Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hepatic impairment (see sections 5.1 and 5.2).
Treatment with bosutinib is associated with elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]).
Transaminase elevations generally occurred early in the course of treatment (of the patients who experienced transaminase elevations of any grade, >80% experienced their first event within the first 3 months). Patients receiving bosutinib should have liver function tests prior to treatment initiation and monthly for the first 3 months of treatment, and as clinically indicated.
Patients with transaminase elevations should be managed by withholding bosutinib temporarily (with consideration given to dose reduction after recovery to Grade 1 or baseline), and/or discontinuation of bosutinib. Elevations of transaminases, particularly in the setting of concomitant increases in bilirubin, may be an early indication of drug-induced liver injury and these patients should be managed appropriately (see sections 4.2 and 4.8).
Treatment with bosutinib is associated with diarrhoea and vomiting; therefore, patients with recent or ongoing clinically significant gastrointestinal disorder should use this medicinal product with caution and only after a careful benefit-risk assessment as respective patients were excluded from the clinical studies. Patients with diarrhoea and vomiting should be managed using standard-of-care treatment, including an antidiarrhoeal or antiemetic medicinal product and/or fluid replacement. In addition, diarrhoea and vomiting can also be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8). The antiemetic agent, domperidone, has the potential to increase QT interval (QTc) prolongation and to induce “torsade de pointes”-arrhythmias; therefore, co-administration with domperidone should be avoided. It should only be used, if other medicinal products are not efficacious. In these situations an individual benefit-risk assessment is mandatory and patients should be monitored for occurrence of QTc prolongation.
Treatment with bosutinib is associated with myelosuppression, defined as anaemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month and then monthly thereafter, or as clinically indicated. Myelosuppression should/can be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8).
Treatment with bosutinib may be associated with fluid retention including pericardial effusion, pleural effusion, pulmonary oedema and/or peripheral oedema. Patients should be monitored and managed using standard-of-care treatment. In addition, fluid retention can also be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8).
Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, bosutinib should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis (see section 4.2).
Bosutinib may predispose patients to bacterial, fungal, viral, or protozoan infections.
Automated machine-read QTc prolongation without accompanying arrhythmia has been observed. Bosutinib should be administered with caution to patients who have a history of or predisposition for QTc prolongation, who have uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, or who are taking medicinal products that are known to prolong the QTc (e.g., anti-arrhythmic medicinal products and other substances that may prolong QTc [see section 4.5]). The presence of hypokalaemia and hypomagnesaemia may further enhance this effect.
Monitoring for an effect on the QTc is advisable and a baseline electrocardiogram (ECG) is recommended prior to initiating therapy with bosutinib and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to bosutinib administration and should be monitored periodically during therapy.
Treatment with bosutinib may result in a clinically significant decline in renal function in CML patients. A decline over time in estimated glomerular filtration rate (eGFR) has been observed in patients treated with bosutinib in clinical studies. In patients with newly-diagnosed CP CML treated with 400 mg, the median decline from baseline in eGFR was 4.9 ml/min/1.73 m² at 3 months, 9.2 ml/min/1.73 m² at 6 months and 11.1 ml/min/1.73 m² at 12 months. Treatment-naïve CML patients treated with 500 mg showed a median eGFR decline of 5.1 ml/min/1.73 m² at 3 months, of 9.2 ml/min/1.73 m² at 12 months and of up to 16.3 ml/min/1.73 m² until 5 years follow-up for patients on treatment. Pretreated and advanced stage CML patients on 500 mg showed a median eGFR decline of 5.3 ml/min/1.73 m² at 3 months, of 7.6 ml/min/1.73 m² at 12 months and of up to 10.9 ml/min/1.73 m² in up to 4 years on treatment. It is important that renal function is assessed prior to treatment initiation and closely monitored during therapy with bosutinib, with particular attention in those patients who have pre-existing renal compromise or in those patients exhibiting risk factors for renal dysfunction, including concomitant use of medicinal products with potential for nephrotoxicity, such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs).
