Imbruvica

Imbruvica

ibrutinib

Manufacturer:

Johnson & Johnson

Distributor:

Johnson & Johnson
Full Prescribing Info
Contents
Ibrutinib.
Description
Each capsule contains 140 mg Ibrutinib.
The excipients are croscarmellose sodium, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The capsule shell contains gelatin and titanium dioxide (E171). Black ink printing: iron oxide black (E172), propylene glycol and shellac glaze.
Action
Pharmacotherapeutic Group: Protein kinase inhibitors.
Pharmacology: Pharmacodynamics: Mechanism of Action: Ibrutinib is a potent, small-molecule inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys-481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. BTK, a member of the Tec kinase family, is an important signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is implicated in the pathogenesis of several B-cell malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and chronic lymphocytic leukemia (CLL). BTK's pivotal role in signalling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion. Preclinical studies have shown that ibrutinib effectively inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.
Lymphocytosis: Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥50% increase from baseline and an absolute count >5,000/mcL), often associated with reduction of lymphadenopathy, has been observed in about three fourths of patients with CLL treated with Ibrutinib (Imbruvica). This effect has also been observed in about one third of patients with relapsed or refractory MCL treated with Ibrutinib (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 month of Ibrutinib (Imbruvica) therapy and typically resolves within a median of 8.0 weeks in patients with MCL and 14 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.
Lymphocytosis was not observed in patients with WM treated with Ibrutinib (Imbruvica).
Clinical efficacy and safety: Mantle cell lymphoma: The safety and efficacy of Ibrutinib (Imbruvica) in patients with relapsed or refractory MCL were evaluated in a single open-label, multi-center phase 2 study (PCYC-1104-CA) of 111 patients. The median age was 68 years (range: 40 to 84 years), 77% were male and 92% were Caucasian. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 3 or greater were excluded from the study. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range: 1 to 5 treatments), including 35% with prior high-dose chemotherapy, 43% with prior bortezomib, 24% with prior lenalidomide, and 11% with prior autologous or allogeneic stem cell transplant. At baseline, 39% of patients had bulky disease (≥5 cm), 49% had high-risk score by Simplified MCL International Prognostic Index (MIPI), and 72% had advanced disease (extranodal and/or bone marrow involvement) at screening.
Ibrutinib (Imbruvica) was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumour response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to Ibrutinib (Imbruvica) are shown in Table 1. (See Table 1.)

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The efficacy data was further evaluated by an Independent Review Committee (IRC) demonstrating an ORR of 69%, with a 21% complete response (CR) rate and a 48% partial response (PR) rate. The IRC estimated median DOR was 19.6 months.
The overall response to Ibrutinib (Imbruvica) was independent of prior treatment including bortezomib and lenalidomide or underlying risk/prognostic factors, bulky disease, gender or age.
The safety and efficacy of Ibrutinib (Imbruvica) were demonstrated in a randomised phase 3, open-label, multicenter study including 280 patients with MCL who received at least one prior therapy (Study MCL3001). Patients were randomised 1:1 to receive either Ibrutinib (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.
Progression-free 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 2 and the Kaplan-Meier curve for PFS in Figure 1. (See Table 2 and Figure 1.)

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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).

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Chronic lymphocytic leukaemia: Patients previously untreated for CLL: A randomised, multicenter, open-label phase 3 study (PCYC-1115-CA) of Ibrutinib (Imbruvica) versus chlorambucil was conducted in patients with treatment-naive 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 Ibrutinib (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 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 Ibrutinib (Imbruvica) arm. Efficacy results for Study PCYC-1115-CA are shown in Table 3 and the Kaplan-Meier curves for PFS and OS are shown in Figures 2 and 3, respectively. (See Table 3 and Figures 2 and 3.)
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.

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Patients with CLL who received at least one prior therapy: The safety and efficacy of Ibrutinib (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. Ibrutinib (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 Ibrutinib (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 Ibrutinib (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 Ibrutinib (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 and 31% had 11q deletion.
Progression free survival (PFS) as assessed by an IRC according to IWCLL criteria indicated a 78% statistically significant reduction in the risk of death or progression for patients in the Ibrutinib (Imbruvica) arm. Analysis of overall survival (OS) demonstrated a 57% statistically significant reduction in the risk of death for patients in the Ibrutinib (Imbruvica) arm. Efficacy results for Study PCYC-1112-CA are shown in Table 4. (See Table 4.)

