Haematology Volume 12 - Issue 5, March 2017

Is IMBRUVICA®▼ the future of CLL treatment? Back


Trying to achieve the best outcomes for patients with chronic lymphocytic leukaemia (CLL) has always been a compromise between balancing efficacy and toxicity.1

Current treatment options in front-line CLL include the chemo-immunotherapy regimen of fludarabine, cyclophosphamide and rituximab (FCR). This has demonstrated strong efficacy in CLL but is associated with high rates of toxicity.1–5 Select elderly patients are able to tolerate aggressive treatment approaches; however, FCR cannot be tolerated by the majority of CLL patients who have comorbid health conditions and begin treatment after the age of 70.1,6,7 One study showed as many as 89% of newly diagnosed patients had at least one comorbid condition.1

For patients who are unable to tolerate the FCR regimen, the combination of bendamustine and rituximab (BR) is an alternative front-line option, which is recommended by treatment guidelines for patients unsuitable for FCR due to high rates of infection.8,9

BR offers a more tolerable option for patients with CLL but demonstrates reduced efficacy compared with FCR.1,4,5 Additionally, there are limited efficacy data on the use of BR as a second-line therapy in relapsed/refractory CLL disease, as there are only a few BR clinical studies with small patient numbers.4,5,10,11 One must also consider treatment outcomes with chemo-immunotherapies like FCR or BR in patients with unmutated IGHV, as these have been demonstrated to be worse than in patients with mutated IGHV.3,5,10,12

Now, a novel agent is showing promising results for patients with CLL. IMBRUVICA (ibrutinub) is a chemotherapy-free, single-agent, oral therapy, which has demonstrated unprecedented survival benefits, as well as generally good tolerability data across all lines of therapy.13–15 In addition, following relapse, a comparison between IMBRUVICA+BR (IBR) versus BR alone showed IBR to be significantly more effective.16–18 When considering outcomes in patients with unmutated IGHV, unlike chemo-immunotherapies, IMBRUVICA efficacy is consistent with that demonstrated in patients with mutated IGHV.3,5,10,19 As such, a recent publication by Kipps et al. has recommended the use of IMBRUVICA in place of chemo-immunotherapy, in patients with unmutated IGHV.12

What do the guidelines currently recommend for the treatment of CLL?

Sustained clinical efficacy evidence

In phase 3 studies in relapsed/refractory or treatment-naïve patients with CLL, IMBRUVICA demonstrated unprecedented survival benefits across all lines of therapy13 compared with ofatumumab or chlorambucil respectively.14,19,21 It is also the only novel agent with long-term data showing durable efficacy, with responses that improve over time (Figure 2).14,15,21

Front-line CLL: treatment-naïve patients

IMBRUVICA is consistently effective in treatment-naïve patients, including older, less fit and higher-risk patient groups.14,19,22 A phase 3 randomised, controlled trial showed improved progression-free survival (PFS), overall survival (OS) and good tolerability for single-agent IMBRUVICA compared with chlorambucil.14,19,25 IMBRUVICA demonstrated strong long-term survival data when prescribed front line, with studies demonstrating 95% OS at 2 years19 and 92% OS after 5 years of treatment.22

Relapsed/refractory patients

IMBRUVICA has demonstrated survival benefits in the relapsed/ refractory setting when given at first relapse, as well as in subsequent relapses. Studies have, however, demonstrated a 10% greater OS benefit when IMBRUVICA is given at first relapse as compared with subsequent relapses.13

When given at first relapse, 93% of patients treated with IMBRUVICA were still alive at 2.5 years and 2-year PFS was 89%.13 When prescribed after second relapse, the proportion of patients still alive at 2.5 years was 83% and 2-year PFS was 80%.13

Recent 5-year follow-up data have demonstrated  sustained long-term efficacy  with IMBRUVICA, with  57% of relapsed/refractory patients still alive at 5 years.22

Is BR alone the best treatment after relapse? 

