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Janssen-Cilag Ltd

50 - 100 Holmers Farm Way, High Wycombe, Bucks, HP12 4EG, UK
Telephone: +44 1494 567 567
Fax: +44 1494 567 568
Medical Information Direct Line: +353 1 800 709 122
Medical Information e-mail: medinfo@janssen-cilag.co.uk
Customer Care direct line: +353 1 620 2300
Medical Information Facsimile: +44 (0) 1494 567 445
Summary of Product Characteristics last updated on medicines.ie: 08/11/2017
SPC Imbruvica 140 mg hard capsules

When a pharmaceutical company changes an SPC or PIL, 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 08/11/2017 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   28-Sep-2017
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



4.2          Posology and method of administration

 

Dose adjustments

 

Moderate and strong CYP3A4 inhibitors increase the exposure of ibrutinib (see sections 4.4 and 4.5).

 

The IMBRUVICA dose should be lowered to 140 280 mg once daily (one two capsules) when used concomitantly with moderate CYP3A4 inhibitors.

 

4.4          Special warnings and precautions for use

 

Bleeding‑related events

There have been reports of haemorrhagic events in patients treated with IMBRUVICA, both with and without thrombocytopenia. These include minor haemorrhagic events such as contusion, epistaxis, and petechiae; and major haemorrhagic 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. Patients with congenital bleeding diathesis have not been studied.

 

IMBRUVICA should be held at least 3 to 7 days pre- and post‑surgery depending upon the type of surgery and the risk of bleeding.

 

The mechanism for the bleeding-related events is not fully understood. Patients with congenital bleeding diathesis have not been studied.

 

Leukostasis

Cases of leukostasis have been reported in patients treated with IMBRUVICA. A high number of circulating lymphocytes (> 400,000/mcL) may confer increased risk. Consider temporarily holding IMBRUVICA. Patients should be closely monitored. Administer supportive care including hydration and/or cytoreduction as indicated.

 

Infections

Infections (including sepsis, neutropenic sepsis, bacterial, viral, or fungal infections) were observed in patients treated with IMBRUVICA. Some of these infections have been associated with hospitalisation and death. Most patients with fatal infections also had neutropenia. Patients should be monitored for fever, neutropenia and infections and appropriate anti‑infective therapy should be instituted as indicated. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

 

 

4.5          Interaction with other medicinal products and other forms of interaction

 

Ibrutinib is primarily metabolised by cytochrome P450 enzyme 3A4 (CYP3A4).

 

Agents that may increase ibrutinib plasma concentrations

Concomitant use of IMBRUVICA and medicinal products that strongly or moderately inhibit CYP3A4 can increase ibrutinib exposure and strong CYP3A4 inhibitors should be avoided.

 

Strong CYP3A4 inhibitors

Co‑administration of ketoconazole, a very strong CYP3A4 inhibitor, in 18 fasted healthy subjects, increased exposure (Cmax and AUC) of ibrutinib by 29‑ and 24‑fold, respectively. Simulations using fasted conditions suggested that the strong CYP3A4 inhibitor clarithromycin may increase the AUC of ibrutinib by a factor of 14. In patients with B‑cell malignancies taking IMBRUVICA with food, co‑administration of the strong CYP3A4 inhibitor voriconazole increased Cmax by 6.7‑fold and AUC by 5.7‑fold. Strong inhibitors of CYP3A4 (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodon and, cobicistat, voriconazole and posaconazole) should be avoided. If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, reduce the IMBRUVICA dose to 140 mg (one capsule) for the duration of the inhibitor use or withhold IMBRUVICAtreatment temporarily (for 7 days or less). Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).