In a renal impairment study, bosutinib exposures were increased in subjects with moderately and severely impaired renal function. Dose reduction is recommended for patients with moderate or severe renal impairment (see sections 4.2 and 5.2).
Patients with serum creatinine >1.5 × ULN were excluded from the CML studies. Based on a population pharmacokinetic analysis increasing exposure (AUC) in patients with moderate and severe renal impairment at initiation of treatment during studies was observed (see sections 4.2 and 5.2).
Clinical data are very limited (n=3) for CML patients with moderate renal impairment receiving an escalated dose of 600 mg bosutinib.
Bosutinib can induce severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Bosutinib should be permanently discontinued in patients who experience a severe skin reaction during treatment.
Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of bosutinib (see section 4.8).
Reactivation of hepatitis B (HBV) in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.
Patients should be tested for HBV infection before initiating treatment with bosutinib. Experts in liver disease and in the treatment of HBV should be consulted before treatment is initiated in patients with positive HBV serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with bosutinib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).
The concomitant use of bosutinib with strong or moderate CYP3A inhibitors should be avoided, as an increase in bosutinib plasma concentration will occur (see section 4.5).
Selection of an alternate concomitant medicinal product with no or minimal CYP3A inhibition potential, if possible, is recommended.
If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, an interruption of bosutinib therapy or a dose reduction in bosutinib should be considered.
The concomitant use of bosutinib with strong or moderate CYP3A inducers should be avoided as a decrease in bosutinib plasma concentration will occur (see section 4.5).
Grapefruit products, including grapefruit juice and other foods that are known to inhibit CYP3A should be avoided (see section 4.5).
The concomitant use of bosutinib with strong CYP3A inhibitors (including, but not limited to itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, nefazodone, mibefradil, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, boceprevir, telaprevir, grapefruit products including grapefruit juice) or moderate CYP3A inhibitors (including, but not limited to fluconazole, ciprofloxacin, erythromycin, diltiazem, verapamil, amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir, aprepitant, crizotinib, imatinib) should be avoided, as an increase in bosutinib plasma concentration will occur.
Caution should be exercised if mild CYP3A inhibitors are used concomitantly with bosutinib.
Selection of an alternate concomitant medicinal product with no or minimal CYP3A enzyme inhibition potential, if possible, is recommended.
If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, an interruption of bosutinib therapy or a dose reduction in bosutinib should be considered.
In a study of 24 healthy subjects in whom 5 daily doses of 400 mg ketoconazole (a strong CYP3A inhibitor) were co-administered with a single dose of 100 mg bosutinib under fasting conditions, ketoconazole increased bosutinib Cmax by 5.2-fold, and bosutinib AUC in plasma by 8.6-fold, as compared with administration of bosutinib alone.
In a study of 20 healthy subjects, in whom a single dose of 125 mg aprepitant (a moderate CYP3A inhibitor) was co-administered with a single dose of 500 mg bosutinib under fed conditions, aprepitant increased bosutinib Cmax by 1.5-fold, and bosutinib AUC in plasma by 2.0-fold, as compared with administration of bosutinib alone.
The concomitant use of bosutinib with strong CYP3A inducers (including, but not limited to carbamazepine, phenytoin, rifampicin, St. John’s Wort), or moderate CYP3A inducers (including, but not limited to bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided, as a decrease in bosutinib plasma concentration will occur.
Based on the large reduction in bosutinib exposure that occurred when bosutinib was co-administered with rifampicin, increasing the dose of bosutinib when co-administering with strong or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of exposure.
Caution is warranted if mild CYP3A inducers are used concomitantly with bosutinib.
Following concomitant administration of a single dose bosutinib with 6 daily doses of 600 mg rifampicin, in 24 healthy subjects in fed state bosutinib exposure (Cmax and AUC in plasma) decreased to 14% and 6%, respectively, of the values when bosutinib 500 mg was administered alone.
