haematol [E-pub ahead of print].

9 Efficacy in IA1 and IA2 in patients who have received 2 or 3 prior lines of therapy 1,2 First interim analysis Ixazomib-Rd (n=361), % Placebo-Rd (n=359), % Median PFS, months NE 12.9 Median OS, months NE NE Second interim analysis Median PFS, months Median OS, months NE NE HR (95% CI) 0.58 ( ) 0.62 ( ) 0.62 ( ) 0.65 ( ) CI, confidence interval; HR, hazard ratio; IA1, first interim analysis; IA2, second interim analysis; NE, not estimable; OS, overall survival; PFS progression free survival. 1. Takeda data on file - UK/DF/1710/0016; 2. Mateos MV et al. Haematologica 2017; pii: haematol [E-pub ahead of print].

10 Ixazomib-Rd significantly improves PFS vs. placebo-rd in patients who have received 2 or 3 prior lines of therapy *1,2 Primary PFS analysis (IA1) 15 months follow-up OS analysis (IA2) 23 months follow-up Ixazomib-Rd Placebo-Rd Ixazomib-Rd Placebo-Rd HR: 0.58 (95% CI 0.40, 0.84; p=0.0033) HR: 0.65 (95% CI 0.41, 1.02; p=0.0569) *The number of prior therapies (1 vs. 2 or 3) was a pre-specified subgroup and stratification factor in the TOURMALINE-MM1 trial. 3 CI, confidence interval; HR, hazard ratio; IA1, first interim analysis; IA2, second interim analysis; OS, overall survival; PFS progression free survival; Rd, lenalidomide-dexamethasone. 1. Takeda data on file - UK/DF/17010/0015; 2. Mateos MV et al. Haematologica 2017; pii: haematol [E-pub ahead of print]; 3. Moreau P et al. N Engl J Med 2016;374:

11 First interim analysis: median follow-up of ~15 months Ixazomib-Rd maintains PFS in patients with high-risk cytogenetics, including those with del(17p) 1,2 Median PFS, months All patients (N=722) Ixazomib-Rd Placebo-Rd 15.6 Standard-risk patients All high-risk patients Patients with del(17p) (n=415) (n=137) (n=69) Figure modified from Avet-Loiseau et al. 2 *p<0.05 for comparison between regimens. Alone or in combination with t(4;14) or t(14;16). Data not included on patients with t(14:16) alone due to small numbers (n=7). HR, hazard ratio; PFS, progression-free survival; Rd, lenalidomide-dexamethasone. 1. Moreau P et al. N Engl J Med 2016;374: ; 2. Avet-Loiseau H et al. European Hematology Association 22 nd Congress 2016; Poster P269. HR All patients * Standard-risk patients 0.640* All high-risk patients * Patients with del(17p) TOURMALINE-MM1 was not powered to assess efficacy in any specific subgroups

12 First interim analysis: median follow-up of ~15 months Improved response rates, TTP, and durable responses are seen with ixazomib-rd vs. placebo-rd Response rates Ixazomib-Rd (n=360) Placebo-Rd (n=362) p value Confirmed ORR, % p=0.04 VGPR,* % p=0.01 CR, % 12 7 p=0.02 PR, % VGPR,* % Median time to response, months p=0.009 Median duration of response ( PR), months Median time to disease progression, months p=0.007 *VGPR is a subset of PR. CR, complete response; ORR, overall response rate; PR, partial response; Rd, lenalidomide-dexamethasone; TTP, time to progression; VGPR, very good partial response. Moreau P et al. N Engl J Med 2016;374:

13 Responses deepened with continued ixazomib-rd treatment *The duration of one cycle of ixazomib-rd is 28 days. CR, complete response; PR, partial response; Rd, lenalidomide-dexamethasone; VGPR, very good partial response. Adapted from Moreau P et al. N Engl J Med 2016;374:

14 A later response to therapy is not detrimental to overall outcomes Outcomes for patients in the TOURMALINE-MM1 study who achieved an early (0 4 month) or late (>4 month) response to therapy* ( PR) were compared. Outcomes Median number treatment cycles Ixazomib-Rd Early (0 4 mos) n=174 Late (>4 mos) n=109 Early (0 4 mos) n=159 Placebo-Rd Late (>4 mos) n= Median PFS **, mos 18.5 NE 14.9 NE 50 5 Median DOR in PR pts, mos n=173 n=108 n=156 n= NE Premature discontinuation of therapy due to slow response should be avoided. Responding patients should stay on therapy until progressive disease or unacceptable toxicity. *Response was assessed every cycle based on central laboratory results and by IRC evaluation using IMWG criteria; **In patients with IRC-assessed best confirmed response; Analysed to address the possibility of guarantee-time bias. DOR, duration of response; mos, months; IMWG, International Myeloma Working Group; IRC, independent review committee; IRd, ixazomib-lenalidomide-dexamethasone; NE, not estimable; PFS, progression-free survival; PR, partial response; Rd, lenalidomide-dexamethasone. Garderet L et al. Blood 2016;128. Abstract 2134.

15 Second interim analysis: median follow-up of 23 months At 23 months follow-up, median OS had not yet been reached 1,2 Following achievement of the primary endpoint (PFS), a subsequent pre-specified interim analysis for OS was conducted deaths (only 35% of the required number of deaths for final OS analysis): 81 and 90 in the ixazomib and placebo regimens, respectively The median OS was not reached in either arm At the same time point, a non-inferential analysis of PFS was conducted 2 HR was 0.82 (95% CI: ) Median PFS was 20 months in the ixazomib regimen and 15.9 months in the placebo regimen CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. 1. Moreau P et al. N Engl J Med 2016;374: ; 2. NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017.

16 A continuation study of TOURMALINE-MM1 in China The China continuation study is a randomised, double-blind, placebocontrolled study conducted in China (n=115), with a similar study design and eligibility criteria as the TOURMALINE-MM1 study. This study evaluated the safety and efficacy of ixazomib-rd vs. placebo- Rd in adult RRMM patients from China Demographics Ixazomib-Rd (n=57) Placebo-Rd (n=58) Median age, years Gender, male/female, % 72/28 66/34 Number of prior lines of therapy, % or Prior PI, % Prior IMiD, % Prior stem cell transplant, % Relapsed *, % Refractory, % Relapsed and refractory, % High-risk cytogenetics, % NR NR ISS stage I or II, % ISS stage III, % 9 7 Creatinine clearance <60 ml/min 7 16 *Patients who had relapsed from at least one previous treatment but were not refractory to any previous treatment; Patients who were refractory to at least one previous treatment but were not relapsed to any previous treatment; Patients who were relapsed from at least one previous treatment and additionally were refractory to at least one previous treatment. Refractory disease was defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy; Cytogenetics information was not available for the majority of patients and was thus not reported. OS, overall survival; PFS, progression-free survival; Rd, lenalidomide-dexamethasone; RRMM, relapsed/refractory multiple myeloma. Hou J et al. J Haematol Oncol 2017; doi: /s

17 A continuation study of TOURMALINE-MM1 in China showed improved OS in patients treated with ixazomib-rd vs. placebo-rd PFS and OS rates with ixazomib-rd were superior to those achieved with placebo-rd in Chinese patients with RRMM The OS benefit was consistent across subgroups defined by age, disease status and prior therapy exposure CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide-dexamethasone; RRMM, relapsed/refractory multiple myeloma.