One randomised, placebo-controlled trial showed  IMBRUVICA+BR significantly  improved PFS and had a  trend towards OS versus BR  alone.16 An adjusted indirect comparison suggests similar  PFS (see Figure 3) and OS  for IMBRUVICA compared  to IMBRUVICA+BR,  and  statistically significant  benefit in PFS and OS for  IMBRUVICA versus BR. In  addition, the HELIOS data  showed that IMBRUVICA  can be given with BR.  IMBRUVICA offers  an alternative option  to traditional chemo-immunotherapy.16

Long-term tolerability data 

IMBRUVICA has demonstrated a manageable safety profile and long-term tolerability data over 5 years of follow-up.22 This safety profile allows for extended IMBRUVICA dosing, with 65% of treatment-naïve and 30% of relapsed/refractory patients continuing treatment with IMBRUVICA at 5 years.22 Additionally, discontinuation of IMBRUVICA due to adverse events is infrequent (≤7%), and tends to occur during the first year of treatment.22 A number of studies have also demonstrated that adverse events with IMBRUVICA are generally grade 1 or 2 and diminish over time.13,14,23,26

IMBRUVICA has also demonstrated a low risk of major bleeds (1–7%) in a wide range of patients,13,14,16,26–28 and few atrial fibrillation events (6.5–10%), most of which were short-lasting.26 Importantly, IMBRUVICA can be given with anticoagulants and antiplatelet agents, with 3% of patients taking such agents experiencing major haemorrhage in clinical studies.‡24,28 Particular care should be taken as there is an increased risk of bleeding (please refer to the IMBRUVICA SPC).

In clinical trials with IMBRUVICA the frequency of grade 3 and above infections was similar to ofatumumab, chlorambucil and BR.14,16,23,27

Warfarin or other vitamin K antagonists should not be administered concomitantly with IMBRUVICA. Supplements such as fish oil and vitamin E preparations should also be avoided.

Continuous therapy versus treatment cycles

Different CLL therapy regimens vary in their dosing requirements, with some therapies, like BR, being dosed in treatment cycles and others, like IMBRUVICA, being dosed continuously with no ‘treatment holidays’.14,16

IMBRUVICA must be dosed continuously once daily to ensure sustained inhibition of Bruton’s tyrosine kinase enzymatic activity.24,30 Multiple studies show that patients are able to tolerate the continuous dosing with IMBRUVICA13,14,22,23 and the single-agent therapy is simple and convenient to use.24 The benefits of the IMBRUVICA dosing schedule include the reduced need for hospital visits as, unlike chemo-immunotherapy regimens, IMBRUVICA administration does not require hospitalisation and can be administered at home. There is also no requirement for dose escalation or prophylactic/pre-treatment.24

Resistance to therapy is also a concern with CLL therapies, and perhaps more so with continuous treatment regimens, as we must consider subsequent therapies that may be available following resistance.31 In phase 3 clinical trials, OS rates with single-agent IMBRUVICA were high, suggesting that there is a limited incidence of primary resistance to IMBRUVICA in CLL patients.14,15 The rate of acquired resistance to IMBRUVICA in CLL patients is also very low,32,33 with those with high‐risk cytogenetics (eg del17p or del11q or a complex karyotype) being most at risk.32 Furthermore, the majority of CLL patients who experienced resistance to IMBRUVICA developed it after a considerable period of being on treatment (388–868 days),32,33 and recent data suggest that other novel therapies may be suitable and effective treatment options in patients refractory to IMBRUVICA.34


The advent of novel therapies like IMBRUVICA has brought considerable changes to the way treatment of CLL is approached. Where, traditionally, treatment has had to be a compromise between efficacy and safety of therapies for patients, IMBRUVICA has demonstrated proven efficacy across all CLL lines of therapy, with long-term data demonstrating a manageable tolerability profile over a 5-year follow-up period.13 Importantly, IMBRUVICA has demonstrated superior PFS and OS versus the standard of care across three phase 3 studies, in both treatment-naive and relapsed/refractory CLL patients.13,14,16

As growing clinical evidence supports IMBRUVICA as an alternative option to traditional chemo-immunotherapy regimens, is it time to rethink our use of BR?