Caution should be exercised when administering bosutinib concomitantly with PPIs. Short-acting antacids should be considered as an alternative to PPIs and administration times of bosutinib and antacids should be separated (i.e. take bosutinib in the morning and antacids in the evening) whenever possible. Bosutinib displays pH-dependent aqueous solubility in vitro. When a single oral dose of bosutinib (400 mg) was co-administered with multiple-oral doses of lansoprazole (60 mg) in a study of 24 healthy fasting subjects, bosutinib Cmax and AUC decreased to 54% and 74%, respectively, of the values seen when bosutinib (400 mg) was given alone.
In a study of 27 healthy subjects, in whom a single dose of 500 mg bosutinib was co-administered with a single dose of 150 mg dabigatran etexilate mesylate (a P-glycoprotein [P-gp] substrate) under fed conditions, bosutinib did not increase Cmax or AUC of dabigatran in plasma, as compared with administration of dabigatran etexilate mesylate alone. The study results indicate that bosutinib does not exhibit clinically relevant P-gp inhibitory effects.
An in vitro study indicates that drug-drug interactions are unlikely to occur at therapeutic doses as a result of induction by bosutinib on the metabolism of medicinal products that are substrates for CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4.
In vitro studies indicate that clinical drug-drug interactions are unlikely to occur at therapeutic doses as a result of inhibition by bosutinib on the metabolism of medicinal products that are substrates for CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.
In vitro studies indicate that bosutinib has a low potential to inhibit breast cancer resistance protein (BCRP, systemically), organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2 at clinically relevant concentrations, but may have the potential to inhibit BCRP in the gastrointestinal tract and OCT1.
Bosutinib should be used with caution in patients who have or may develop prolongation of QT, including those patients taking anti-arrhythmic medicinal products such as amiodarone, disopyramide, procainamide, quinidine and sotalol or other medicinal products that may lead to QT prolongation such as chloroquine, halofantrine, clarithromycin, domperidone, haloperidol, methadone, and moxifloxacin (see section 4.4).
Women of childbearing potential should be advised to use effective contraception during treatment with bosutinib and for at least 1 month after the last dose and to avoid becoming pregnant while receiving bosutinib. In addition, the patient should be advised that vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption.
There are limited amount of data in pregnant women from the use of bosutinib. Studies in animals have shown reproductive toxicity (see section 5.3). Bosutinib is not recommended for use during pregnancy, or in women of childbearing potential not using contraception. If bosutinib is used during pregnancy, or the patient becomes pregnant while taking bosutinib, she should be apprised of the potential hazard to the foetus.
It is unknown whether bosutinib and its metabolites are excreted in human milk. A study of [14C] radiolabelled bosutinib in rats demonstrated excretion of bosutinib-derived radioactivity in breast milk (see section 5.3). A potential risk to the breast-feeding infant cannot be excluded.
Breast-feeding should be discontinued during treatment with bosutinib.
Based on non-clinical findings, bosutinib has the potential to impair reproductive function and fertility in humans (see section 5.3). Men being treated with bosutinib are advised to seek advice on conservation of sperm prior to treatment because of the possibility of decreased fertility due to therapy with bosutinib.
Bosutinib has no or negligible influence on the ability to drive and use machines. However, if a patient taking bosutinib experiences dizziness, fatigue, visual impairment or other undesirable effects with a potential impact on the ability to drive or use machines safely, the patient should refrain from these activities for as long as the undesirable effects persist.
A total of 1,272 leukaemia patients received at least 1 dose of single-agent bosutinib. The median duration of therapy was 13.8 months (range: 0.03 to 123.3 months). These patients were either newly diagnosed, with CP CML or were resistant or intolerant to prior therapy with chronic, accelerated, or blast phase CML or Ph+ acute lymphoblastic leukaemia (ALL). Of these patients, 268 (400 mg starting dose) and 248 (500 mg starting dose) are from the 2 Phase 3 studies in previously untreated CML patients, 570 and 63 are from 2 Phase ½ studies in previously treated Ph+ leukaemias, and 123 patients from a Phase 4 study in previously treated CML. The median duration of therapy was 14.1 months (range: 0.3 to 24.7 months), 61.6 months (0.03 to 99.6 months), 11.1 months (range: 0.03 to 123.3 months), 30.2 months (range: 0.3 to 85.6 months), and 5.7 months (range: 0.07 to 17.8 months), respectively. The safety analyses included data from an ongoing extension study.
