- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Legal category
Excipient(s) with known effectOne hard capsule contains 156.11 mg lactose (as monohydrate).For the full list of excipients, see section 6.1.
PosologyThe recommended dose of Tasigna is:- 300 mg twice daily in newly diagnosed patients with CML in the chronic phase,- 400 mg twice daily in patients with chronic or accelerated phase CML with resistance or intolerance to prior therapy.Treatment should be continued as long as the patient continues to benefit.For a dose of 300 mg twice daily, 150 mg hard capsules are available.If a dose is missed the patient should not take an additional dose, but take the usual prescribed next dose.
Dose adjustments or modificationsTasigna may need to be temporarily withheld and/or dose reduced for haematological toxicities (neutropenia, thrombocytopenia) that are not related to the underlying leukaemia (see Table 1).
Table 1 Dose adjustments for neutropenia and thrombocytopenia
|Newly diagnosed chronic phase CML at 300 mg twice daily and imatinib-resistant or intolerant CML in chronic phase at 400 mg twice daily||ANC* <1.0 x 109/l and/or platelet counts <50 x 109/l||1. Treatment with Tasigna must be interrupted and blood count monitored. 2. Treatment must be resumed within 2 weeks at prior dose if ANC >1.0 x 109/l and/or platelets >50 x 109/l. 3. If blood counts remain low, a dose reduction to 400 mg once daily may be required.|
|Imatinib-resistant or intolerant CML in accelerated phase at 400 mg twice daily||ANC* <0.5 x 109/l and/or platelet counts <10 x 109/l||1. Treatment with Tasigna must be interrupted and blood count monitored. 2. Treatment must be resumed within 2 weeks at prior dose if ANC >1.0 x 109/l and/or platelets >20 x 109/l. 3. If blood counts remain low, a dose reduction to 400 mg once daily may be required.|
Cardiac disordersIn clinical studies, patients with uncontrolled or significant cardiac disease (e.g. recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia) were excluded. Caution should be exercised in patients with relevant cardiac disorders (see section 4.4).Increases in total serum cholesterol levels have been reported with Tasigna therapy (see section 4.4). Lipid profiles should be determined prior to initiating Tasigna therapy, assessed at month 3 and 6 after initiating therapy and at least yearly during chronic therapy.Increases in blood glucose levels have been reported with Tasigna therapy (see section 4.4). Blood glucose levels should be assessed prior to initiating Tasigna therapy and monitored during treatment.
Paediatric populationThe safety and efficacy of Tasigna in children from birth to less than 18 years have not yet been established (see section 5.1). Therefore, its use in paediatric patients is not recommended due to a lack of data on safety and efficacy.
Method of administrationTasigna should be taken twice daily approximately 12 hours apart and must not be taken with food. The hard capsules should be swallowed whole with water. No food should be consumed for 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken.For patients who are unable to swallow hard capsules, the content of each hard capsule may be dispersed in one teaspoon of apple sauce (puréed apple) and should be taken immediately. Not more than one teaspoon of apple sauce and no food other than apple sauce must be used (see sections 4.4 and 5.2).
MyelosuppressionTreatment with Tasigna is associated with (National Cancer Institute Common Toxicity Criteria grade 3-4) thrombocytopenia, neutropenia and anaemia. Occurrence is more frequent in patients with imatinib-resistant or intolerant CML, in particular in patients with accelerated-phase CML. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction (see section 4.2).
QT prolongationTasigna has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval on the surface ECG in a concentration-dependent manner.In the Phase III study in patients with newly diagnosed CML in chronic phase receiving 300 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient had a QTcF >480 msec. No episodes of torsade de pointes were observed.In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase receiving 400 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 5 and 8 msec, respectively. QTcF of >500 msec was observed in <1% of these patients. No episodes of torsade de pointes were observed in clinical studies.In a healthy volunteer study with exposures that were comparable to the exposures observed in patients, the time-averaged mean placebo-subtracted QTcF change from baseline was 7 msec (CI ± 4 msec). No subject had a QTcF >450 msec. Additionally, no clinically relevant arrhythmias were observed during the conduct of the trial. In particular, no episodes of torsade de pointes (transient or sustained) were observed.Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT, and/or food (see section 4.5). The presence of hypokalaemia and hypomagnesaemia may further enhance this effect. Prolongation of the QT interval may expose patients to the risk of fatal outcome.Tasigna should be used with caution in patients who have or who are at significant risk of developing prolongation of QTc, such as those:- with congenital long QT prolongation- with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia.- taking anti-arrhythmic medicinal products or other substances that lead to QT prolongation.Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with Tasigna and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to Tasigna administration and should be monitored periodically during therapy.
