IMBRUVICA 140 mg, 280 mg, 420 mg and 560 mg film-coated tablets

  • Name:

    IMBRUVICA 140 mg, 280 mg, 420 mg and 560 mg film-coated tablets

  • Company:
    info
  • Active Ingredients:

    Ibrutinib

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 04/09/20

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Summary of Product Characteristics last updated on medicines.ie: 4/9/2020

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Janssen Sciences Ireland

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 4 September 2020 PIL

Reasons for updating

  • Change to section 4 - possible side effects

Free text change information supplied by the pharmaceutical company

4.       Possible side effects

 

Very common (may affect more than 1 in 10 people)

  • fever, chills, body aches, feeling tired, cold or flu symptoms, being short of breath – these could be signs of an infection (viral, bacterial or fungal). These could include infections of the nose, sinus or throat (upper respiratory tract infection), or lung, or skin.
  • bruising or increased tendency of bruising.
  • mouth sores
  • feeling dizzy
  • headache
  • constipation
  • feeling or being sick (nausea or vomiting)
  • diarrhoea, your doctor may need to give you a fluid and salt replacement or another medicine
  • skin rash
  • painful arms or legs
  • back pain or joint pain
  • muscle cramps, aches or spasms
  • low number of cells that help blood clot (platelets), very low number of white blood cells – shown in blood tests
  • an increase in the number or proportion of white blood cells shown in blood tests
  • high level of “uric acid” in the blood (shown in blood tests), which may cause gout
  • swollen hands, ankles or feet
  • high blood pressure
  • increased level of “creatinine” in the blood.
     
    Common (may affect up to 1 in 10 people)
  • severe infections throughout the body (sepsis)
  • infections of the urinary tract
  • nose bleeds, small red or purple spots caused by bleeding under the skin
  • blood in your stomach, gut, stools or urine, heavier periods, or bleeding that you cannot stop from an injury
  • heart failure
  • fast heart rate, missed heart beats, weak or uneven pulse, lightheadedness, shortness of breath, chest discomfort (symptoms of heart rhythm problems)
  • an increase in the number or proportion of white blood cells shown in blood tests
  • low white blood cell counts with fever (febrile neutropenia)
  • unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have happened during treatment of cancer and sometimes even without treatment (tumour lysis syndrome)
  • non‑melanoma skin cancer, most frequently squamous cell and basal cell skin cancer
  • feeling dizzy
  • blurred vision
  • redness of the skin
  • high level of “uric acid” in the blood (shown in blood tests), which may cause gout
  • inflammation within the lungs that may lead to permanent damage
  • breaking of the nails
  • weakness, numbness, tingling or pain in your hands or feet or other parts of the body (peripheral neuropathy).
     
    Uncommon (may affect up to 1 in 100 people)
  • liver failure, including events with fatal outcome
  • severe fungal infections
  • confusion, headache with slurred speech or feeling faint – these could be signs of serious internal bleeding in your brain
  • unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have happened during treatment of cancer and sometimes even without treatment (tumour lysis syndrome)
  • allergic reaction, sometimes severe, that may include a swollen face, lip, mouth, tongue or throat, difficulty swallowing or breathing, itchy rash (hives)
  • inflammation of the fatty tissue underneath the skin
  • temporary episode of neurologic dysfunctiondecreased brain or nerve function caused by loss of blood flow, stroke
  • painful skin ulceration (pyoderma gangrenosum) or red, raised painful patches on the skin, fever and an increase in white blood cells (these may be signs of acute febrile neutrophilic dermatosis or Sweet’s syndrome).
     

Updated on 4 September 2020 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.1     Therapeutic indications 

IMBRUVICA as a single agent or in combination with rituximab or obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1).

 

4.2     Posology and method of administration

….

 CLL and WM

The recommended dose for the treatment of CLL and WM, either as a single agent or in combination, is 420 mg once daily (for details of the combination regimens, see section 5.1).

The recommended dose for the treatment of WM is 420 mg once daily.

 

Treatment should continue until disease progression or no longer tolerated by the patient.

 

When administering IMBRUVICA in combination with anti-CD20 therapiestherapy, it is recommended to administer IMBRUVICA prior to rituximab or obinutuzumab anti-CD20 therapy when given on the same day.

 

4.4     Special warnings and precautions for use

…………..

Cerebrovascular accidents

Cases of cerebrovascular accident, transient ischaemic attack and ischaemic stroke including fatalities have been reported with the use of ibrutinibin patients treated with IMBRUVICA, with and without concomitant atrial fibrillation and/or hypertension. Latency fromAmong cases with reported latency, the initiation of treatment with ibrutinib IMBRUVICA to the onset of ischaemic central nervous vascular conditions was in the most cases after several months (more than 1 month in 78% and more than 6 months in 44% of cases) emphasising the need for regular monitoring of patients (please see section 4.4 Cardiac arrhythmia and Hypertension and section 4.8).

 

 

4.8     Undesirable effects

 

Summary of the safety profile

The safety profile is based on pooled data from 12001552 patients treated with IMBRUVICA in three phase 2 clinical studies and sixseven randomised phase 3 studies and from post‑marketing experience. Patients treated for MCL in clinical studies received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM in clinical studies received IMBRUVICA at 420 mg once daily. All patients in clinical studies received IMBRUVICA until disease progression or no longer tolerated.

 

The most commonly occurring adverse reactions (≥20%) were diarrhoea, neutropenia, musculoskeletal pain, rash, haemorrhage (e.g., bruising), thrombocytopenia, neutropenia, musculoskeletal pain, nausea, pyrexia, arthralgia, and thrombocytopeniaupper respiratory tract infection. The most common grade 3/4 adverse reactions (≥5%) were neutropenia, lymphocytosis, thrombocytopenia, pneumonia,  and hypertensionand thrombocytopenia

 

………

System organ class

Frequency

(All grades)

Adverse reactions

All Grades (%)

Grade ≥3 (%)

 

Infections and infestations

Very common

Pneumonia*#

Upper respiratory tract infection

Skin infection*

1614

1820

1415

108

1

3

 

Common

Sepsis*#

Urinary tract infection

Sinusitis*

54

109

10

43

2

1

 

Uncommon

Cryptococcal infections*

<1

0

 

Pneumocystis infections* #

1

<1

 

Aspergillus infections*

<1

<1

 

Hepatitis B reactivation@ #

<1

<1

 

Neoplasms benign and malignant (incl cysts and polyps)

Common

Non‑melanoma skin cancer*

Basal cell carcinoma

Squamous cell carcinoma

6

34

2

1

<1

<1

 

Blood and lymphatic system disorders

Very common

Neutropenia*

Thrombocytopenia*

Lymphocytosis*

3038

2132

19

2629

109

14

 

Common

Febrile neutropenia

Leukocytosis

Lymphocytosis

54

25

1

54

14

1

 

Rare

Leukostasis syndrome

<1

<1

 

Immune system disorders

Common

Interstitial lung disease*,#,a

2

<1

 

Metabolism and nutrition disorders

Very common

Hyperuricaemia

10

1

 