At least 1 adverse reaction of any toxicity grade was reported for 1,240 (97.5%) patients. The most frequent adverse reactions reported for ≥20% of patients were diarrhoea (78.1%), nausea (40.8%), thrombocytopenia (34.9%), abdominal pain (34.0%), vomiting (33.0%), rash (31.5%), anaemia (25.6%), pyrexia (21.8%), fatigue (21.4%), and ALT increased (25.0%). At least 1 Grade 3 or Grade 4 adverse reaction was reported for 814 (63.9%) patients. The Grade 3 or Grade 4 adverse reactions reported for ≥5% of patients were thrombocytopenia (20.3%), anaemia (10.2%), neutropenia (10.5%), ALT increased (12.7%), diarrhoea (9.6%), rash (5.0%), lipase increased (8.2%), and AST increased (5.8%).
The following adverse reactions were reported in patients in bosutinib clinical studies (Table 2). These represent an evaluation of the adverse reaction data from 1,272 patients with either newly-diagnosed CP CML or with chronic, accelerated, or blast phase CML resistant or intolerant to prior therapy or Ph+ ALL who have received at least 1 dose of single-agent bosutinib. These adverse reactions are presented by system organ class and frequency. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 2. Adverse reactions for bosutinib:
Very common: Respiratory tract infection (including Lower respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection), Nasopharyngitis
Common: Pneumonia (including Atypical pneumonia), Influenza, Bronchitis
Uncommon: Tumour lysis syndrome**
Very common: Thrombocytopenia (including Platelet count decreased), Neutropenia (including Neutrophil count decreased), Anaemia (including haemoglobin decreased)
Common: Leukopenia (including White blood cell count decreased)
Uncommon: Febrile neutropenia, Granulocytopenia
Uncommon: Anaphylactic shock, Hypersensitivity
Very common: Decreased appetite
Common: Dehydration, Hyperkalaemia, Hypophosphataemia
Very common: Headache
Common: Dizziness, Dysgeusia
Common: Tinnitus
Common: Pericardial effusion, Electrocardiogram QTc prolonged (including Long QTc syndrome)
Uncommon: Pericarditis
Common: Hypertension (including Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertensive crisis)
Very common: Dyspnoea, Cough
Common: Pleural effusion
Uncommon: Pulmonary hypertension, Respiratory failure, Acute pulmonary oedema
Very common: Diarrhoea, Vomiting, Nausea, Abdominal pain (including Abdominal discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain)
Common: Gastritis, Gastrointestinal haemorrhage (including Anal haemorrhage, Gastric haemorrhage, Intestinal haemorrhage, Lower gastrointestinal haemorrhage, Rectal haemorrhage)
Uncommon: Pancreatitis (including Pancreatitis acute)
Very common: Alanine aminotransferase increased, Aspartate aminotransferase increased
Common: Hepatotoxicity (including Hepatitis, Hepatitis toxic, Liver disorder), Hepatic function abnormal (including Liver function test abnormal, Liver function test increased, Transaminases increased), Blood bilirubin increased (including Hyperbilirubinaemia), Gamma-glutamyltransferase increased
Uncommon: Liver injury (including Drug-induced liver injury)
Very common: Rash (including Rash generalised, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic)
Common: Urticaria, Acne, Pruritus
Uncommon: Exfoliative rash, Drug eruption
Rare: Erythema multiforme
Unknown: Stevens-Johnson Syndrome**, Toxic epidermal necrolysis**
Very common: Arthralgia, Back pain
Common: Myalgia
Common: Acute kidney injury, Renal failure, Renal impairment
Very common: Pyrexia, Asthenia, Oedema (including Face oedema, Localised oedema, Oedema peripheral), Fatigue (including Malaise)
Common: Chest pain (including Chest discomfort), Pain
Very common: Lipase increased (including Hyperlipasaemia)
Common: Blood creatinine increased, Amylase increased, Blood creatine phosphokinase increased