Sudden deathUncommon cases (0.1 to 1%) of sudden deaths have been reported in patients with imatinib-resistant or intolerant CML in chronic phase or accelerated phase with a past medical history of cardiac disease or significant cardiac risk factors. Co-morbidities in addition to the underlying malignancy were also frequently present as were concomitant medicinal products. Ventricular repolarisation abnormalities may have been contributory factors. No cases of sudden death were reported in the Phase III study in newly diagnosed patients with CML in chronic phase.
Fluid retention and oedemaSevere forms of fluid retention such as pleural effusion, pulmonary oedema, and pericardial effusion were uncommonly (0.1 to 1%) observed in a Phase III study of newly diagnosed CML patients. Similar events were observed in post-marketing reports. Unexpected, rapid weight gain should be carefully investigated. If signs of severe fluid retention appear during treatment with nilotinib, the aetiology should be evaluated and patients treated accordingly (see section 4.2 for instructions on managing non-haematological toxicities).
Cardiovascular eventsCardiovascular events were reported in a randomised Phase III study in newly diagnosed CML patients and observed in post-marketing reports. In this clinical study with a median on-therapy time of 60.5 months, Grade 3-4 cardiovascular events included peripheral arterial occlusive disease (1.4% and 1.1% at 300 mg and 400 mg nilotinib twice daily, respectively), ischaemic heart disease (2.2% and 6.1% at 300 mg and 400 mg nilotinib twice daily, respectively) and ischaemic cerebrovascular events (1.1% and 2.2% at 300 mg and 400 mg nilotinib twice daily, respectively). Patients should be advised to seek immediate medical attention if they experience acute signs or symptoms of cardiovascular events. The cardiovascular status of patients should be evaluated and cardiovascular risk factors monitored and actively managed during Tasigna therapy according to standard guidelines. Appropriate therapy should be prescribed to manage cardiovascular risk factors (see section 4.2 for instructions on managing non-haematological toxicities).
Laboratory tests and monitoring
Blood lipidsIn a Phase III study in newly diagnosed CML patients, 1.1% of the patients treated with 400 mg nilotinib twice daily showed a Grade 3-4 elevation in total cholesterol; no Grade 3-4 elevations were however observed in the 300 mg twice daily dose group (see section 4.8). It is recommended that the lipid profiles be determined before initiating treatment with Tasigna, assessed at month 3 and 6 after initiating therapy and at least yearly during chronic therapy (see section 4.2). If a HMG-CoA reductase inhibitor (a lipid-lowering agent) is required, please refer to section 4.5 before initiating treatment since certain HMG-CoA reductase inhibitors are also metabolised by the CYP3A4 pathway.
Blood glucoseIn a Phase III study in newly diagnosed CML patients, 6.9% and 7.2% of the patients treated with 400 mg nilotinib and 300 mg nilotinib twice daily, respectively, showed a Grade 3-4 elevation in blood glucose. It is recommended that the glucose levels be assessed before initiating treatment with Tasigna and monitored during treatment, as clinically indicated (see section 4.2). If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.
Interactions with other medicinal productsThe administration of Tasigna with agents that are strong CYP3A4 inhibitors (including, but not limited to, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted if possible (see section 4.5). If transient interruption of treatment is not possible, close monitoring of the individual for prolongation of the QT interval is indicated (see sections 4.2, 4.5 and 5.2).Concomitant use of Tasigna with medicinal products that are potent inducers of CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital and St. John's Wort) is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving Tasigna, co-administration of alternative therapeutic agents with less potential for CYP3A4 induction should be selected (see section 4.5).
Food effectThe bioavailability of nilotinib is increased by food. Tasigna must not be taken in conjunction with food (see sections 4.2 and 4.5) and should be taken 2 hours after a meal. No food should be consumed for at least one hour after the dose is taken. Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided. For patients who are unable to swallow hard capsules, the content of each hard capsule may be dispersed in one teaspoon of apple sauce and should be taken immediately. Not more than one teaspoon of apple sauce and no food other than apple sauce must be used (see section 5.2).
Hepatic impairmentHepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single dose administration of 200 mg of nilotinib resulted in increases in AUC of 35%, 35% and 19% in subjects with mild, moderate and severe hepatic impairment, respectively, compared to a control group of subjects with normal hepatic function. The predicted steady-state Cmax of nilotinib showed an increase of 29%, 18% and 22%, respectively. Clinical studies have excluded patients with alanine transaminase (ALT) and/or aspartate transaminase (AST) >2.5 (or >5, if related to disease) times the upper limit of the normal range and/or total bilirubin >1.5 times the upper limit of the normal range. Metabolism of nilotinib is mainly hepatic. Patients with hepatic impairment might therefore have increased exposure to nilotinib and should be treated with caution (see section 4.2).