 

Moderate CYP3A4 inhibitors

In patients with B‑cell malignancies taking IMBRUVICA with food, co‑administration of the CYP3A4 inhibitor erythromycin increased Cmax by 3.4‑fold and AUC by 3.0‑fold.  Simulations using fasted conditions suggested that moderate CYP3A4 inhibitors, diltiazem, erythromycin and voriconazole, may increase the AUC of ibrutinib 5‑9 fold. Moderate inhibitors (e.g., voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) should be avoided. If a moderate CYP3A4 inhibitor (e.g., fluconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, amiodarone and dronedarone) is indicated, must be used, reduce IMBRUVICA dose  treatment to 28140 mg (twoone capsules) for the duration of the inhibitor use. Monitor patient closely for toxicity and follow dose modification guidance as needed (see sections 4.2 and 4.4).

 

Mild CYP3A4 inhibitors

Simulations using clinically relevant fasted conditions suggested that the mild CYP3A4 inhibitors azithromycin and fluvoxamine may increase the AUC of ibrutinib by < 2‑fold. No dose adjustment is required in combination with mild inhibitors. Monitor patient closely for toxicity and follow dose modification guidance as needed.

 

 

 

5.1          Pharmacodynamic properties

Lymphocytosis was not observed in patients with WM treated with IMBRUVICA.

 

In vitro platelet aggregation

In an in vitro study, ibrutinib demonstrated inhibition of collagen‑induced platelet aggregation. Ibrutinib did not show meaningful inhibition of platelet aggregation using other agonists of platelet aggregation.

Updated on 30/08/2017 and displayed until 08/11/2017
Reasons for adding or 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
Date of revision of text on the SPC:   24-Aug-2017
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

 

Cardiac arrhythmia

Atrial fibrillation, atrial flutter and cases of ventricular tachyarrhythmia 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 arrhythmia. 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.

 

 ……………………

 

 

Viral reactivation

Cases of hepatitis B reactivation 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.

 

 

4.8     Undesirable effects

 

 

System organ class

Frequency

(All grades)

Adverse reactions

All Grades (%)

Grade ≥ 3 (%)

Infections and infestations

Very common

Pneumonia*#

Upper respiratory tract infection

Sinusitis*

Skin infection*

16

19

11

10

10

1

1

3

Common

Sepsis*#

Urinary tract infection

4

9

4

2

Uncommon

Hepatitis B reactivation@

<1

<1

 

 

Cardiac disorders

Common

Atrial fibrillation

 Ventricular tachyarrhythmia*b

6

1

3

0

 

 

     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.

 

 

Updated on 19/06/2017 and displayed until 30/08/2017
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   18-May-2017
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



Section 4.5: revision of information on the effect of proton pump inhibitors.

Section 5.2: addition of information on pH dependent solubility.

Updated on 23/05/2017 and displayed until 19/06/2017
Reasons for adding or updating:
  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   18-May-2017
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



6.3     Shelf life

 

years.

Updated on 24/03/2017 and displayed until 23/05/2017
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   23-Feb-2017
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

 

Effects on the QT interval

In a phase 2 study, ECG evaluations showed IMBRUVICA produced a mild decrease in QTcF interval (mean 7.5 ms). Although the underlying mechanism and safety relevance of this finding are not known, clinicians should use clinical judgment when assessing whether to prescribe ibrutinib to patients at risk from further shortening their QTc duration (e.g., Congenital Short QT Syndrome or patients with a family history of such a syndrome).

 

5.1     Pharmacodynamic properties

 

 

Effect on QT/QTc interval and cardiac electrophysiology

The effect of ibrutinib on the QTc interval was evaluated in 20 healthy male and female subjects in a randomised, double‑blind thorough QT study with placebo and positive controls. At a supratherapeutic dose of 1680 mg, ibrutinib did not prolong the QTc interval to any clinically relevant extent. The largest upper bound of the 2‑sided 90% CI for the baseline adjusted mean differences between ibrutinib and placebo was below 10 ms. In this same study, a concentration dependent shortening in the QTc interval was observed (‑5.3 ms [90% CI: ‑9.4, ‑1.1] at a Cmax of 719 ng/mL following the supratherapeutic dose of 1680 mg).

