IMBRUVICA 140 mg hard capsules.
Each hard capsule contains 140 mg of ibrutinib.
For the full list of excipients, see section 6.1.
Hard capsule (capsule).
White opaque, hard capsule of 22 mm in length, marked with “ibr 140 mg” in black ink.
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.
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 section 5.1 for details of the combination regimen).
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 sections 4.4 and 4.5).
The IMBRUVICA dose should be lowered to 140 mg once daily (one capsule) when used concomitantly with moderate CYP3A4 inhibitors.
The 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.
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), 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 below:
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Toxicity occurrence
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MCL dose modification after recovery
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CLL/WM dose modification after recovery
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First
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restart at 560 mg daily
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restart at 420 mg daily
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Second
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restart at 420 mg daily
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restart at 280 mg daily
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Third
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restart at 280 mg daily
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restart at 140 mg daily
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Fourth
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discontinue IMBRUVICA
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discontinue IMBRUVICA
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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 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 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 section 5.2).
Hepatic impairment
Ibrutinib is metabolised in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure (see section 5.2). 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 IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with severe hepatic impairment (Child-Pugh class C).
Severe cardiac disease
Patients with severe cardiovascular disease were excluded from IMBRUVICA clinical studies.
Paediatric population
The safety and efficacy of IMBRUVICA in children aged 0 to 18 years have not been established. No data are available.
Method of administration
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. IMBRUVICA must not be taken with grapefruit juice or Seville oranges (see section 4.5).
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Use of preparations containing St. John's Wort is contraindicated in patients treated with IMBRUVICA.
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.
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.
Cytopenias
Treatment-emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia and anaemia) were reported in patients treated with IMBRUVICA. Monitor complete blood counts monthly.
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.
Atrial fibrillation/flutter
Atrial fibrillation and atrial flutter have been reported in patients treated with 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 eva luated clinically and if indicated have an electrocardiogram (ECG) performed.
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.
Tumour lysis syndrome
Tumour lysis syndrome has been reported with 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 IMBRUVICA than in patients treated with comparators in pooled comparative randomised phase 3 studies. Monitor patients for the appearance of non-melanoma skin cancer.
Effects on the QT interval
In a phase 2 study, ECG eva luations 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).
Drug-drug interactions
Co-administration of strong or moderate CYP3A4 inhibitors with 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 IMBRUVICA exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of 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 IMBRUVICA toxicity if a CYP3A4 inhibitor must be used (see sections 4.2 and 4.5). If a CYP3A4 inducer must be used, closely monitor patients for signs of IMBRUVICA lack of efficacy.
Women of childbearing potential
Women of childbearing potential must use a highly effective method of contraception while taking IMBRUVICA (see section 4.6).
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 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, nefazodon and cobicistat) 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) or withhold treatment 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
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 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 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.
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 IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A4 (see section 4.2).
Agents that may decrease ibrutinib plasma concentrations
Administration of 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 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 patie