Serum lipaseElevation 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, Tasigna should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis.
Total gastrectomyThe bioavailability of nilotinib might be reduced in patients with total gastrectomy (see section 5.2). More frequent follow-up of these patients should be considered.
Tumour lysis syndromeDue to possible occurrence of tumour lysis syndrome (TLS) correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiating therapy with Tasigna (see section 4.8).
LactoseTasigna hard capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Substances that may increase nilotinib serum concentrationsConcomitant administration of nilotinib with imatinib (a substrate and moderator of P-gp and CYP3A4), had a slight inhibitory effect on CYP3A4 and/or P-gp. The AUC of imatinib was increased by 18% to 39%, and the AUC of nilotinib was increased by 18% to 40%. These changes are unlikely to be clinically important.The exposure to nilotinib in healthy subjects was increased 3-fold when co-administered with the strong CYP3A4 inhibitor ketoconazole. Concomitant treatment with strong CYP3A4 inhibitors, including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin, should therefore be avoided (see section 4.4). Increased exposure to nilotinib might also be expected with moderate CYP3A4 inhibitors. Alternative concomitant medicinal products with no or minimal CYP3A4 inhibition should be considered.
Substances that may decrease nilotinib serum concentrationsRifampicin, a potent CYP3A4 inducer, decreases nilotinib Cmax by 64% and reduces nilotinib AUC by 80%. Rifampicin and nilotinib should not be used concomitantly.The concomitant administration of other medicinal products that induce CYP3A4 (e.g. phenytoin, carbamazepine, phenobarbital and St. John's Wort) is likewise likely to reduce exposure to nilotinib to a clinically relevant extent. In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be selected.Nilotinib has pH dependent solubility, with lower solubility at higher pH. In healthy subjects receiving esomeprazole at 40 mg once daily for 5 days, gastric pH was markedly increased, but nilotinib absorption was only decreased modestly (27% decrease in Cmax and 34% decrease in AUC0-∞). Nilotinib may be used concurrently with esomeprazole or other proton pump inhibitors as needed.In a healthy subjects study, no significant change in nilotinib pharmacokinetics was observed when a single 400 mg dose of Tasigna was administered 10 hours after and 2 hours before famotidine. Therefore, when the concurrent use of a H2 blocker is necessary, it may be administered approximately 10 hours before and approximately 2 hours after the dose of Tasigna.In the same study as above, administration of an antacid (aluminium hydroxide/magnesium hydroxide/simethicone) 2 hours before or after a single 400 mg dose of Tasigna also did not alter nilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of Tasigna.
Substances that may have their systemic concentration altered by nilotinibIn vitro, nilotinib is a relatively strong inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1, with Ki value being lowest for CYP2C9 (Ki=0.13 microM).A single-dose drug-drug interaction study in healthy volunteers with 25 mg warfarin, a sensitive CYP2C9 substrate, and 800 mg nilotinib did not result in any changes in warfarin pharmacokinetic parameters or warfarin pharmacodynamics measured as prothrombin time (PT) and international normalised ratio (INR). There are no steady-state data. This study suggests that a clinically meaningful drug-drug interaction between nilotinib and warfarin is less likely up to a dose of 25 mg of warfarin. Due to lack of steady-state data, control of warfarin pharmacodynamic markers (INR or PT) following initiation of nilotinib therapy (at least during the first 2 weeks) is recommended.In CML patients, nilotinib administered at 400 mg twice daily for 12 days increased the systemic exposure (AUC and Cmax) of oral midazolam (a substrate of CYP3A4) 2.6-fold and 2.0-fold, respectively. Nilotinib is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of other drugs primarily metabolised by CYP3A4 (e.g. certain HMG-CoA reductase inhibitors) may be increased when co-administered with nilotinib. Appropriate monitoring and dose adjustment may be necessary for drugs that are CYP3A4 substrates and have a narrow therapeutic index (including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus) when co-administered with nilotinib.
Anti-arrhythmic medicinal products and other substances that may prolong the QT intervalNilotinib should be used with caution in patients who have or may develop prolongation of the QT interval, 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, haloperidol, methadone and moxifloxacin (see section 4.4).
Food interactionsThe absorption and bioavailability of Tasigna are increased if it is taken with food, resulting in a higher serum concentration (see sections 4.2, 4.4 and 5.2). Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided.