Updated on 22/02/2017 and displayed until 24/03/2017
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   10-Feb-2017
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company

 Section 4.4

Addition of:

Cases of Progressive Multifocal Leukoencephalopathy (PML) including fatal ones have been reported following the use of ibrutinib within the context of a prior or concomitant immunosuppressive therapy. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected then appropriate diagnostic evaluations should be undertaken and treatment suspended until PML is excluded. If any doubt exists, referral to a neurologist and appropriate diagnostic measures for PML including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments should be considered.

Updated on 17/01/2017 and displayed until 22/02/2017
Reasons for adding or updating:
  • 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
Date of revision of text on the SPC:   15-Dec-2016
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

 

 

Atrial fibrillation/flutter

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

 

 

 

 

4.8     Undesirable effects

 

 

 

Skin and subcutaneous tissue disorders

Very common

Rash*

22

2

Common

Urticariaa

Erythemaa

Onychoclasisa

1

2

2

<1

0

0

Uncommon

Angioedemaa

<1

<1

Not known

Stevens‑Johnson syndromea

Not known

Not known

 

5.1     Pharmacodynamic properties

 

Notes added to nottom of Tables: 3, 4, 5 and 7

Updated on 06/09/2016 and displayed until 17/01/2017
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • 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
Date of revision of text on the SPC:   25-Aug-2016
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



Addition in red text

 

Section 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 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.

 

4.2     Posology and method of administration

 

Chronic lymphocytic leukaemia and Waldenström’s macroglobulinaemia (WM)

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

The recommended dose for the treatment of WM is 420 mg (three capsules) once daily.

 

 

4.8     Undesirable effects

 

Summary of the safety profile

The safety profile is based on pooled data from 555981 patients treated with IMBRUVICA in three phase 2 clinical studies and twofour 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, haemorrhage (e.g., bruising), musculoskeletal pain, nausea, rash, upper respiratory tract infection, haemorrhage, bruising, rash, and nauseapyrexia. The most common grade 3/4 adverse reactions (≥ 5%) were anaemia, neutropenia, pneumonia, and thrombocytopenia, and febrile neutropenia.

 

Tabulated list of adverse reactions

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

 

 

Drug interaction table updated

 

Change of frequency

Urinary tract infection -changed from very common to common

Tumour lysis syndrome  changed from uncommon to common 

Urticaria – common changed from uncommon to common
dizziness - changed from very common to common

 

Removal of  anaemia and dry mouth

 

Of the 555981 patients treated with IMBRUVICA for Bcell malignanciesCLL, MCL or WM, 45% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation and haemorrhageinfections, subdural haematoma, and atrial fibrillation. Adverse reactions leading to dose reduction occurred in approximately 65% of patients.

 

Elderly

Of the 555981 patients treated with IMBRUVICA, 6962% were 65 years of age or older. Grade 3 or higher pneumoniaadverse reactions occurred more frequently among elderly patients treated with IMBRUVICA (4813% of patients age ≥ 65 versus 417% of younger patients < 65 years of age). Grade 3 or higher adverse reactions occurring more frequently among elderly patients included pneumonia, atrial fibrillation and urinary tract infection.

 

5.1     Pharmacodynamic properties

 

IMBRUVICA. This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings. In both disease types, lymphocytosis typically occurs during the first monthfew weeks of IMBRUVICA therapy (median time 1.1 weeks) and typically resolves within a median of 8.0 weeks in patients with MCL and 18.714 weeks in patients with CLL. A large increase in the number of circulating lymphocytes (e.g., > 400,000/mcL) has been observed in some patients.