CUncommon

Tumour lysis syndromea

Hyperuricaemia

1

8

1

2

 

Nervous system disorders

Very common

Dizziness

Headache

12

1319

<1

1

 

Common

Peripheral neuropathy*,a

Dizziness

58

9

<1

0

 

Uncommon

Cerebrovascular accident a, #

Transient ischaemic attacka

Ischaemic stroke a, #

<1

<1

<1

<1

<1

<1

 

Rare

Ischaemic stroke a, #

<1

<1

 

Eye disorders

Common

Vision blurred

7

0

 

Cardiac disorders

Common

Cardiac failurea,*

Atrial fibrillation

Ventricular tachyarrhythmia*,a,#

2

7

1

1

4

<1

 

Uncommon

Ventricular tachyarrhythmia*,a,b

1

<1

 

Vascular disorders

Very common

Haemorrhage*#

Bruising*

Hypertension*

3132

2225

1218

1

1

58

 

Common

Epistaxis

Petechiae

8

76

<1

0

 

Uncommon

Subdural haematoma#

1

<1

 

Gastrointestinal disorders

Very common

Diarrhoea

Vomiting

Stomatitis*

Nausea

Constipation

3942

1314

1214

2528

16

3

<11

1

1

<1

 

Hepatobiliary disorders

Uncommon

Hepatic failure*,a #

<1

<1

 

Skin and subcutaneous tissue disorders

Very common

Rash*

3135

3

 

Common

Urticariaa

Erythemaa

Onychoclasisa

1

2

3

<1

0

0

 

Uncommon

Angioedemaa

Panniculitis*,a

Neutrophilic dermatoses*, a

<1

<1

<1

<1

0<1

<1

 

Not known

Stevens‑Johnson syndromea

Not known

Not known

 

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Muscle spasms

Musculoskeletal pain*

1420

14

3037

12

<1

3

 

General disorders and administration site conditions

Very common

Pyrexia

Oedema peripheral

2022

1518

21

1

 

Investigations

Very common

Blood creatinine increased

11

<1

 

     Frequencies are rounded to the nearest integer.

*     Includes multiple adverse reaction terms.

#     Includes events with fatal outcome.

@    Lower level term (LLT) used for selection.

a     Spontaneous reports from post‑marketing experience.

b     Frequency calculated from monotherapy clinical studies.

 

Description of selected adverse reactions

Discontinuation and dose reduction due to adverse reactions

Of the 12001552 patients treated with IMBRUVICA for B‑cell malignancies, 56% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation, thrombocytopenia, haemorrhage, neutropenia, rash, and arthralgiaand thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 78% of patients.

 

Elderly

Of the 12001552 patients treated with IMBRUVICA, 6452% were 65 years of age or older. Grade 3 or higher pneumonia (12% of patients age ≥65 versus 5% of patients <65 years) and thrombocytopenia (12% of patients age ≥65 years versus 6% of patients <65 years) occurred more frequently among elderly patients treated with IMBRUVICA (12% of patients age ≥65 versus 7% of patients <65 years of age).

 

5.1     Pharmacodynamic properties

 

 

………………

Combination therapy

The safety and efficacy of IMBRUVICA in patients with treatment naïvepreviously untreated CLL/SLL were further evaluated in a randomised, multi-center, open-label, phase 3 study (PCYC-1130-CA) of IMBRUVICA in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab

 

The safety and efficacy of IMBRUVICA in patients with previously untreated CLL or SLL were further evaluated in a randomised, multi-center, open-label, phase 3 study (E1912) of IMBRUVICA in combination with rituximab (IR) versus standard fludarabine, cyclophosphamide, and rituximab (FCR) chemo-immunotherapy. The study enrolled previously untreated patients with CLL or SLL who were 70 years or younger. Patients with del17p were excluded from the study. Patients (n=529) were randomised 2:1 to receive either IR or FCR.  IMBRUVICA was administered at a dose of 420 mg daily until disease progression or unacceptable toxicity. Fludarabine was administered at a dose of 25 mg/m2, and cyclophosphamide was administered at a dose of 250 mg/m2, both on Days 1, 2, and 3 of Cycles 1-6. Rituximab was initiated in Cycle 2 for the IR arm and in Cycle 1 for the FCR arm and was administered at a dose of 50 mg/m2 on Day 1 of the first cycle, 325 mg/m2 on Day 2 of the first cycle, and 500 mg/m2 on Day 1 of 5 subsequent cycles, for a total of 6 cycles. Each cycle was 28 days.

 

The median age was 58 years (range, 28 to 70 years), 67% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1 (98%) or 2 (2%). At baseline, 43% of patients presented with Rai Stage III or IV, and 59% of patients presented with CLL/SLL with high risk factors (TP53 mutation [6%], del11q [22%], or unmutated IGHV [53%]).

 

With a median follow-up time on study of 37 months, efficacy results for E1912 are shown in Table 7. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria, and OS are shown in Figures 6 and 7, respectively.

 

Table 7:      Efficacy results in Study E1912

Endpoint

Ibrutinib+rituximab (IR)
N=354

Fludarabine, Cyclophosphamide, and Rituximab (FCR)
N=175

Progression Free Survival

Number of events (%)

41 (12)

44 (25)

Disease progression

39

38

Death events

2

6

Median (95% CI), months

NE (49.4, NE)

NE (47.1, NE)

HR (95% CI)

0.34 (0.22, 0.52)

P-valuea

<0.0001

Overall Survival

Number of deaths (%)

4 (1)

10 (6)

HR (95% CI)

0.17 (0.05, 0.54)

P-valuea

0.0007

Overall Response Rateb (%)

96.9

85.7

a   P-value is from unstratified log-rank test.

b    Investigator evaluated.

HR = hazard ratio; NE = not evaluable

 

Figure 6:     Kaplan-Meier Curve of PFS (ITT Population) in Study E1912

Graph added to SmPC

 

The treatment effect of ibrutinib was consistent across the high-risk CLL/SLL population (TP53 mutation, del11q, or unmutated IGHV), with a PFS HR of 0.23 [95% CI (0.13, 0.40)], p <0.0001, as shown in Table 8. The 3-year PFS rate estimates for the high-risk CLL/SLL population were 90.4% [95% CI (85.4, 93.7)] and 60.3% [95% CI (46.2, 71.8)] in the IR and FCR arms, respectively

 

Table 8:      Subgroup Analysis of PFS (Study E1912)

 

N

Hazard Ratio

95% CI

All subjects

529

0.340

0.222, 0.522

High risk (TP53/del11q/unmutated IGHV)

Yes

313

0.231

0.132, 0.404

No

216

0.568

0.292, 1.105

del11q

Yes

117

0.199

0.088, 0.453

No

410

0.433

0.260, 0.722

Unmutated IGHV

Yes

281

0.233

0.129, 0.421

No

112

0.741

0.276, 1.993

Bulky disease

<5 cm

316

0.393

0.217, 0.711

≥5 cm

194

0.257

0.134, 0.494

Rai stage

0/I/II

301

0.398

0.224, 0.708

III/IV

228

0.281

0.148, 0.534

ECOG

0

335

0.242

0.138, 0.422

1-2

194

0.551

0.271, 1.118

Hazard ratio based on non‑stratified analysis

 

 

Figure 7:     Kaplan-Meier Curve of OS (ITT Population) in Study E1912

Graph added to the SmPC.