** Adverse reaction identified post marketing.
The descriptions included below are based on the safety population of 1,272 patients who received at least 1 dose of bosutinib for either newly-diagnosed CP CML or were resistant or intolerant to prior therapy with CP, AP, or BP CML, or Ph+ ALL.
Of the 297 (23%) patients with reports of adverse reactions of anaemia, 3 patients discontinued bosutinib due to anaemia. In these patients, the maximum toxicity of Grade 1 or 2 was experienced in 174 (58%) patients, Grade 3 in 96 patients (32%), and Grade 4 in 27 (9%) patients. Among these patients, the median time to first event was 28 days (range: 1 to 2,633 days) and the median duration per event was 15 days (range: 1 to 1,529 days).
Of the 197 (15%) patients with reports of adverse reactions of neutropenia, 15 patients discontinued bosutinib due to neutropenia. Maximum Grade 1 or 2 events were experienced by 63 (32%) patients. The maximum toxicity of Grade 3 neutropenia was experienced in 90 (46%) patients and of Grade 4 in 44 (22%) patients. The median time to first event was 59 days (range: 27 to 505 days), and the median duration per event was 15 days (range: 1 to 913 days).
Of the 445 (35%) patients with reports of adverse reactions of thrombocytopenia, 41 (9%) patients discontinued treatment with bosutinib due to thrombocytopenia. Maximum Grade 1 or 2 events were experienced by 186 (42%) patients. The maximum toxicity of thrombocytopenia of Grade 3 was experienced in 161 (36%) patients and Grade 4 in 98 (22%) patients. Among patients with thrombocytopenia reactions, the median time to first event was 28 days (range: 1 to 1,688 days), and median duration per event was 15 days (range: 1 to 1,762 days).
Among patients with reports of adverse reactions of elevations in either ALT or AST (all grades), the median time of onset observed was 29 days with a range of onset 1 to 2,465 days for ALT and AST. The median duration of an event was 18 days (range: 1 to 775 days), and 15 days (range: 1 to 803 days) for ALT and AST, respectively.
In the entire development program, concurrent elevation in transaminases ≥3 × ULN and bilirubin >2 × ULN with alkaline phosphatase <2 × ULN occurred without alternative causes in 1/1,611 (<0.1%) subjects treated with bosutinib. This finding was in a study of bosutinib in combination with letrozole in a patient with metastatic breast cancer.
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4).
Of the 994 (78%) patients that experienced diarrhoea, 10 patients discontinued bosutinib due to this event. Concomitant medicinal products were given to treat diarrhoea in 662 (66%) patients. The maximum toxicity of diarrhoea was Grade 1 or 2 in 88% of patients, Grade 3 in 12% of patients; 1 patient (<1%) experienced a Grade 4 event. Among patients with diarrhoea, the median time to first event was 2 days (range: 1 to 2,415 days) and the median duration of any grade of diarrhoea was 2 days (range: 1 to 2,511 days).
Among the 994 patients with diarrhoea, 180 patients (18%) were managed with treatment interruption and of these 170 (94%) were rechallenged with bosutinib. Of those who were rechallenged, 167 (98%) did not have a subsequent event or did not discontinue bosutinib due to a subsequent event of diarrhoea.
Four patients (0.3%) experienced QTcF interval prolongation (greater than 500 ms). Nine (0.8%) patients experienced QTcF increase from baseline exceeding 60 ms. Patients with uncontrolled or significant cardiovascular disease including QTc prolongation, at baseline, were not included in clinical studies (see sections 5.1 and 5.3).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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