 

 

The safety and efficacy of IMBRUVICA were demonstrated in a randomised phase 3, openlabel, multicenter study including 280 patients with MCL who received at least one prior therapy (Study MCL3001). Patients were randomised 1:1 to receive either IMBRUVICA orally at 560 mg once daily for 21 days or temsirolimus intravenously at 175 mg on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each subsequent 21-day cycle. Treatment on both arms continued until disease progression or unacceptable toxicity. The median age was 68 years (range, 34; 88), 74% were male and 87% were Caucasian. The median time since diagnosis was 43 months, and median number of prior treatments was 2 (range: 1 to 9 treatments), including 51% with prior high‑dose chemotherapy, 18% with prior bortezomib, 5% with prior lenalidomide, and 24% with prior stem cell transplant. At baseline, 53% of patients had bulky disease (≥ 5 cm), 21% had high‑risk score by Simplified MIPI, 60% had extranodal disease and 54% had bone marrow involvement at screening.

 

Progessionfree survival (PFS) was assessed by IRC according to the revised International Working Group (IWG) for non‑Hodgkin’s lymphoma (NHL) criteria. Efficacy results for Study MCL3001 are shown in Table 3 and the KaplanMeier curve for PFS in Figure 1.

 

Table 3:      Efficacy Results in patients with relapsed or refractory MCL (Study MCL3001)

Endpoint

IMBRUVICA

N = 139

Temsirolimus

N = 141

Progression‑Free Survivala

Median Progression‑Free Survival (95% CI), (months)

14.6 (10.4, NE)

6.2 (4.2, 7.9)

HR = 0.43 [95% CI: 0.32, 0.58]

Overall Response Rate (%)

71.9

40.4

p-value

p < 0.0001

a    IRC evaluated;

 

A smaller proportion of patients treated with ibrutinib experienced a clinically meaningful worsening of lymphoma symptoms versus temsirolimus (27% versus 52%) and time to worsening of symptoms occurred more slowly with ibrutinib versus temsirolimus (HR 0.27, p < 0.0001).

 

 

Combination therapy

The safety and efficacy of IMBRUVICA in patients previously treated for CLL were further evaluated in a randomised, multicenter, doubleblinded 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 28day 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 7.

 

Table 7:           Efficacy Results in patients with chronic lymphocytic leukaemia (Study CLL3001)

Endpoint

IMBRUVICA + BR

N = 289

Placebo + BR

N = 289

Progression Free Survival

Median (95% CI), months

Not reached

13.3 (11.3, 13.9)

HR = 0.203 [95% CI: 0.150, 0.276]

Overall Response Ratea %

82.7

67.8

Overall Survival (OS)b

HR = 0.628 [95% CI: 0.385, 1.024]

a     IRC evaluated, ORR (CR, Cri, nPR, PR)

b     Median OS not reached for both arms

 

 

 

 

 

Updated on 18/08/2016 and displayed until 06/09/2016
Reasons for adding or 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
Date of revision of text on the SPC:   21-Jul-2016
Legal Category:   Product subject to medical prescription which may not be renewed (A)

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4.4     Special warnings and precautions for use

 

Interstitial Lung Disease (ILD)

Cases of ILD have been reported in patients treated with IMBRUVICA. Monitor patients for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt IMBRUVICA and manage ILD appropriately. If symptoms persist, consider the risks and benefits of IMBRUVICA treatment and follow the dose modification guidelines.

 

4.8     Undesirable effects

 

Immune system disorders

Common

Interstitial lung disease*,a

 

 

Updated on 01/06/2016 and displayed until 18/08/2016
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • 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 - Pharmacological properties
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   26-May-2016
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 is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

 

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

 

IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo‑immunotherapy.

 

IMBRUVICA 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.

 

4.4     Special warnings and precautions for use

 

Non‑melanoma skin cancer

Non‑melanoma skin cancers were reported more frequently in patients treated with IMBRUVICA than in patients treated with comparators in pooled comparative randomised phase 3 studies. Monitor patients for the appearance of non‑melanoma skin cancer.