 

 

Updated on 21 August 2020 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Free text change information supplied by the pharmaceutical company

Tell your doctor immediately if you develop left upper belly (abdominal) pain, pain below the left rib cage or at the tip of your left shoulder (these may be symptoms of rupture of the spleen) after you stop taking IMBRUVICA.Tell your doctor immediately if you notice breathlessness, difficulty breathing when lying down, swelling of the feet, ankles or legs and weakness/tiredness (these may be signs of heart failure) during treatment with IMBRUVICA. 

Haemophagocytic lymphohistiocytosis

There have been rare reports of excessive activation of white blood cells associated with inflammation (haemophagocytic lymphohistiocytosis), which can be fatal if not diagnosed and treated early. If you experience multiple symptoms such as fever, swollen glands, bruising, or skin rash, contact your doctor immediately.

 

Common (may affect up to 1 in 10 people)

addition

  • heart failure

Uncommon (may affect up to 1 in 100 people)

addition

  • painful skin ulceration (pyoderma gangrenosum) or red, raised painful patches on the skin, fever and an increase in white blood cells (these may be signs of acute febrile neutrophilic dermatosis or Sweet’s syndrome).

 

Updated on 21 August 2020 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4     Special warnings and precautions for use

 ……………

 

Splenic rupture

Cases of splenic rupture have been reported following discontinuation of IMBRUVICA treatment. Disease status and spleen size should be carefully monitored (e.g. clinical examination, ultrasound) when IMBRUVICA treatment is interrupted or ceased. Patients who develop left upper abdominal or shoulder tip pain should be evaluated and a diagnosis of splenic rupture should be considered.

 

 

………..

 

Cardiac arrhythmia and cardiac failure

Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia and cardiac failure have been reported in patients treated with IMBRUVICA. Cases of atrial fibrillation and atrial flutter have been reported particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor all patients clinically for cardiac manifestations, including cardiac arrhythmia and cardiac failure. Patients who develop arrhythmic symptoms or new onset of dyspnoea, dizziness or fainting should be evaluated clinically and if indicated have an electrocardiogram (ECG) performed.

 

In patients who develop signs and/or symptoms of ventricular tachyarrhythmia, IMBRUVICA should be temporarily discontinued and a thorough clinical benefit/risk assessment should be performed before possibly restarting therapy.

 

In patients with preexisting atrial fibrillation requiring anticoagulant therapy, alternative treatment options to IMBRUVICA should be considered. In patients who develop atrial fibrillation on therapy with IMBRUVICA a thorough assessment of the risk for thromboembolic disease should be undertaken. In patients at high risk and where alternatives to IMBRUVICA are non‑suitable, tightly controlled treatment with anticoagulants should be considered.

 

Patients should be monitored for signs and symptoms of cardiac failure during IMBRUVICA treatment. In some of these cases cardiac failure resolved or improved after IMBRUVICA withdrawal or dose reduction.

 

……………….

 

Haemophagocytic lymphohistiocytosis (HLH)

Cases of HLH (including fatal cases) have been reported in patients treated with IMBRUVICA. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of extreme systemic inflammation. HLH is characterised by fever, hepatosplenomegaly, hypertriglyceridaemia, high serum ferritin and cytopenias. Patients should be informed about symptoms of HLH. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered.

 

4.8     Undesirable effects

 

Cardiac disorders

Common

Cardiac failurea,*

Atrial fibrillation

2

7

1

4

Uncommon

Ventricular tachyarrhythmia*,a,b

1

<1

 

 

 

Skin and subcutaneous tissue disorders

Very common

Rash*

31

3

Common

Urticariaa

Erythemaa

Onychoclasisa

1

2

3

<1

0

0

Uncommon

Angioedemaa

<1

<1

Panniculitis*,a

Neutrophilic dermatoses*, a

1

<1

0

<1

Not known

Stevens‑Johnson syndromea

Not known

Not known

 

 

Updated on 27 May 2020 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4     Special warnings and precautions for use

 

Viral reactivation

Cases of hepatitis B reactivation, including fatal events, have been reported in patients receiving IMBRUVICA. Hepatitis B virus (HBV) status should be established before initiating treatment with IMBRUVICA. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. If patients have positive hepatitis B serology, a liver disease expert should be consulted before the start of treatment and the patient should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Agents that may have their plasma concentrations altered by ibrutinib

Ibrutinib is a P‑gp and breast cancer resistance protein (BCRP) inhibitor in vitro. As no clinical data are available on this interaction, it cannot be excluded that ibrutinib could inhibit intestinal P‑gp and BCRP after a therapeutic dose. To minimise the potential for an interaction in the GI tract, oral narrow therapeutic range, P‑gp or BCRP substrates such as digoxin or methotrexate should be taken at least 6 hours before or after IMBRUVICA. Ibrutinib may also inhibit BCRP in the liver and increase the exposure of medicinal products that undergo BCRP‑mediated hepatic efflux, such as rosuvastatin.

 

Based on in vitro data, ibrutinib is a weak reversible inhibitor towards CYP3A4 at the intestinal level and may therefore increase the exposure to CYP3A4 substrates sensitive to gut CYP3A metabolism. No clinical data are available on this interaction. Caution should be exercised if co‑administering ibrutinib with CYP3A4 substrates administered orally with narrow therapeutic range (such as dihydroergotamine, ergotamine, fentanyl, cyclosporine, sirolimus and tacrolimus).

 

Based on in vitro data, ibrutinib is a weak CYP2B6 inducer and may have the potential to affect the expression of other enzymes and transporters regulated via the constitutive androstane receptor (CAR), e.g. CYP2C9, CYP2C19, UGT1A1 and MRP2. The clinical relevance is not known, but the exposure to substrates of CYP2B6 (such as efavirenz and bupropion) and of co‑regulated enzymes may be reduced upon co‑administration with ibrutinib.In a drug interaction study in patients with B-cell malignancies, a single 560 mg dose of ibrutinib did not have a clinically meaningful effect on the exposure of the CYP3A4 substrate midazolam. In the same study, 2 weeks of treatment with ibrutinib at 560 mg daily had no clinically relevant effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel), the CYP3A4 substrate midazolam, nor the CYP2B6 substrate bupropion.

 

4.6     Fertility, pregnancy and lactation

 

Women of child‑bearing potential/Contraception in females

Based on findings in animals, IMBRUVICA may cause foetal harm when administered to pregnant women. Women should avoid becoming pregnant while taking IMBRUVICA and for up to 3 months after ending treatment. Therefore, women of child‑bearing potential must use highly effective contraceptive measures while taking IMBRUVICA and for three months after stopping treatment. It is currently unknown whether ibrutinib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method.