Women of childbearing potentialWomen of childbearing potential have to use highly effective contraception during treatment with Tasigna and for up to two weeks after ending treatment.
PregnancyThere are no or limited amount of data from the use of nilotinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Tasigna should not be used during pregnancy unless the clinical condition of the woman requires treatment with nilotinib. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.
Breast-feedingIt is unknown whether nilotinib is excreted in human milk. Available toxicological data in animals have shown excretion of nilotinib in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. Tasigna should not be used during breast-feeding.
FertilityAnimal studies did not show an effect on fertility in male and female rats (see section 5.3).
Summary of the safety profileThe data described below reflect exposure to Tasigna in a total of 717 patients from a randomised Phase III study in patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279) and from an open-label multicentre Phase II study in patients with imatinib-resistant or intolerant CML in chronic phase (n=321) and accelerated phase (n=137) treated at the recommended dose of 400 mg twice daily.
In patients with newly diagnosed CML in chronic phaseThe median duration of exposure was 60.5 months (range 0.1-70.8 months).The most frequent (≥10%) non-haematological adverse reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia and upper abdominal pain. Most of these adverse reactions were mild to moderate in severity. Constipation, dry skin, asthenia, muscle spasms, diarrhoea, arthralgia, abdominal pain, vomiting and peripheral oedema were observed less commonly (<10% and ≥5%) were of mild to moderate severity, manageable and generally did not require dose reduction.Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (18%), neutropenia (15%) and anaemia (8%). Biochemical adverse drug reactions include alanine aminotransferase increased (24%), hyperbilirubinaemia (16%), aspartate aminotransferase increased (12%), lipase increased (11%), blood bilirubin increased (10%), hyperglycaemia (4%), hypercholesterolaemia (3%) and hypertriglyceridaemia (<1%). Pleural and pericardial effusions, regardless of causality, occurred in 2% and <1% of patients, respectively, receiving Tasigna 300 mg twice daily. Gastrointestinal haemorrhage, regardless of causality, was reported in 3% of these patients.The change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient had an absolute QTcF >500 msec while on the study medicinal product. QTcF increase from baseline exceeding 60 msec was observed in <1% of patients while on the study medicinal product. No sudden deaths or episodes of torsade de pointes (transient or sustained) were observed. No decrease from baseline in mean left ventricular ejection fraction (LVEF) was observed at any time during treatment. No patient had a LVEF of <45% during treatment nor an absolute reduction in LVEF of more than 15%.Discontinuation due to adverse drug reactions was observed in 10% of patients.
In patients with imatinib-resistant or intolerant CML in chronic phase and accelerated phaseThe data described below reflect exposure to Tasigna in 458 patients in an open-label multicentre Phase II study in patients with imatinib-resistant or intolerant CML in chronic phase (n=321) and accelerated phase (n=137) treated at the recommended dose of 400 mg twice daily.The most frequent (≥10%) non-haematological drug-related adverse events were rash, pruritus, nausea, fatigue, headache, vomiting, myalgia, constipation and diarrhoea. Most of these adverse events were mild to moderate in severity. Alopecia, muscle spasms, decreased appetite, arthralgia, abdominal pain, bone pain, peripheral oedema, asthenia, upper abdominal pain, dry skin, erythema and pain in extremity were observed less commonly (<10% and ≥5%) and have been of mild to moderate severity (Grade 1 or 2). Discontinuation due to adverse drug reactions was observed in 16% of chronic phase and 10% of accelerated phase patients.Treatment-emergent haematological toxicities include myelosuppression: thrombocytopenia (31%), neutropenia (17%) and anaemia (14%). Pleural and pericardial effusions as well as complications of fluid retention occurred in <1% of patients receiving Tasigna. Cardiac failure was observed in <1% of patients. Gastrointestinal and CNS haemorrhage were reported in 1% and <1% of patients, respectively.QTcF exceeding 500 msec was observed in <1% of patients. No episodes of torsade de pointes (transient or sustained) were observed.