  1. Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology Am Soc Hematol Educ Program 2013;2013:158–67.
  2. Cramer P, Fink A-M, Busch R, Eichhorst B, et al. Second-line therapies of patients initially treated with fludarabine and cyclophosphamide or fludarabine, cyclophosphamide and rituximab for chronic lymphocytic leukemia within the CLL8 protocol of the German CLL Study Group. Leuk Lymphoma 2013;54:1821–2.
  3. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164–74.
  4. Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial
    of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012;30:3209–16.
  5. Eichhorst B, Fink A-M, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016;17:928–42.
  6. Knauf W, Re D. Chronic lymphocytic leukemia: raising expectations in the treatment of elderly patients. J Leuk 2015;3:181.
  7. Barrientos JC. Management of chronic lymphocytic leukemia in the elderly. Cancer Control 2015;22(Suppl 4):17–23.
  8. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26 (Suppl 5):v78–84.
  9. Eichhorst B, Robak T, Montserrat E, et al. Appendix 6: Chronic lymphocytic leukaemia: eUpdate published online September 2016. Ann Oncol 2016;27(Suppl 5):v143–44.
  10. Gentile M, Cirlik K, Ciolli S, et al. Combination of bendamustine and rituximab as front-line therapy for patients with chronic lymphocytic leukaemia: multicenter, retrospective clinical practice experience with 279 cases outside of controlled clinical trials. Eur J Cancer 2016;60:154–65.
  11. Laurenti L, Innocenti I, Autore F, et al. Bendamustine in combination with rituximab for elderly patients with previously untreated B-cell chronic lymphocytic leukemia: a retrospective analysis of real-life practice in Italian hematology departments. Leuk Res 2015;39:1066–70.
  12. Kipps T, Stevenson FK, Wu CJ, et al. Chronic lymphocytic leukaemia. Nat Rev Dis Primers 2017;3:17008. doi:10.1038/nrdp.2017.8.
  13. O’Brien SM, Byrd JC, Hillmen P, et al. Outcomes with ibrutinib by line of therapy in patients with CLL: analyses from phase 3 data. Poster presented at the American Society of Clinical Oncology (ASCO) Annual Meeting; 3–7 June, 2016; Chicago, IL, USA.
  14. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 2015;373:2425–37.
  15. Pagel JM, Brown JR, Hillmen P, et al. Updated efficacy including genetic subgroup analysis and overall safety in the phase 3 RESONATE trial of Ibrutinib vs. ofatumumab in previously-treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Poster presented at XVI International Workshop on Chronic Lymphocytic Leukaemia (iwCLL); 6–9 September, 2015; Sydney, Australia.
  16. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol 2016;17:200–11.
  17. Fraser G, Cramer P, Demirkan F, et al. Ibrutinib plus bendamustine and rituximab in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma: a 2-year follow-up of the HELIOS study. Abstract presented at the American Society of Clinical Oncology (ASCO) Annual Meeting; 3–7 June, 2016; Chicago, IL, USA.
  18. Hillmen P, Fraser, G, Jeffrey J, et al. Comparing single-agent ibrutinib, bendamustine + rituximab (BR), and ibrutinib + BR in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): an indirect comparison of the RESONATETM and HELIOS trials. Abstract HELIOS trials. Abstract presented at the 57th American Society of Hematology Annual Meeting and Exposition; 5–8 December, 2015; Orlando, FL, USA.
  19. Barr PM, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Oral presentation at the 58th ASH Annual Meeting & Exposition; 3–6 December, 2016; San Diego, CA, USA.
  20. NCCN. Chronic lymphocytic leukemia/small lymphocytic leukemia Clinical Practice Guideline v1. 2017. (https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site; accessed 16 February 2017).
  21. Brown JR, Hillmen P, O’Brien S, et al. Efficacy of Ibrutinib by baseline high-risk genetic features, including novel gene mutations, and safety with longer follow-up from the phase 3 RESONATETM trial in previously treated CLL/SLL. Poster presented at the American Society of Hematology Meeting on Lymphoma Biology; 18–21 June, 2016; Colorado Springs, CO, USA.
  22. O’Brien SM, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Presentation and abstract at the 58th ASH Annual Meeting & Exposition; 3–6 December, 2016; San Diego, CA, USA.
  23. Byrd JC, Furmans RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497–506.
  24. IMBRUVICA® Summary of Product Characteristics. Janssen-Cilag International NV. 2016.
  25. Tedeschi A, Barr PM, Robak R, et al. Results from the international, randomized, phase 3 study of Ibrutinib versus chlorambucil in patients 65 years and older with treatment-naive CLL/SLL (RESONATE-2TM). Abstract and oral presentation presented at the 57th American Society of Hematology Annual Meeting and Exposition; 5–8 December, 2015; Orlando, FL, USA.
  26. Brown JR, O’Brien SM, Moslehi J, et al. Pooled analysis of atrial fibrillation adverse events in ibrutinib randomized controlled registration trials. Poster presented at the 2016 ASH Meeting on Hematologic Malignancies, 16–17 September, 2016, Chicago, IL, USA.
  27. Byrd JC, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213–23.
  28. Jones JA, Hillmen P, Coutre S, et al. Pattern of use of anticoagulation and/or antiplatelet agents in patients with chronic lymphocytic leukemia treated with single-agent ibrutinib. Abstract and poster presented at the 56th Annual Meeting of the American Society of Hematology; 6–9 December, 2014; San Francisco, CA, USA.
  29. Nosari A. Infectious complications in chronic lymphocytic leukemia. Mediterr J Hematol Infect Dis 2012;4:e2012070.
  30. Chavez J, Sahakian E, Pinilla-Ibarz J. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia. Core Evid 2013;8:37–45.
  31. Woyach JA, Johnson AJ. Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood 2015;126:471–7.
  32. Woyach JA, Furman RR, Ta-Mind Liu MS, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med 2014;370:2286–94.
  33. Chang BY, Furman RR, Zapatka M, et al. Use of tumor genomic profiling to reveal mechanisms of resistance to BTK inhibitor Ibrutinib in chronic lymphocytic leukemia. Poster presented at the 49th Annual Meeting of the American Society of Clinical Oncology; 31 May–4 June, 2013; Chicago, IL, USA.
  34. Jones J, Choi MY, Mato AR, et al. Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib. Presentation at the 58th Annual Meeting & Exposition of the American Society of Hematology, 3–6 December, 2016; San Diego, CA, USA.