 

 

 

 

 

 

4.8     Undesirable effects

 

 

Infections and infestations

Uncommon

Cryptococcal infections*

<1

0

Pneumocystis infections* #

1

1

Aspergillus infections*

1

<1

Hepatitis B reactivation@ #

<1

<1

 

Hepatobiliary disorders

Uncommon

Hepatic failure*,a #

<1

<1

 

 

5.1     Pharmacodynamic properties

 

Administrative updates~ spelling correction

 

 

5.2     Pharmacokinetic properties

 

Hepatic impairment

Ibrutinib is metabolised in the liver. A hepatic impairment trial was performed in non‑cancer subjects administered a single dose of 140 mg of medicinal product under fasting conditions. The effect of impaired liver function varied substantially between individuals, but on average a 2.7‑, 8.2‑, and 9.8‑fold increase in ibrutinib exposure (AUClast) was observed in subjects with mild (n=6, Child‑Pugh class A), moderate (n=10, Child‑Pugh class B) and severe (n=8, Child‑Pugh class C) hepatic impairment, respectively. The free fraction of ibrutinib also increased with degree of impairment, with 3.0, 3.8 and 4.8% in subjects with mild, moderate and severe liver impairment, respectively, compared to 3.3% in plasma from matched healthy controls within this study. The corresponding increase in unbound ibrutinib exposure (AUCunbound, last) is estimated to be 4.1‑, 9.8‑, and 13‑fold in subjects with mild, moderate, and severe hepatic impairment, respectively (see section 4.2).

 

Co‑administration with CYP substrates

In vitro studies indicated that ibrutinib is a weak reversible inhibitor toward CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and intestinal (but not hepatic) CYP3A4 and does not display clinically relevant time‑dependent inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6. The dihydrodiol metabolite of ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, and CYP2D6. The dihydrodiol metabolite is at most a weak inducer of CYP450 isoenzymes in vitro. Although ibrutinib is a sensitive CYP3A4 substrate, it does not have a clinically relevant effect on its own exposure.

 

Co‑administration with transport substrates/inhibitors

In vitro studies indicated that ibrutinib is not a substrate of P‑gp, nor other major transporters, except OCT2. The dihydrodiol metabolite and other metabolites are P‑gp substrates. Ibrutinib is an in vitro inhibitor of P‑gp and BCRP (see section 4.5).

 

Updated on 27 May 2020 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 16 January 2020 SmPC

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  • Change to section 4.8 - Undesirable effects
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4.8     Undesirable effects

 

Long-term safety

The long-term safety data over 4 years from 1177 patients (CLL/SLL n=807 and MCL n=370) treated with IMBRUVICA were analyzed. The median duration of treatment for CLL/SLL was 45 months with 70% and 40% of patients receiving treatment for more than 2 years and 4 years. The median duration of treatment for MCL was 11 months with 31% and 14% of patients receiving treatment for more than 2 years and 4 years. The overall known safety profile of IMBRUVICA-exposed patients remained consistent, other than an increasing prevalence of hypertension, with no new safety concerns identified. The prevalence for Grade 3 or greater hypertension was 4% (year 0‑1), 6% (year 1-2), 8% (year 2-3), and 8% (year 3-4). The incidence for the 4-year period was 10%.

The long-term safety data over 5 years from 1178 patients (treatment-naïve CLL/SLL n = 162, relapsed/refractory CLL/SLL n = 646, and relapsed/refractory MCL n = 370) treated with IMBRUVICA were analysed. The median duration of treatment for CLL/SLL was 51 months (range, 0.2 to 98 months) with 70% and 52% of patients receiving treatment for more than 2 years and 4 years, respectively. The median duration of treatment for MCL was 11 months (range, 0 to 87 months) with 31% and 17% of patients receiving treatment for more than 2 years and 4 years, respectively. The overall known safety profile of IMBRUVICA-exposed patients remained consistent, other than an increasing prevalence of hypertension, with no new safety concerns identified. The prevalence for Grade 3 or greater hypertension was 4% (year 0‑1), 6% (year 1-2), 8% (year 2-3), 9% (year 3-4), and 9% (year 4-5). The incidence for the 5-year period was 11%.

 

5.1     Pharmacodynamic properties

Final Analysis at 5665-month follow-up

With a median follow-up time on study of 5665 months in Study PCYC-1112-CA, an 8685% reduction in the risk of death or progression by investigator assessment was observed for patients in the IMBRUVICA arm. The median investigator-assessed PFS according to IWCLL criteria was 44.1 months [95% CI (38.5447, 56.8718)] in the IMBRUVICA arm and 8.1 months [95% CI (7.79, 8.25)] in the ofatumumab arm, respectively; HR=0.1514 [95% CI (0.11, 0.2019)]. The updated Kaplan-Meier curve for PFS is shown in Figure 7. The investigator-assessed ORR in the IMBRUVICA arm was 87.72% versus 22.4% in the ofatumumab arm. At the time of long-term follow-upfinal analysis, 133 (67.9%) of the 196 subjects originally randomized to the ofatumumab treatment arm had crossed over to ibrutinib treatment. The Kaplan-Meier landmark estimate for OS at 60-months was 62.2% in the IMBRUVICA arm.  The median investigator-assessed PFS2 (time from randomisation until PFS event after first subsequent anti-neoplastic therapy) according to IWCLL criteria was 65.4 months [95% CI (51.61, not estimable)] in the IMBRUVICA arm and 38.5 months [95% CI (19.98, 47.24)] in the ofatumumab arm, respectively; HR=0.54 [95% CI (0.41, 0.71)]. The median OS was 67.7 months [95% CI (61.0, not estimable)] in the IMBRUVICA arm.

 

The treatment effect of ibrutinib in Study PCYC-1112-CA was consistent across high-risk patients with deletion 17p/TP53 mutation, deletion 11q, and/or unmutated IGHV.

 

Figure 7:    Kaplan‑Meier Curve of PFS (ITT Population) in Study PCYC‑1112‑CA with 56 Months Follow-upat Final Analysis with 65 Months Follow-up

 

 

.

 

Combination therapy

The safety and efficacy of IMBRUVICA in WM were further evaluated in patients with treatment-naïve or previously treated WM in a randomized, multicenter, double-blinded phase 3 study of IMBRUVICA in combination with rituximab versus placebo in combination with rituximab (PCYC‑1127‑CA). Patients (n=150) were randomized 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with rituximab until disease progression or unacceptable toxicity. Rituximab was administered weekly at a dose of 375 mg/m2 for 4 consecutive weeks (weeks 1-4) followed by a second course of weekly rituximab for 4 consecutive weeks (weeks 17-20).

 

The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were Caucasian. Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of patients had a baseline ECOG performance status of 2. Forty-five percent of patients were treatment-naïve, and 55% of patients were previously treated. The median time since diagnosis was 52.6 months (treatment-naïve patients=6.5 months and previously treated patients=94.3 months). Among previously treated patients, the median number of prior treatments was 2 (range, 1 to 6 treatments). At baseline, the median serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), 63% of patients were anaemic (haemoglobin ≤11 g/dL or 6.8 mmol/L) and MYD88 L265P mutations were present in 77% of patients, absent in 13% of patients, and 9% of patients were not evaluable for mutation status.