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The efficacy was similar across all of the subgroups examined, including in patients with and without deletion 17p, a pre-specified stratification factor (Table 5). (See Table 5.)

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The Kaplan-Meier curve for PFS is shown in Figure 4. (See Figure 4.)

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Combination therapy: The safety and efficacy of Ibrutinib (Imbruvica) in patients previously treated for CLL were further evaluated in a randomised, multicenter, double-blinded phase 3 study of Ibrutinib (Imbruvica) in combination with BR versus placebo + BR (Study CLL3001). Patients (n = 578) were randomised 1:1 to receive either Ibrutinib (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 Ibrutinib (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 6. (See Table 6.)

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Waldenström's macroglobulinaemia: The safety and efficacy of Ibrutinib (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).
Ibrutinib (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 Waldenström's macroglobulinaemia. Responses to Ibrutinib (Imbruvica) are shown in Table 7. (See Table 7.)

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The median time to response was 1.0 month (range: 0.7-13.4 months).
Efficacy results were also assessed by an Independent Review Committee (IRC) demonstrating an ORR of 83%, with a 11% VGPR rate and a 51% PR rate.
Pediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Ibrutinib (Imbruvica) in all subsets of the pediatric population in MCL, CLL and lymphoplasmacytic lymphoma (LPL) (see Dosage & Administration).
Pharmacokinetics: Absorption: Ibrutinib is rapidly absorbed after oral administration with a median Tmax of 1 to 2 hours. Absolute bioavailability in fasted condition (n = 8) was 2.9% (90% CI = 2.1 - 3.9) and doubled when combined with a meal. Pharmacokinetics of ibrutinib does not significantly differ in patients with different B-cell malignancies. Ibrutinib exposure increases with doses up to 840 mg. The steady state AUC observed in patients at 560 mg is (mean ± standard deviation) 953 ± 705 ng h/mL. Administration of ibrutinib in fasted condition resulted in approximately 60% of exposure (AUClast) as compared to either 30 minutes before, 30 minutes after (fed condition) or 2 hours after a high fat breakfast.
Distribution: Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1,000 ng/mL. The apparent volume of distribution at steady state (Vd, ss/F) was approximately 10,000 L.
Metabolism: Ibrutinib is metabolised primarily by CYP3A4 to produce a dihydrodiol metabolite with an inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. Involvement of CYP2D6 in the metabolism of ibrutinib appears to be minimal. Therefore, no precautions are necessary in patients with different CYP2D6 genotypes.
Elimination: Apparent clearance (CL/F) is approximately 1,000 L/h. The half-life of ibrutinib is 4 to 13 hours.
After a single oral administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the faeces and < 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in faeces and none in urine.
Special populations: Elderly: Population pharmacokinetics indicated that age does not significantly influence ibrutinib clearance from the circulation.
Paediatric population: No pharmacokinetic studies were performed with Ibrutinib (Imbruvica) inpatients under 18 years of age.
Gender: Population pharmacokinetics data indicated that gender does not significantly influence ibrutinib clearance from the circulation.
Race: There are insufficient data to evaluate the potential effect of race on ibrutinib pharmacokinetics.
Body weight: Population pharmacokinetics data indicated that body weight (range: 41-146 kg; mean [SD]: 83 [19 kg]) had a negligible effect on ibrutinib clearance.
Renal impairment: Ibrutinib has minimal renal clearance; urinary excretion of metabolites is <10% of the dose. No specific studies have been conducted to date in subjects with impaired renal function. There are no data in patients with severe renal impairment or patients on dialysis (see Dosage & Administration).
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 Dosage & Administration).
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 Interactions).