Prescribing information

▼This medicinal product is subject to additional monitoring and it is therefore important to report any suspect adverse reactions related to this medicinal product.


Each hard capsule contains 140 mg of ibrutinib.

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Treatment of adult patients with: relapsed or refractory mantle cell lymphoma (MCL) as a single agent; previously untreated chronic lymphocytic leukaemia (CLL), as a single agent; CLL who have received ≥ one prior therapy as a single agent or or in combination with bendamustine and rituximab (BR); Waldenström’s macroglobulinaemia (WM) who have received ≥  one prior therapy, or in first line treatment in patients unsuitable for chemo‑immunotherapy, as a single agent.


Adults: Orally, once daily, swallowed whole with water. MCL – 4 capsules; CLL as single dose or in combination and WM – 3 capsules.
Concomitant moderate/strong CYP3A4 inhibitors – reduce to 1 capsule (or, with strong inhibitors, withhold IMBRUVICA for up to 7 days).
Withhold IMBRUVICA therapy for any new onset/worsening grade ≥ 3 non‑haematological toxicity, grade ≥ 3 neutropenia with infection or fever, or grade 4 haematological toxicities. Re‑initiate when toxicities resolved to grade 1 or baseline. If toxicities recur, reduce dose by 1 capsule. Consider reducing dose by an additional capsule if toxicities persist/recur. Discontinue IMBRUVICA if toxicities persist/recur following two dose reductions.
Children: Safety/efficacy not established ≤ 18 years old. No data available
Elderly: No dose adjustment required.
Renal impairment: Mild/moderate ‑ no dose adjustment. Severe ‑ no data; consider benefit/risk and monitor closely. No data with dialysis.
Hepatic impairment: Mild (Child‑Pugh class A) ‑ 2 capsules daily; moderate (Child‑Pugh class B) ‑ 1 capsule daily; monitor for toxicities. Severe (Child‑Pugh class C) ‑ not recommended.
Severe cardiac disease: No clinical data.

Hypersensitivity to active substance/excipients.
St. John’s Wort preparations.

Bleeding‑related events: Minor and major haemorrhagic events reported, some fatal; caution with anticoagulant therapy ‑ do not use concomitantly with warfarin or other vitamin K antagonists, avoid fish oil and vitamin E preparations. Withhold IMBRUVICA ≥ 3 to 7 days pre‑/post‑surgery.

Leukostasis: Cases reported; consider temporary withhold of IMBRUVICA; monitor closely, give supportive care.

Infections: Infections seen, some resulting in hospitalisation and death; monitor for fever, neutropenia and infections and give anti‑infective therapy. Cases of Progressive Multifocal Leukoencephalopathy (PML) including fatal ones reported following ibrutinib use with prior or concomitant immunosuppressive therapy. Consider PML diagnosis in patients with new/worsening neurological/cognitive/behavioral signs/symptoms. If suspected, evaluate and suspend treatment until PML is excluded. If in doubt, refer to a neurologist and consider appropriate diagnostic measures for PML.

Cytopenias: Treatment‑emergent grade 3/4 cytopenias reported; monitor complete blood counts monthly.

Interstitial Lung Disease (ILD): Cases reported; monitor for pulmonary symptoms indicative of ILD; interrupt IMBRUVICA and manage ILD if symptoms develop. If symptoms persist, consider IMBRUVICA risks and benefits; follow dose modification guidelines.