 

Progression free survival (PFS) as assessed by IRC indicated an 80% statistically significant reduction in the risk of death or progression in the IMBRUVICA arm. Efficacy results for Study PCYC-1127-CA are shown in Table 11 and the Kaplan-Meier curve for PFS is shown in Figure 8. PFS hazard ratios for treatment-naïve patients, previously treated patients, and patients with or without MYD88 L265P mutations were consistent with the PFS hazard ratio for the ITT population.

 

Updated on 27 November 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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4.4     Special warnings and precautions for use

 

Cerebrovascular accidents

Cases of cerebrovascular accident, transient ischaemic attack and ischaemic stroke including fatalities have been reported with the use of ibrutinib, with and without concomitant atrial fibrillation and/or hypertension. Latency from the initiation of treatment with ibrutinib to the onset of ischemic central nervous vascular conditions was in the most cases after several months (more than 1 month in 78% and more than 6 months in 44% of cases) emphasizing the need for regular monitoring of patients (please see section 4.4 Cardiac arrhythmia and Hypertension and section 4.8).

 

 

4.8     Undesirable effects

 

 

Uncommon

Cerebrovascular accidenta, #

Transient ischaemic attacka

Ischaemic strokea, #

<1

1

<1

<1

<1

<1

 

 

Updated on 27 November 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 17 September 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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4.4       Special warnings and precautions for use

 

Bleeding‑related events

There have been reports of haemorrhagicbleeding events in patients treated with IMBRUVICA, both with and without thrombocytopenia. These include minor haemorrhagicbleeding events such as contusion, epistaxis, and petechiae; and major haemorrhagicbleeding events, some fatal, including gastrointestinal bleeding, intracranial haemorrhage, and haematuria.

 

Patients were excluded from participation in IMBRUVICA phase 2 and 3 studies if they required warfarin or other vitamin K antagonists. Warfarin or other vitamin K antagonists should not be administered concomitantly with IMBRUVICA.

 

Supplements such as fish oil and vitamin E preparations should be avoided. Use of IMBRUVICA in patients requiring other anticoagulants or medicinal products that inhibit platelet function may increase the risk of bleeding, and particular care should be taken if anticoagulant therapy is used.Use of either anticoagulants or medicinal products that inhibit platelet function (antiplatelet agents) concomitantly with IMBRUVICA increases the risk of major bleeding. A higher risk for major bleeding was observed with anticoagulant than with antiplatelet agents. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

 

Supplements such as fish oil and vitamin E preparations should be avoided.

Infections

Cases of invasive fungal infections, including cases of Aspergillosis, Cryptococcosis and Pneumocystis jiroveci infections have been reported following the use of ibrutinib. Reported cases of invasive fungal infections have been associated with fatal outcomes.

4.8       Undesirable effects

 

 

 

 

 

System organ class

Frequency

(All grades)

Adverse reactions

All Grades (%)

Grade ≥3 (%)

Infections and infestations

Very common

Pneumonia*#

Upper respiratory tract infection

Skin infection*

16

18

14

10

1

3

Common

Sepsis*#

Urinary tract infection

Sinusitis*

5

10

10

4

2

1

Uncommon

Cryptococcal infections*

<1

0

Pneumocystis infections* #

1

1

Aspergillus infections*

1

<1

Hepatitis B reactivation@

<1

<1

Hepatobiliary disorders

Not known Uncommon

Hepatic failure*,a

<1

<1

Updated on 17 September 2019 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 12 August 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 9 August 2019 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

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4.1     Therapeutic indications

 

IMBRUVICA as a single agent is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

 

IMBRUVICA as a single agent or in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1).

 

IMBRUVICA as a single agent or in combination with bendamustine and rituximab (BR) is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.

 

IMBRUVICA as a single agent is indicated for the treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo‑immunotherapy. IMBRUVICA in combination with rituximab is indicated for the treatment of adult patients with WM.

 

 

4.2     Posology and method of administration

 

When administering IMBRUVICA in combination with anti-CD20 therapies, it is recommended to administer IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.

 

4.4     Special warnings and precautions for use

 

Hypertension

Hypertension has occurred in patients treated with IMBRUVICA (see section 4.8). Regularly monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust antihypertensive medication throughout treatment with IMBRUVICA as appropriate.

 

 

4.8     Undesirable effects

 

Summary of the safety profile

The safety profile is based on pooled data from 9811200 patients treated with IMBRUVICA in three phase 2 clinical studies and foursix randomised phase 3 studies and from post‑marketing experience. Patients treated for MCL in clinical studies received IMBRUVICA at 560 mg once daily and patients treated for CLL or WM in clinical studies received IMBRUVICA at 420 mg once daily. All patients in clinical studies received IMBRUVICA until disease progression or no longer tolerated.

 

The most commonly occurring adverse reactions (≥20%) were diarrhoea, rash, neutropenia, haemorrhage (e.g., bruising), neutropenia, musculoskeletal pain, nausea, rash, and pyrexiathrombocytopenia. The most common grade 3/4 adverse reactions (≥5%) were neutropenia, pneumonia, and thrombocytopenia, and febrile neutropenia.

 

Tabulated list of adverse reactions

Adverse reactions in patients treated with ibrutinib for B‑cell malignancies and post‑marketing adverse reactions are listed below by system organ class and frequency grouping. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Table 1:      Adverse reactions reported in clinical studies or during post marketing surveillance in patients with B-cell malignancies

System organ class

Frequency

(All grades)

Adverse reactions

All Grades (%)

Grade ≥3 (%)

Infections and infestations

Very common

Pneumonia*#

Upper respiratory tract infection

Sinusitis*

Skin infection*

16

1918

11

1014

10

1

1

3

Common

Sepsis*#

Urinary tract infection

Sinusitis*

45

910

10

4

2

1

Uncommon

Hepatitis B reactivation@

<1

<1

Neoplasms benign and malignant (incl cysts and polyps)

Common

Non‑melanoma skin cancer*

Basal cell carcinoma

Squamous cell carcinoma

6

3

2

1

<1

<1

Blood and lymphatic system disorders

Very common

Neutropenia

Thrombocytopenia

30

2021

26

10

Common

Febrile neutropenia

Leukocytosis

Lymphocytosis

5

2

21

5

1

1

UncommonRare

Leukostasis syndrome

<1

<1

Immune system disorders

Common

Interstitial lung disease*,#,a

2

<1

Metabolism and nutrition disorders

Common

Tumour lysis syndromea

Hyperuricaemia

1

78

1

2

Nervous system disorders

Very common

Headache

13

1

Common

Peripheral neuropathy*,a

Dizziness

5

9

<1

0

Eye disorders

Common

Vision blurred

7

0

Cardiac disorders

Common

Atrial fibrillation

Ventricular tachyarrhythmia*b

67

1

34

0

Uncommon

Ventricular tachyarrhythmia*,a,b

1

<1

Vascular disorders

Very common

Haemorrhage*#

Bruising*

Hypertension*

3031

22

12

1

<1

5

Common

Subdural haematoma#

Epistaxis

Petechiae

Hypertension*

1

8

7

10

1

<1

0

4

Uncommon

Subdural haematoma#

1

1

Gastrointestinal disorders

Very common

Diarrhoea

Vomiting

Stomatitis*

Nausea

Constipation

4139

1413

1312

2725

16

3

<1

1

1

<1

Hepatobiliary disorders

Not known

Hepatic failure*,a

Not known

Not known

Skin and subcutaneous tissue disorders

Very common

Rash*

2231

23

Common

Urticariaa

Erythemaa

Onychoclasisa

1

2

23

<1

0

0

Uncommon

 