Toxicology: Preclinical Safety Data: The following adverse effects were seen in studies of 13-weeks duration in rats and dogs. Ibrutinib was found to induce gastrointestinal effects (soft faeces/diarrhoea and/or inflammation) and lymphoid depletion in rats and dogs with a No Observed Adverse Effect Level (NOAEL) of 30 mg/kg/day in both species. Based on mean exposure (AUC) at the 560 mg/day clinical dose, AUC ratios were 2.6 and 21 at the NOAEL in male and female rats, and 0.4 and 1.8 at the NOAEL in male and female dogs, respectively. Lowest Observed Effect Level (LOEL) (60 mg/kg/day) margins in the dog are 3.6-fold (males) and 2.3-fold (females). In rats, moderate pancreatic acinar cell atrophy (considered adverse) was observed at doses of ≥100 mg/kg in male rats (AUC exposure margin of 2.6-fold) and not observed in females at doses up to 300 mg/kg/day (AUC exposure margin of 21.3-fold). Mildly decreased trabecular and cortical bone was seen in female rats administered ≥100 mg/kg/day (AUC exposure margin of 20.3-fold). All gastrointestinal, lymphoid and bone findings recovered following recovery periods of 6-13 weeks. Pancreatic findings partially recovered during comparable reversal periods. Juvenile toxicity studies have not been conducted.
Carcinogenicity/genotoxicity: Carcinogenicity studies have not been conducted with ibrutinib. Ibrutinib has no genotoxic properties when tested in bacteria, mammalian cells or in mice.
Reproductive toxicity: In pregnant rats, ibrutinib at a dose of 80 mg/kg/day was associated with increased post-implantation loss and increased visceral (heart and major vessels) malformations and skeletal variations with an exposure margin 14 times the AUC found in patients at a daily dose of 560 mg. At a dose of ≥40 mg/kg/day, ibrutinib was associated with decreased foetal weights (AUC ratio of ≥5.6 as compared to daily dose of 560 mg in patients). Consequently the foetal NOAEL was 10 mg/kg/day (approximately 1.3 times the AUC of ibrutinib at a dose of 560 mg daily) (see Use in Pregnancy & Lactation).
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 Use in Pregnancy & 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).
Indications/Uses
Ibrutinib (Imbruvica) as a single agent is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL), previously untreated chronic lymphocytic leukaemia (CLL) (see Pharmacology: Pharmacodynamic under Actions), Waldenström's macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy.
Ibrutinib (Imbruvica) as a single agent or in combination with bendamustine and rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.
Dosage/Direction for Use
Treatment with this medicinal product should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Posology: Mantle cell lymphoma: The recommended dose for the treatment of MCL is 560 mg (four capsules) once daily.
Chronic lymphocytic leukaemia and Waldenström's macroglobulinaemia: The recommended dose for the treatment of CLL, either as a single agent or in combination, is 420 mg (three capsules) once daily (see Pharmacology: Pharmacodynamics under Actions).
The recommended dose for the treatment of WM is 420 mg (three capsules) once daily. Treatment should continue until disease progression or no longer tolerated by the patient.
Dose adjustments: Moderate and strong CYP3A4 inhibitors increase the exposure of ibrutinib (see Precautions and Interactions).
The Ibrutinib (Imbruvica) dose should be lowered to 140 mg once daily (one capsule) when used concomitantly with moderate CYP3A4 inhibitors.
The Ibrutinib (Imbruvica) dose should be reduced to 140 mg once daily (one capsule) or withheld for up to 7 days when it is used concomitantly with strong CYP3A4 inhibitors.
Ibrutinib (Imbruvica) therapy should be withheld for any new onset or worsening grade ≥ 3 non-haematological toxicity, grade 3 or greater neutropenia with infection or fever, or grade 4 haematological toxicities. Once the symptoms of the toxicity have resolved to grade 1 or baseline (recovery), Ibrutinib (Imbruvica) therapy may be reinitiated at the starting dose. If the toxicity reoccurs, the once daily dose should be reduced by one capsule (140 mg). A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue the medicinal product.
Recommended dose modifications are described as follows: see Table 8.