 

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

 

Ibrutinib is primarily metabolised by cytochrome P450 enzyme 3A4 (CYP3A)

 

4.6     Fertility, pregnancy and lactation

 

Fertility

No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED]16 mg/kg/day)No male or female fertility studies have been conducted (see section 5.3). No human data on the effects of ibrutinib on fertility are available.

 

 

 

4.8     Undesirable effects

 

Summary of the safety profile

The safety profile is based on pooled data from 420555 patients treated with IMBRUVICA in three phase 2 clinical studies and onetwo randomised phase 3 studiesy 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 neutropenia, anaemia, diarrhoea, musculoskeletal pain, upper respiratory tract infection, haemorrhage, bruising, rash, and nausea and pyrexia. The most common grade 3/4 adverse reactions (≥ 5%) were anaemia, neutropenia, pneumonia and thrombocytopenia.

 

Tabulated list of adverse reactions

Treatment‑emergent aAdverse reactions for MCL, CLL or WM and post‑marketing adverse reactions are listed below by system organ class and frequency grouping. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), 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 drug reactions reported in clinical studies or during post marketing surveillance in patients with B-cell malignanciesTreatment‑emergent adverse reactions in patients treated with ibrutinib for MCL, CLL or WM (N = 420555) and post‑marketing adverse reactions

System organ class

Frequency

(All grades)

Adverse reactions

Infections and infestations

Very common

Pneumonia*

Upper respiratory tract infection

Urinary tract infection

Sinusitis*

Skin infection*

Common

Sepsis*

Neoplasms benign and malignant (incl cysts and polyps)

Common

Non‑melanoma skin cancer*

Basal cell carcinoma

Squamous cell carcinoma

 

Blood and lymphatic system disorders

Very common

Neutropenia

Thrombocytopenia

Anaemia

Common

Febrile neutropenia

Leukocytosis

Lymphocytosis

Uncommon

Leukostasis syndrome

Metabolism and nutrition disorders

Common

Dehydration

Hyperuricaemia

Uncommon

Tumour lysis syndrome

Nervous system disorders

Very common

Dizziness

Headache

Eye disorders

Common

Vision blurred

Cardiac disorders

Common

Atrial fibrillation

Vascular disorders

Very common

Haemorrhage*

Epistaxis

Bruising*

Petechiae

 

 

Common

Subdural haematoma

Epistaxis

Petechiae

Hypertension*

 

 

 

Gastrointestinal disorders

Very common

Diarrhoea

Vomiting

Stomatitis*

Nausea

Constipation

Common

Dry mouth

Hepatobiliary disorders

Not known

Hepatic failure*,a

Skin and subcutaneous tissue disorders

Very common

Rash*

Common

Erythema

Uncommon

Angioedema

Urticaria

Not known

Erythema

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Muscle spasms

Musculoskeletal pain*

 

General disorders and administration site conditions

Very common

Pyrexia

Oedema peripheral

*    Includes multiple adverse reaction terms.

a     Spontaneous reports from post‑marketing experience.

 

Discontinuation and dose reduction due to adverse drug reactions

Of the 420555 patients treated with IMBRUVICA for CLL, MCL or WM, 4% discontinued treatment primarily due to adverse reactions. These included infections, and subdural haematoma, and atrial fibrillation. Adverse reactions leading to dose reduction occurred in approximately 76% of patients.

 

Elderly

Of the 420555 patients treated with IMBRUVICA, 5969% were above 65 years of age or older. Grade 3 or higher adverse reactions occurred more frequently among elderly patients treated with IMBRUVICA (5348% of patients age ≥ 65 versus 4241% of younger patients ). Grade 3 or higher adverse reactions occurring more frequently among elderly patients were included pneumonia, atrial fibrillation and urinary tract infection.

 

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

……..

 

Chronic lymphocytic leukaemia

Patients previously untreated for CLL

A randomised, multicenter, openlabel phase 3 study (PCYC‑1115‑CA) of IMBRUVICA versus chlorambucil was conducted in patients with treatmentnaïve 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 28day 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 ml/min, and 20% of patients presented with del11q.