Angioedemaa

Panniculitis*,a

<1

<1

<1

0

Not known

Stevens‑Johnson syndromea

Not known

Not known

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Muscle spasms

Musculoskeletal pain*

1214

14

2830

1

<1

3

General disorders and administration site conditions

Very common

Pyrexia

Oedema peripheral

20

1415

2

1

     Frequencies are rounded to the nearest integer.

*     Includes multiple adverse reaction terms.

#     Includes events with fatal outcome.

@    Lower level term (LLT) used for selection.

a     Spontaneous reports from post‑marketing experience.

b     Frequency calculated from monotherapy clinical studies.

 

Description of selected adverse reactions

Discontinuation and dose reduction due to adverse reactions

Of the 9811200 patients treated with IMBRUVICA for B‑cell malignancies, 5% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation, and haemorrhage, and thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 67% of patients.

 

Elderly

Of the 9811200 patients treated with IMBRUVICA, 6264% were 65 years of age or older. Grade 3 or higher pneumonia occurred more frequently among elderly patients treated with IMBRUVICA (1312% of patients age ≥65 versus 7% of patients <65 years of age).

 

Long-term safety

The long-term safety data over 4 years from 1177 patients (CLL/SLL n=807 and MCL n=370) treated with IMBRUVICA were analyzed. The median duration of treatment for CLL/SLL was 45 months with 70% and 40% of patients receiving treatment for more than 2 years and 4 years. The median duration of treatment for MCL was 11 months with 31% and 14% of patients receiving treatment for more than 2 years and 4 years. The overall known safety profile of IMBRUVICA-exposed patients remained consistent, other than an increasing prevalence of hypertension, with no new safety concerns identified. The prevalence for Grade 3 or greater hypertension was 4% (year 0‑1), 6% (year 1-2), 8% (year 2-3), and 8% (year 3-4). The incidence for the 4-year period was 10%.

 

5.1     Pharmacodynamic properties

 

 

 

 

CLL

Patients previously untreated for CLL

Single agent

A randomised, multicenter, open‑label phase 3 study (PCYC‑1115‑CA) of IMBRUVICA versus chlorambucil was conducted in patients with treatment‑naïve CLL who were 65 years of age or older. Patients between 65 and 70 years of age were required to have at least one comorbidity that precluded the use of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab. Patients (n=269) were randomised 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil at a starting dose of 0.5 mg/kg on days 1 and 15 of each 28‑day cycle for a maximum of 12 cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability. After confirmed disease progression, patients on chlorambucil were able to crossover to ibrutinib.

 

The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were Caucasian. Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an ECOG performance status of 2. The study enrolled 269 patients with CLL. At baseline, 45% had advanced clinical stage (Rai Stage III or IV), 35% of patients had at least one tumor ≥5 cm, 39% with baseline anemia, 23% with baseline thrombocytopenia, 65% had elevated β2 microglobulin >3500 mcg/L, 47% had a CrCL<60 mlmL/min, and 20% of patients presented with del11q, 6% of patients presented with del 17p/tumor protein 53 (TP53) mutation, and 44% of patients presented with unmutated immunoglobulin heavy chain variable region (IGHV).

 

 

 

 

48-month follow-up

With a median follow-up time on study of 48 months in Study PCYC-1115-CA and its extension study, an 86% reduction in the risk of death or progression by investigator assessment was observed for patients in the IMBRUVICA arm. The median investigator-assessed PFS was not reached in the IMBRUVICA arm and was 15 months [95% CI (10.22, 19.35)] in the chlorambucil arm; (HR=0.14 [95% CI (0.09, 0.21)]). The 4-year PFS estimate was 73.9% in the IMBRUVICA arm and 15.5% in the chlorambucil arm, respectively. The updated Kaplan-Meier curve for PFS is shown in Figure 4. The investigator-assessed ORR was 91.2% in the IMBRUVICA arm versus 36.8% in the chlorambucil arm. The CR rate according to IWCLL criteria was 16.2% in the IMBRUVICA arm versus 3.0% in the chlorambucil arm. At the time of long-term follow-up, a total of 73 subjects (54.9%) originally randomized to the chlorambucil arm subsequently received ibrutinib as cross-over treatment. The Kaplan-Meier landmark estimate for OS at 48-months was 85.5% in the IMBRUVICA arm.

 

The treatment effect of ibrutinib in Study PCYC-1115-CA was consistent across high-risk patients with del 17p/TP53 mutation, del 11q, and/or unmutated IGHV.

 

Figure 4:    Kaplan‑Meier Curve of PFS (ITT Population) in Study PCYC‑1115‑CA with 48 Months Follow-up

 

 

Combination therapy

The safety and efficacy of IMBRUVICA in patients with treatment naïve CLL/SLL were further evaluated in a randomized, multi-center, open-label, Phase 3 study (PCYC-1130-CA) of IMBRUVICA in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab. The study enrolled patients who were 65 years of age or older or <65 years of age with coexisting medical conditions, reduced renal function as measured by creatinine clearance <70 mL/min, or presence of del17p/TP53 mutation. Patients (n=229) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity or chlorambucil at a dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for 6 cycles. In both arms, patients received 1000 mg of obinutuzumab on Days 1, 8 and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided between day 1 (100 mg) and day 2 (900 mg).

 

The median age was 71 years (range, 40 to 87 years), 64% were male, and 96% were Caucasian. All patients had a baseline ECOG performance status of 0 (48%) or 1-2 (52%). At baseline, 52% had advanced clinical stage (Rai Stage III or IV), 32% of patients had bulky disease (≥5 cm), 44% with baseline anemia, 22% with baseline thrombocytopenia, 28% had a CrCL <60 mL/min, and the median Cumulative Illness Rating Score for Geriatrics (CIRS-G) was 4 (range, 0 to 12). At baseline, 65% of patients presented with CLL/SLL with high risk factors (del17p/TP53 mutation [18%], del11q [15%], or unmutated IGHV [54%]).

 

Progression‑free survival (PFS) was assessed by IRC according to IWCLL criteria indicated a 77% statistically significant reduction in the risk of death or progression in the IMBRUVICA arm. With a median follow‑up time on study of 31 months, the median PFS was not reached in the IMBRUVICA+obinutuzumab arm and was 19 months in the chlorambucil+obinutuzumab arm. Efficacy results for Study PCYC‑1130‑CA are shown in Table 5 and the Kaplan-Meier curve for PFS is shown in Figure 5.