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Missed dose: If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. The patient should not take extra capsules to make up the missed dose.
Special populations: Elderly: No specific dose adjustment is required for elderly patients (aged ≥65 years).
Renal impairment: No specific clinical studies have been conducted in patients with renal impairment. Patients with mild or moderate renal impairment were treated in Ibrutinib (Imbruvica) clinical studies. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). Hydration should be maintained and serum creatinine levels monitored periodically. Administer Ibrutinib (Imbruvica) to patients with severe renal impairment (<30 mL/min creatinine clearance) only if the benefit outweighs the risk and monitor patients closely for signs of toxicity. There are no data in patients with severe renal impairment or patients on dialysis (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: Ibrutinib is metabolised in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure (see Pharmacology: Pharmacokinetics under Actions). For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 280 mg daily (two capsules). For patients with moderate liver impairment (Child-Pugh class B), the recommended dose is 140 mg daily (one capsule). Monitor patients for signs of Ibrutinib (Imbruvica) toxicity and follow dose modification guidance as needed. It is not recommended to administer Ibrutinib (Imbruvica) to patients with severe hepatic impairment (Child-Pugh class C).
Severe cardiac disease: Patients with severe cardiovascular disease were excluded from Ibrutinib (Imbruvica) clinical studies.
Paediatric population: The safety and efficacy of Ibrutinib (Imbruvica) in children aged 0 to 18 years have not been established. No data are available.
Method of administration: Ibrutinib (Imbruvica) should be administered orally once daily with a glass of water approximately at the same time each day. The capsules should be swallowed whole with water and should not be opened, broken, or chewed. Ibrutinib (Imbruvica) must not be taken with grapefruit juice or Seville oranges (see Interactions).
Overdosage
There are limited data on the effects of Ibrutinib (Imbruvica) overdose. No maximum tolerated dose was reached in the phase 1 study in which patients received up to 12.5 mg/kg/day (1,400 mg/day). 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)]. There is no specific antidote for Ibrutinib (Imbruvica). Patients who ingested more than the recommended dose should be closely monitored and given appropriate supportive treatment.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Use of preparations containing St. John's Wort is contraindicated in patients treated with Ibrutinib (Imbruvica).
Special Precautions
Bleeding-related events: There have been reports of haemorrhagic events in patients treated with Ibrutinib (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 Ibrutinib (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 Ibrutinib (Imbruvica). Supplements such as fish oil and vitamin E preparations should be avoided. Use of Ibrutinib (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.
Ibrutinib (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.
Leukostasis: Cases of leukostasis have been reported in patients treated with Ibrutinib (Imbruvica). A high number of circulating lymphocytes (>400,000/mcL) may confer increased risk. Consider temporarily holding Ibrutinib (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 Ibrutinib (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.
Cytopenias: Treatment-emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia and anemia) were reported in patients treated with Ibrutinib (Imbruvica). Monitor complete blood counts monthly.
Atrial fibrillation/flutter: Atrial fibrillation and atrial flutter have been reported in patients treated with Ibrutinib (Imbruvica), particularly in patients with cardiac risk factors, 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.
In patients with preexisting atrial fibrillation requiring anticoagulant therapy, alternative treatment options to Ibrutinib (Imbruvica) should be considered. In patients who develop atrial fibrillation on therapy with Ibrutinib (Imbruvica) a thorough assessment of the risk for thromboembolic disease should be undertaken. In patients at high risk and where alternatives to Ibrutinib (Imbruvica) are non-suitable, tightly controlled treatment with anticoagulants should be considered.
Tumour lysis syndrome: Tumour lysis syndrome has been reported with Ibrutinib (Imbruvica) therapy. Patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. Monitor patients closely and take appropriate precautions.
Non-melanoma skin cancer: Non-melanoma skin cancers were reported more frequently in patients treated with Ibrutinib (Imbruvica) than in patients treated with comparators in pooled comparative randomized phase 3 studies. Monitor patients for the appearance of non-melanoma skin cancer.
Effects on the QT interval: In a phase 2 study, ECG evaluations showed Ibrutinib (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).
Drug-drug interactions: Co-administration of strong or moderate CYP3A4 inhibitors with Ibrutinib (Imbruvica) may lead to increased ibrutinib exposure and consequently a higher risk for toxicity. On the contrary, co-administration of CYP3A4 inducers may lead to decreased Ibrutinib (Imbruvica) exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of Ibrutinib (Imbruvica) with strong or moderate CYP3A4 inhibitors/inducers should be avoided whenever possible and co-administration should only be considered when the potential benefits clearly outweigh the potential risks. Patients should be closely monitored for signs of Ibrutinib (Imbruvica) toxicity if a CYP3A4 inhibitor must be used (see Dosage & Administration and Interactions). If a CYP3A4 inducer must be used, closely monitor patients for signs of Ibrutinib (Imbruvica) lack of efficacy.
Women of childbearing potential: Women of childbearing potential must use a highly effective method of contraception while taking Ibrutinib (Imbruvica) (see Use in Pregnancy & Lactation).
Use In Pregnancy & Lactation
Women of child-bearing potential/Contraception in females: Based on findings in animals, Ibrutinib (Imbruvica) may cause foetal harm when administered to pregnant women. Women should avoid becoming pregnant while taking Ibrutinib (Imbruvica) and for up to 3 months after ending treatment. Therefore, women of child-bearing potential must use highly effective contraceptive measures while taking Ibrutinib (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.
Use in Pregnancy: Ibrutinib (Imbruvica) should not be used during pregnancy. There are no data from the use of Ibrutinib (Imbruvica) in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in Lactation: It is not known whether ibrutinib or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Ibrutinib (Imbruvica).
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) (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). No human data on the effects of ibrutinib on fertility are available.
Adverse Reactions
Summary of the safety profile: The safety profile is based on pooled data from 981 patients treated with Ibrutinib (Imbruvica) in three phase 2 clinical studies and four randomised phase 3 studies and from post-marketing experience. Patients treated for MCL in clinical studies received Ibrutinib (Imbruvica) at 560 mg once daily and patients treated for CLL or WM in clinical studies received Ibrutinib (Imbruvica) at 420 mg once daily. All patients in clinical studies received Ibrutinib (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, and pyrexia. The most common grade 3/4 adverse reactions (≥5%) were neutropenia, pneumonia, 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 as follows 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. (See Table 9.)