 

Progression free survival (PFS) as assessed by IRC according to International Workshop on CLL (IWCLL) criteria indicated an 84% statistically significant reduction in the risk of death or progression in the IMBRUVICA arm. Efficacy results for Study PCYC‑1115‑CA are shown in Table 3 and the KaplanMeier curves for PFS and OS are shown in Figures 1 and 2, respectively.

 

There was a statistically significant sustained platelet or hemoglobin improvement in the ITT population in favor of ibrutinib versus chlorambucil. In patients with baseline cytopenias, sustained hematologic improvement was: platelets 77.1% versus 42.9%; hemoglobin 84.3% versus 45.5% for ibrutinib and chlorambucil respectively.

 

Table 3:           Efficacy results in Study PCYC‑1115‑CA

Endpoint

IMBRUVICA

N = 136

Chlorambucil

N = 133

Progression free survivala

Number of events (%)

15 (11.0)

64 (48.1)

Median (95% CI), months

Not reached

18.9 (14.1, 22.0)

HRb (95% CI)

0.161 (0.091, 0.283)

Overall response ratea (CR +PR)

82.4%

35.3%

Pvalue

< 0.0001

Overall survival

 

Number of deaths (%)

3 (2.2)

17 (12.8)

HR (95% CI)

0.163 (0.048, 0.558)

a     IRC evaluated, median follow-up 18.4 months;

b     HR = hazard ratio;

c     Median OS not reached for both arms. p < 0.005 for OS.

 

Figure 1:    KaplanMeier curve of progression‑free survival (ITT Population) in Study PCYC‑1115‑CA


 

Figure 2:    KaplanMeier curve of overall survival (ITT Population) in Study PCYC‑1115‑CA

 

5.3     Preclinical safety data

 

In pregnant rabbits, ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal malformations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased post‑implantation loss. Ibrutinib caused malformations in rabbits at a dose of 15 mg/kg/day (approximately 2.0 times the exposure (AUC) in patients with MCL administered ibrutinib 560 mg daily and 2.8 times the exposure in patients with CLL or WM receiving ibrutinib dose 420 mg per day). Consequently the foetal NOAEL was 5 mg/kg/day (approximately 0.7 times the AUC of ibrutinib at a dose of 560 mg daily) (see section 4.6).

 

Fertility

No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED]16 mg/kg/day).Fertility studies with ibrutinib have not been conducted.

 

 

 

 

Updated on 29/03/2016 and displayed until 01/06/2016
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Date of revision of text on the SPC:   25-Feb-2016
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4.8     Undesirable effects

 

Addition of

 

Hepatobiliary disorders

Not known

Hepatic failure*,a

 

4.9     Overdose

Addition of

In a separate study, one healthy subject who received a dose of 1,680 mg experienced reversible grade 4 hepatic enzyme increases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)].

Updated on 19/11/2015 and displayed until 29/03/2016
Reasons for adding or updating:
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  • Change to section 5.1 - Pharmacodynamic properties
Date of revision of text on the SPC:   22-Oct-2015
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Addition of in vitro drug interaction study reports
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  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   23-Jul-2015
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Addition of:

Skin and subcutaneous tissue disorders

Very common

Rash*

Uncommon

Angioedema

Urticaria

Not known

Erythema

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Date of revision of text on the SPC:   03-Jul-2015
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Approval of new indication:

IMBRUVICA 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.

Updated on 27/03/2015 and displayed until 14/07/2015
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  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
Date of revision of text on the SPC:   26-Feb-2015
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Update to Section 4.2 hepatic impairment text and inclusion of tumour lysis syndrome as an uncommon ADR.

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Date of revision of text on the SPC:   21-Oct-2014
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Change to Section 9 - Date of first authorisation: 21 October 2014
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None provided

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Active Ingredients

 
   Ibrutinib