 

Table 5:      Efficacy results in Study PCYC-1130-CA

Endpoint

IMBRUVICA+Obinutuzumab
N=113

Chlorambucil+Obinutuzumab
N=116

Progression Free Survivala

Number of events (%)

24 (21.2)

74 (63.8)

Median (95% CI), months

Not reached

19.0 (15.1, 22.1)

HR (95% CI)

0.23 (0.15, 0.37)

Overall Response Ratea (%)

88.5

73.3

CRb

19.5

7.8

PRc

69.0

65.5

CI=confidence interval; HR=hazard ratio; CR=complete response; PR=partial response.

a     IRC evaluated.

b     Includes 1 patient in the IMBRUVICA+obinutuzumab arm with a complete response with incomplete marrow recovery (CRi).

c    PR=PR+nPR.

 

Figure 5:         Kaplan-Meier Curve of PFS (ITT Population) in Study PCYC-1130-CA

 

 

 

The treatment effect of ibrutinib was consistent across the high-risk CLL/SLL population (del 17p/TP53 mutation, del 11q, or unmutated IGHV), with a PFS HR of 0.15 [95% CI (0.09, 0.27)], as shown in Table 6. The 2-year PFS rate estimates for the high-risk CLL/SLL population were 78.8% [95% CI (67.3, 86.7)] and 15.5% [95% CI (8.1, 25.2)] in the IMBRUVICA+obinutuzumab and chlorambucil+obinutuzumab arms, respectively.

 

Table 6:      Subgroup Analysis of PFS (Study PCYC-1130-CA)

 

N

Hazard Ratio

95% CI

All subjects

229

0.231

0.145, 0.367

High risk (del17p/TP53/del11q/unmutated IGHV)

Yes

148

0.154

0.087, 0.270

No

81

0.521

0.221, 1.231

Del17p/TP53

Yes

41

0.109

0.031, 0.380

No

188

0.275

0.166, 0.455

FISH

Del17p

32

0.141

0.039, 0.506

Del11q

35

0.131

0.030, 0.573

Others

162

0.302

0.176, 0.520

Unmutated IGHV

Yes

123

0.150

0.084, 0.269

No

91

0.300

0.120, 0.749

Age

<65

46

0.293

0.122, 0.705

≥65

183

0.215

0.125, 0.372

Bulky disease

<5 cm

154

0.289

0.161, 0.521

≥5 cm

74

0.184

0.085, 0.398

Rai stage

0/I/II

110

0.221

0.115, 0.424

III/IV

119

0.246

0.127, 0.477

ECOG per CRF

0

110

0.226

0.110, 0.464

1-2

119

0.239

0.130, 0.438

Hazard ratio based on non‑stratified analysis

 

Any grade infusion-related reactions were observed in 25% of patients treated with IMBRUVICA+obinutuzumab and 58% of patients treated with chlorambucil+obinutuzumab. Grade 3 or higher or serious infusion-related reactions were observed in 3% of patients treated with IMBRUVICA+obinutuzumab and 9% of patients treated with chlorambucil+obinutuzumab.

 

Patients with CLL who received at least one prior therapy

Single agent

The safety and efficacy of IMBRUVICA in patients with CLL were demonstrated in one uncontrolled study and one randomised, controlled study. The open‑label, multi‑center study (PCYC‑1102‑CA) included 51 patients with relapsed or refractory CLL, who received 420 mg once daily. IMBRUVICA was administered until disease progression or unacceptable toxicity. The median age was 68 years (range: 37 to 82 years), median time since diagnosis was 80 months, and median number of prior treatments was 4 (range: 1 to 12 treatments), including 92.2% with a prior nucleoside analog, 98.0% with prior rituximab, 86.3% with a prior alkylator, 39.2% with prior bendamustine and 19.6% with prior ofatumumab. At baseline, 39.2% of patients had Rai Stage IV, 45.1% had bulky disease (≥5 cm), 35.3% had deletion 17p and 31.4% had deletion 11q.

 

ORR was assessed according to the 2008 IWCLL criteria by investigators and IRC. At a median duration follow up of 16.4 months, the ORR by IRC for the 51 relapsed or refractory patients was 64.7% (95% CI: 50.1%; 77.6%), all PRs. The ORR including PR with lymphocytosis was 70.6%. Median time to response was 1.9 months. The DOR ranged from 3.9 to 24.2+ months. The median DOR was not reached.

 

A randomised, multi‑center, open‑label phase 3 study of IMBRUVICA versus ofatumumab (PCYC‑1112‑CA) was conducted in patients with relapsed or refractory CLL. Patients (n=391) were randomised 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or ofatumumab for up to 12 doses (300/2,000 mg). Fifty‑seven patients randomised to ofatumumab crossed over following progression to receive IMBRUVICA. The median age was 67 years (range: 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range: 1 to 13 treatments). At baseline, 58% of patients had at least one tumour ≥5 cm. Thirty‑two percent of patients had deletion 17p (with 50% of patients having deletion 17p/TP53 mutation), and 3124% had 11q deletion, and 47% of patients had unmutated IGHV.

 

 

Figure 46:       Kaplan‑Meier curve of PFS (ITT Population) in Study PCYC‑1112- CA

 

 

56-month follow-up

With a median follow-up time on study of 56 months in Study PCYC-1112-CA, an 86% reduction in the risk of death or progression by investigator assessment was observed for patients in the IMBRUVICA arm. The median investigator-assessed PFS according to IWCLL criteria was 44.1 months [95% CI (38.54, 56.87)] in the IMBRUVICA arm and 8.1 months [95% CI (7.79, 8.25)] in the ofatumumab arm, respectively; HR=0.14 [95% CI (0.11, 0.19)]. The updated Kaplan-Meier curve for PFS is shown in Figure 7. The investigator-assessed ORR in the IMBRUVICA arm was 87.2% versus 22.4% in the ofatumumab arm. At the time of long-term follow-up, 133 (67.9%) of the 196 subjects originally randomized to the ofatumumab treatment arm had crossed over to ibrutinib treatment. The Kaplan-Meier landmark estimate for OS at 60-months was 62.2% in the IMBRUVICA arm.

 

The treatment effect of ibrutinib in Study PCYC-1112-CA was consistent across high-risk patients with deletion 17p/TP53 mutation, deletion 11q, and/or unmutated IGHV.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 7:    Kaplan‑Meier Curve of PFS (ITT Population) in Study PCYC‑1112‑CA with 56 Months Follow-up

 

 

Combination therapy

The safety and efficacy of IMBRUVICA in patients previously treated for CLL were further evaluated in a randomised, multicenter, double‑blinded phase 3 study of IMBRUVICA in combination with BR versus placebo+BR (Study CLL3001). Patients (n=578) were randomised 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with BR until disease progression, or unacceptable toxicity. All patients received BR for a maximum of six 28‑day cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2 and 3, and on Cycles 2‑6, Days 1 and 2 for up to 6 cycles. Rituximab was administered at a dose of 375 mg/m2 in the first cycle, Day 1, and 500 mg/m2 Cycles 2 through 6, Day 1. Ninety patients randomised to placebo+BR crossed over to receive IMBRUVICA following IRC confirmed progression. The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6 years and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, 56% of patients had at least one tumour ≥5 cm, 26% had del11q.