Click on icon to see table/diagram/image

Discontinuation and dose reduction due to adverse drug reactions: Of the 981 patients treated with Ibrutinib (Imbruvica) for B-cell malignancies, 5% discontinued treatment primarily due to adverse reactions. These included pneumonia, atrial fibrillation and haemorrhage. Adverse reactions leading to dose reduction occurred in approximately 5% of patients.
Elderly: Of the 981 patients treated with Ibrutinib (Imbruvica), 62% were 65 years of age or older. Grade 3 or higher pneumonia occurred more frequently among elderly patients treated with Ibrutinib (Imbruvica) (13% of patients age ≥65 versus 7% of patients <65 years of age).
Caution: Patient must seek medical attention immediately at the first sign of any adverse drug reaction.
Drug Interactions
Ibrutinib is primarily metabolised by cytochrome P450 enzyme 3A4 (CYP3A4).
Agents that may increase ibrutinib plasma concentrations: Concomitant use of Ibrutinib (Imbruvica) and medicinal products that strongly or moderately inhibit CYP3A4 can increase ibrutinib exposure and should be avoided.
Strong CYP3A4 inhibitors: Co-administration of ketoconazole, a 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. Strong inhibitors of CYP3A4 (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone and cobicistat) should be avoided. If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, reduce the Ibrutinib (Imbruvica) dose to 140 mg (one capsule) or withhold treatment temporarily (for 7 days or less). Monitor patient closely for toxicity and follow dose modification guidance as needed (see Dosage & Administration and Precautions).
Moderate CYP3A4 inhibitors: 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 must be used, reduce Ibrutinib (Imbruvica) treatment to 140 mg (one capsule) for the duration of the inhibitor use. Monitor patient closely for toxicity and follow dose modification guidance as needed (see Dosage & Administration and Precautions).
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.
Co-administration of grapefruit juice, containing CYP3A4 inhibitors, in eight healthy subjects, increased exposure (Cmax and AUC) of ibrutinib by approximately 4- and 2-fold, respectively. Grapefruit and Seville oranges should be avoided during Ibrutinib (Imbruvica) treatment, as these contain moderate inhibitors of CYP3A4 (see Dosage & Administration).
Agents that may decrease ibrutinib plasma concentrations: Administration of Ibrutinib (Imbruvica) with inducers of CYP3A4 can decrease ibrutinib plasma concentrations.
Co-administration of rifampicin, a strong CYP3A4 inducer, in 18 fasted healthy subjects, decreased exposure (Cmax and AUC) of ibrutinib by 92 and 90%, respectively. Avoid concomitant use of strong or moderate CYP3A4 inducers (e.g., carbamazepine, rifampicin, phenytoin). Preparations containing St. John's Wort are contraindicated during treatment with Ibrutinib (Imbruvica), as efficacy may be reduced. Consider alternative agents with less CYP3A4 induction. If the benefit outweighs the risk and a strong or moderate CYP3A4 inducer must be used, monitor patient closely for lack of efficacy (see Contraindications and Precautions). Mild inducers may be used concomitantly with Ibrutinib (Imbruvica), however, patients should be monitored for potential lack of efficacy.
As ibrutinib solubility is pH dependent, there is a theoretical risk that medicinal products increasing stomach pH (e.g., proton pump inhibitors) may decrease ibrutinib exposure. This interaction has not been studied in vivo.
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 Ibrutinib (Imbruvica). Ibrutinib may also inhibit BCRP in the liver and increase the exposure of drugs 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.
Caution For Usage
Instructions and Special Precautions for Handling and Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Storage
Store at temperatures not exceeding 30°C.
ATC Classification
L01EL01 - ibrutinib ; Belongs to the class of Bruton's tyrosine kinase (BTK) inhibitors. Used in the treatment of cancer.
Presentation/Packing
Cap 140 mg x 90's, 120's.
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