Cardiac arrhythmia: Reported particularly in patients with cardiac risk factors/hypertension/acute infections/previous history of atrial fibrillation; periodic clinical monitoring; consider ECG if arrhythmic symptoms or new onset dyspnoea, dizziness or fainting develop; temporarily discontinue IMBRUVICA in patients who develop signs and/or symptoms of ventricular tachyarrhythmia; consider alternative to IMBRUVICA when pre‑existing atrial fibrillation requiring anticoagulant therapy or high risk of thromboembolic disease; where no suitable alternatives to IMBRUVICA, consider tightly controlled treatment with anticoagulants.

Tumour lysis syndrome: Cases reported; patients with high tumour burden at risk; monitor closely, take precautions.

Non‑melanoma skin cancer: Reported more frequently in IMBRUVICA‑treated patients than in comparator‑treated patients in pooled comparative randomised phase 3 studies. Monitor patients for appearance of non‑melanoma skin cancer.

Viral reactivation: Cases of hepatitis B reactivation reported; establish hepatitis B status before initiating IMBRUVICA treatment; patients who test positive for hepatitis B infection should consult liver disease expert before initiating treatment; monitor patient and manage per local medical standards to prevent hepatitis B reactivation.

Drug‑drug interactions: Strong/moderate CYP3A4 inhibitors may increase ibrutinib exposure; CYP3A4 inducers may decrease IMBRUVICA exposure. Avoid where possible, if not monitor closely for toxicities/lack of efficacy.

Very common: Pneumonia, upper respiratory tract infection, sinusitis, skin infection, neutropenia, thrombocytopenia, headache, haemorrhage, bruising, diarrhoea, vomiting, stomatitis, nausea, constipation, rash, arthralgia, muscle spasms, musculoskeletal pain, pyrexia, oedema peripheral. Common: sepsis, urinary tract infection, non‑melanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, febrile neutropenia, leukocytosis, lymphocytosis, interstitial lung disease, tumour lysis syndrome, hyperuricaemia, dizziness, vision blurred, atrial fibrillation, ventricular tachyarrhythmia, subdural haematoma, epistaxis, petechiae, hypertension, urticaria, erythema, onychoclasis. Uncommon: hepatitis B reactivation, leukostasis syndrome, angioedema. Not known: hepatic failure, Stevens‑Johnson syndrome.
Refer to the SmPC for other side effects.
Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system to allow for continued monitoring of the benefit/risk balance of the medicinal product. 

Not to be used during pregnancy. Women of child‑bearing potential must use highly effective contraceptive measures during and for 3 months after stopping treatment; if using hormonal contraceptives, add barrier method.

Discontinue breast‑feeding during treatment.

CYP3A4 inhibitors: Strong: Avoid where possible or reduce dose (or withhold IMBRUVICA for ≤ 7 days and monitor closely; e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodon and cobicistat. Moderate: Avoid where possible or reduce dose and monitor closely; e.g., voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone. Avoid grapefruit and Seville oranges. Mild: No dose adjustment required; monitor closely.
CYP3A4 inducers: Strong/moderate: Avoid or monitor closely for lack of efficacy; carbamazepine, rifampin, phenytoin. Mild: may be used; monitor for lack of efficacy.
Medicines that increase stomach pH (e.g., proton pump inhibitors) have been used without restrictions in the pivotal clinical trials.
Potential interactions: Narrow therapeutic range oral P‑gp or BCRP substrates (e.g., digoxin or methotrexate) should be taken ≥ 6 h before/after IMBRUVICA. Exposure of drugs that undergo BCRP‑mediated hepatic efflux (e.g., rosuvastatin) or CYP3A4‑mediated intestinal metabolism may be increased. Use caution with oral CYP3A4 substrates with narrow therapeutic range (e.g., dihydroergotamine, ergotamine, fentanyl, cyclosporine, sirolimus and tacrolimus). Ibrutinib is a weak CYP2B6 inducer and may affect expression of other CAR‑regulated enzymes and transporters, e.g. CYP2C9, CYP2C19, UGT1A1 and MRP2. Exposure to substrates of CYP2B6 (e.g., efavirenz, bupropion) and of co‑regulated enzymes may be reduced.
Refer to SmPC for full details of interactions.

LEGAL CLASSIFICATION: Medicinal product subject to restricted medical prescription

MARKETING AUTHORISATION NUMBERS: EU/1/14/945/001 and EU/1/14/945/002

MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV, Turnhoutseweg 30, B‑2340 Beerse, Belgium

Products mentioned in this document may not be registered in all countries. Prescribing Information may vary per country. Health Care Providers must refer to their country prescribing information.

Prescribing information generation date or last revised: August 2017

Based on August 2017 EU Summary of Product Characteristics