 

Progression free survival (PFS) was assessed by IRC according to IWCLL criteria. Efficacy results for Study CLL3001 are shown in Table 79.

 

Table 79:         Efficacy Results in patients with CLL (Study CLL3001)

Endpoint

IMBRUVICA+BR

N=289

Placebo+BR

N=289

PFSa

Median (95% CI), months

Not reached

13.3 (11.3, 13.9)

HR=0.203 [95% CI: 0.150, 0.276]

ORRb %

82.7

67.8

OSc

HR=0.628 [95% CI: 0.385, 1.024]

CI=confidence interval; HR=hazard ratio; ORR=overall response rate; OS=overall survival; PFS=progression-free survival

a     IRC evaluated.

b    IRC evaluated, ORR (complete response, complete response with incomplete marrow recovery, nodular partial response, partial response).

c    Median OS not reached for both arms.

 

WM

Single agent

The safety and efficacy of IMBRUVICA in WM (IgM‑excreting lymphoplasmacytic lymphoma) were evaluated in an open‑label, multi‑center, single‑arm trial of 63 previously treated patients. The median age was 63 years (range: 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the median number of prior treatments was 2 (range: 1 to 11 treatments). At baseline, the median serum IgM value was 3.5 g/dL, and 60% of patients were anemic (haemoglobin ≤11 g/dL or 6.8 mmol/L).

 

IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The primary endpoint in this study was ORR per investigator assessment. The ORR and DOR were assessed using criteria adopted from the Third International Workshop of WM. Responses to IMBRUVICA are shown in Table 810.

 

Table 810:       ORR and DOR in patients with WM

 

Total (N=63)

ORR (%)

87.3

95% CI (%)

(76.5, 94.4)

VGPR (%)

14.3

PR (%)

55.6

MR (%)

17.5

Median DOR months (range)

NR (0.03+, 18.8+)

CI=confidence interval; DOR=duration of response; NR=not reached; MR=minor response; PR=partial response; VGPR=very good partial response; ORR=MR+PR+VGPR

Median follow-up time on study=14.8 months

 

The median time to response was 1.0 month (range: 0.7‑13.4 months).

Efficacy results were also assessed by an IRC demonstrating an ORR of 83%, with a 11% VGPR rate and a 51% PR rate.

 

Combination therapy

The safety and efficacy of IMBRUVICA in WM were further evaluated in patients with treatment-naïve or previously treated WM in a randomized, multicenter, double-blinded phase 3 study of IMBRUVICA in combination with rituximab versus placebo in combination with rituximab (PCYC‑1127‑CA). Patients (n=150) were randomized 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with rituximab until disease progression or unacceptable toxicity. Rituximab was administered weekly at a dose of 375 mg/m2 for 4 consecutive weeks (weeks 1-4) followed by a second course of weekly rituximab for 4 consecutive weeks (weeks 17-20).

 

The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were Caucasian. Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of patients had a baseline ECOG performance status of 2. Forty-five percent of patients were treatment-naïve, and 55% of patients were previously treated. The median time since diagnosis was 52.6 months (treatment-naïve patients=6.5 months and previously treated patients=94.3 months). Among previously treated patients, the median number of prior treatments was 2 (range, 1 to 6 treatments). At baseline, the median serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), 63% of patients were anemic (hemoglobin ≤11 g/dL) and MYD88 L265P mutations were present in 77% of patients, absent in 13% of patients, and 9% of patients were not evaluable for mutation status.

 

Progression free survival (PFS) as assessed by IRC indicated an 80% statistically significant reduction in the risk of death or progression in the IMBRUVICA arm. Efficacy results for Study PCYC-1127-CA are shown in Table 11 and the Kaplan-Meier curve for PFS is shown in Figure 8. PFS hazard ratios for treatment-naïve patients, previously treated patients, and patients with or without MYD88 L265P mutations were consistent with the PFS hazard ratio for the ITT population.

 

Table 11:         Efficacy results in Study PCYC-1127-CA

Endpoint

IMBRUVICA+R
N=75

Placebo+R
N=75

Progression Free Survivala

Number of events (%)

14 (18.7)

42 (56.0)

Median (95% CI), months

Not reached

20.3 (13.7, 27.6)

HR (95% CI)

0.20 (0.11, 0.38)

TTnT

Median (95% CI), months

Not reached

18.1 (11.1, NE)

HR (95% CI)

0.1 (0.04, 0.23)

Best Overall Response (%)

 

 

CR

2.7

1.3

VGPR

22.7

4.0

PR

46.7

26.7

MR

20.0

14.7

Overall Response Rate (CR, VGPR, PR, MR)b (%)

92.0

46.7

Median duration of overall response, months (range)

Not reached (1.9+, 36.4+)

24.8 (1.9, 30.3+)

Response Rate (CR, VGPR, PR)b (%)

72.0

32.0

Median duration of response, months (range)

Not reached (1.9+, 36.4+)

21.2 (4.6, 25.8)

Rate of Sustained Hemoglobin Improvementb, c (%)

73.3

41.3

CI=confidence interval; CR=complete response; HR=hazard ratio; MR=minor response; NE=not estimable; PR=partial response; R=Rituximab; TTnT=time to next treatment; VGPR=very good partial response

a     IRC evaluated.

b     p-value associated with response rate was <0.0001.

c     Defined as increase of ≥2 g/dL over baseline regardless of baseline value, or an increase to >11 g/dL with a ≥0.5 g/dL improvement if baseline was ≤11 g/dL.

Median follow-up time on study=26.5 months.

 

Figure 8:         Kaplan-Meier Curve of PFS (ITT Population) in Study PCYC-1127-CA

Grade 3 or 4 infusion-related reactions were observed in 1% of patients treated with IMBRUVICA+rituximab and 16% of patients treated with placebo+rituximab.

 

Tumor flare in the form of IgM increase occurred in 8.0% of subjects in the IMBRUVICA+rituximab arm and 46.7% of subjects in the placebo+rituximab arm.

 

Study PCYC-1127-CA had a separate monotherapy arm of 31 patients with previously treated WM who failed prior rituximab-containing therapy and received single agent IMBRUVICA. The median age was 67 years (range, 47 to 90 years). Eighty-one percent of patients had a baseline ECOG performance status of 0 or 1, and 19% had a baseline ECOG performance status of 2. The median number of prior treatments was 4 (range, 1 to 7 treatments). The response rate per IRC observed in the monotherapy arm was 71% (0% CR, 29% VGPR, 42% PR). The overall response rate per IRC observed in the monotherapy arm was 87% (0% CR, 29% VGPR, 42% PR, 16% MR). With a median follow-up time on study of 34 months (range, 8.6+ to 37.7 months), the median duration of response has not been reached.

 

Updated on 28 June 2019 PIL

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