18 Efficacy summary Ixazomib when combined with Rd (an all-oral triplet regimen) was associated with: A significant and clinically meaningful improvement in PFS vs. placebo-rd months vs months, respectively; HR: 0.74; p=0.01 Similar median PFS in both high- and standard-risk cytogenetics patients 1, months vs months, respectively Significantly improved PFS vs. placebo-rd in patients who have received 2 or 3 prior lines of therapy 3 NE vs months, respectively; HR: 0.58 Responses deepened with continued ixazomib-rd treatment 1 A later response was not detrimental to overall outcome 5 Significantly improved OS vs. placebo-rd in a Chinese continuation study months vs months, respectively; HR: 0.42; p=0.001 HR, hazard ratio; NE, not estimable; PFS, progression-free survival; Rd, lenalidomide-dexamethasone; TTP, time to progression. 1. Moreau P et al. N Engl J Med 2016;374: ; 2. Avet-Loiseau H et al. European Hematology Association 22 nd Congress 2016; Poster P269.; 3. Mateos MV et al. Haematologica 2017; pii: haematol [E-pub ahead of print]; 4.Garderet L et al. Blood 2016;128. Abstract 2134; 5. Hou J et al. J Haematol Oncol 2017; doi: /s

19 TOURMALINE-MM1: Safety

20 Summary of treatment exposure and treatment-emergent adverse events Median follow-up: 23.3 months for ixazomib-rd and 22.9 months for placebo-rd Median number of treatment cycles: 17 (range 1 34) for ixazomib-rd, and 15 (1 34) for placebo-rd 48% and 43% of patients received 18 cycles in the ixazomib and placebo groups, respectively 20% and 19% of patients received 25 cycles in the ixazomib and placebo groups, respectively Adverse event (AE) Ixazomib-Rd (n=361), % Placebo-Rd (n=359), % Any AE Any grade 3 AE Any serious AE AE resulting in discontinuation of study regimen * On-study death (death within 30 days of last dose) 4 6 Higher frequency of grade 3 AEs, primarily due to thrombocytopenia Rates of AEs resulting in discontinuation or on-study death were similar between the two arms *Discontinuation of the study regimen was defined as discontinuation of the full study regimen and included discontinuation because of disease progression. AE, adverse event; Rd, lenalidomide-dexamethasone. Moreau P et al. N Engl J Med 2016;374:

21 Ixazomib-Rd was generally well tolerated with manageable side effects AEs after median follow-up of 23 months Ixazomib-Rd (n=361), % Placebo-Rd (n=359), % Preferred terms All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 Diarrhoea Constipation 35 < <1 0 Nausea Fatigue Vomiting <1 0 Rash* Back pain 24 < Upper respiratory tract infection 23 < <1 0 Thrombocytopenia * Peripheral neuropathies* Peripheral oedema Thromboembolism* 8 2 < <1 Neutropenia* *Represents multiple MedDRA preferred terms. In addition, grade 5 arrhythmia was reported in two patients in the ixazomib 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 ixazomib group; grade 5 heart failure was reported in one patient in the ixazomib group and in three patients in the placebo group; and grade 5 myocardial infarction was reported in one patient in the ixazomib group and in two patients in the placebo group. AE, adverse event; Rd, lenalidomide-dexamethasone. Moreau P et al. N Engl J Med 2016;374:

22 Other infrequent adverse events: no safety concerns identified Median follow-up of 23 months Ixazomib-Rd (n=361), % Placebo-Rd (n=359), % Preferred terms All grades All grades Arrhythmias* Hypertension 6 5 Hypertensive crisis <1 0 Hypotension* 6 6 Heart failure* 4 4 Myocardial infarction* 1 2 Acute renal failure* 9 11 Liver impairment* 7 6 Interstitial lung disease* 1 2 Encephalopathy* <1 1 Events of special interest New primary malignancy*, 5 4 *Represents multiple MedDRA preferred terms; Includes treatment-emergent AEs and new primary malignancies reported during follow-up period; In addition, grade 5 arrhythmia was reported in two patients in the ixazomib 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 ixazomib group; grade 5 heart failure was reported in one patient in the ixazomib group and in three patients in the placebo group; and grade 5 myocardial infarction was reported in one patient in the ixazomib group and in two patients in the placebo group. Rd, lenalidomide-dexamethasone. Moreau P et al. N Engl J Med 2016;374:

23 Quality of life maintained with ixazomib-rd vs. placebo-rd: EORTC-QLQ-C30 Quality of life was maintained with the addition of ixazomib to a standard Rd regimen EORTC-QLQ-C30 Mean global health status score 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; QoL, quality of life; Rd, lenalidomide-dexamethasone. Moreau P et al. N Engl J Med 2016;374:

24 Safety summary 1,2 Ixazomib added limited additional toxicity to that seen with placebo-rd Low rates of peripheral neuropathy: Grade 3 events (2%) similar to placebo-rd and no Grade 4 events 1 Numerically higher all-grade thrombocytopenia with ixazomib-rd (31%) vs. placebo-rd (16%) 1 Thrombocytopenia was not associated with increased rates of bleeding, clinically significant bleeding events, or increased rate of platelet transfusions 2 No cardiovascular, pulmonary or renal safety signals to date 1 Patient-reported quality of life was maintained with the addition of a third agent to standard doublet regimen 1 Rd, lenalidomide-dexamethasone. 1. Moreau P et al. N Engl J Med 2016;374: ; 2. NINLARO (ixazomib capsules) Summary of Product Characteristics March 2017.

25 Ixazomib-Rd: Dosing and administration

26 Ixazomib phase III dosing schedule day half-life; supported once-weekly dosing 1 Maximum tolerated dose of 2.97 mg/m 2 ; converted to 5.5 mg fixed dose 1,2 5.5 mg associated with improved response rates but higher toxicities than 4.0 mg 3 Pharmacokinetic studies Phase I dose escalation studies Phase II study TOURMALINE -MM1 The agreed phase III dosing schedule of ixazomib is 4.0 mg once weekly 1. Kumar SK et al. Blood 2014;124: ; 2. Kumar SK et al. Lancet Oncology 2014;15: ; 3. Kumar SK et al. Blood 2016; 128:

27 Ixazomib-Rd is taken as a 28-day treatment cycle cycles continue one after the other Each dose of ixazomib should be taken approximately the same time each day on an empty stomach (at least one hour before and two hours after food) Dexamethasone should be taken with food, therefore ixazomib and dexamethasone should not be taken at the same time Ixazomib should be swallowed whole with a glass of water the capsule should not be crushed, chewed or opened If a dose on ixazomib is missed or delayed, the dose should be taken only if the next scheduled dose is 72 hours away Rd, lenalidomide-dexamethasone. NINLARO (ixazomib capsules) Summary of Product Characteristics July 2017.

28 Summary Ixazomib-Rd demonstrated improved efficacy with limited additional toxicity compared to placebo-rd Ixazomib-Rd showed significant and clinically meaningful improvement in PFS vs. placebo-rd which was maintained following subgroup analysis for cytogenetic risk and 2 3 prior lines of therapy 1 3 Ixazomib-Rd significantly increased TTP compared to placebo-rd and demonstrated increased and deepening responses over time 1 Ixazomib-Rd treatment resulted in numerically greater rates of all grade peripheral neuropathy vs. placebo-rd (27% vs. 22%) but no increase in grade 3 events Thrombocytopenia of grade 3 or 4 severity occurred more frequently in the ixazomib group than in the placebo group, however, this was not associated with increased bleeding or platelet transfusions 1 A Chinese continuation study showed increased OS with ixazomib-rd compared to placebo-rd 4 Patient-reported quality of life was maintained with the addition of a ixazomib to Rd 1 OS, overall survival; PFS, progression-free survival; Rd, lenalidomide-dexamethasone; TTP, time to progression. 1. Moreau P et al. N Engl J Med 2016;374: ; 2. Avet-Loiseau H et al. European Hematology Association 22 nd Congress 2016; Poster P269; 3. Mateos MV et al. Haematologica 2017; pii: haematol [E-pub ahead of print]; 4. Hou J et al. J Haematol Oncol 2017; doi: /s

29 Abbreviated Prescribing Information: NINLARO (ixazomib) (Refer to Summary of Product Characteristics (SmPC) before prescribing) 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/mm 3, platelet count should be 75,000/mm 3, 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: Coadministration 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