Most frequently reported adverse reactions in Tasigna clinical studiesNon-haematological adverse reactions (excluding laboratory abnormalities) that are reported in at least 5% of the patients in Tasigna clinical studies are shown in Table 2. These are ranked under heading of frequency; with the most frequent appearing first, using one decimal precision for percentages and the following convention: very common (≥1/10) or common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.Table 2 Non-haematological adverse reactions (≥5% of all patients)*
|Newly diagnosed CML-CP300 mg twice dailyn=279||Imatinib-resistant or intolerant CML-CP and CML-AP400 mg twice daily n=458|
|60-month analysis||24-month analysis|
|System organ class/ Adverse reaction||Frequency||All grades||Grade 3-4||Frequency||All grades||Grade 3-4||CML-CPn=321Grade 3-4||CML-APn=137Grade 3-4|
|Metabolism and nutrition disorders|
|Decreased appetite **||Common||4||0||Common||8||<1||<1||0|
|Nervous system disorders|
|Headache||Very common||16||2||Very common||15||1||2||<1|
|Nausea||Very common||14||<1||Very common||20||<1||<1||<1|
|Upper abdominal pain||Very common||10||1||Common||5||<1||<1||0|
|Skin and subcutaneous tissue disorders|
|Rash||Very common||33||<1||Very common||28||1||2||0|
|Pruritus||Very common||18||<1||Very common||24||<1||<1||0|
|Musculoskeletal and connective tissue disorders|
|Myalgia||Very common||10||<1||Very common||10||<1||<1||<1|
|Pain in extremity||Common||5||<1||Common||5||<1||<1||<1|
|General disorders and administration site conditions|
|Fatigue||Very common||12||0||Very common||17||1||1||<1|
Infections and infestations:Common: folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis).Uncommon: pneumonia, urinary tract infection, gastroenteritis, bronchitis, herpes virus infection, candidiasis (including oral candidiasis).Not known: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.
Neoplasms benign, malignant and unspecified (including cysts and polyps):Common: skin papilloma.Not known: oral papilloma, paraproteinaemia.
Blood and lymphatic system disorders:Common: leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia.Uncommon: thrombocythaemia, leukocytosis.
Immune system disorders:Not known: hypersensitivity.Endocrine disorders:Uncommon: hyperthyroidism, hypothyroidism.Not known: hyperparathyroidism secondary, thyroiditis.
Metabolism and nutrition disorders:Very common: hypophosphataemia (including blood phosphorus decreased).Common: electrolyte imbalance (including hypomagnesaemia, hyperkalaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hypercalcaemia, hyperphosphataemia), diabetes mellitus, hyperglycaemia, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia.Uncommon: dehydration, increased appetite, gout, dyslipidaemia.Not known: hyperuricaemia, hypoglycaemia.
Psychiatric disorders:Common: depression, insomnia, anxiety.Not known: disorientation, confusional state, amnesia, dysphoria.
Nervous system disorders:Common: dizziness, peripheral neuropathy, hypoaesthesia, paraesthesia.Uncommon: intracranial haemorrhage, ischaemic stroke, transient ischaemic attack, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperaesthesia.Not known: cerebrovascular accident, brain oedema, optic neuritis, lethargy, dysaesthesia, restless legs syndrome.
Eye disorders:Common: eye haemorrhage, periorbital oedema, eye pruritus, conjunctivitis, dry eye (including xerophthalmia).Uncommon: visual impairment, vision blurred, conjunctival haemorrhage, visual acuity reduced, eyelid oedema, photopsia, hyperaemia (scleral, conjunctival, ocular), eye irritation.Not known: papilloedema, chorioretinopathy, diplopia, photophobia, eye swelling, blepharitis, eye pain, conjunctivitis allergic, ocular surface disease.
Ear and labyrinth disorders:Common: vertigo.Not known: hearing impaired, ear pain, tinnitus.
Cardiac disorders:Common: angina pectoris, arrhythmia (including atroventricular block, cardiac flutter, extrasystoles, tachycardia, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged.Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur, pericardial effusion, cyanosis.Not known: ventricular dysfunction, pericarditis, ejection fraction decreased.
Vascular disorders:Common: hypertension, flushing, peripheral artery stenosis.Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, haematoma, arteriosclerosis.Not known: shock haemorrhagic, hypotension, thrombosis.
Respiratory, thoracic and mediastinal disorders:Common: dyspnoea, dyspnoea exertional, epistaxis, cough, dysphonia.Uncommon: pulmonary oedema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation.Not known: pulmonary hypertension, wheezing, oropharyngeal pain.
Gastrointestinal disorders:Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, flatulence.Uncommon: gastrointestinal haemorrhage, melaena, mouth ulceration, gastroesophageal reflux, stomatitis, oesophageal pain, dry mouth, gastritis, sensitivity of teeth.Not known: gastrointestinal ulcer perforation, retroperitoneal haemorrhage, haematemesis, gastric ulcer, oesophagitis ulcerative, subileus, enterocolitis, haemorrhoids, hiatus hernia, rectal haemorrhage, gingivitis.
Hepatobiliary disorders:Very common: hyperbilirubinaemia (including blood bilirubin increased).Common: hepatic function abnormal.Uncommon: hepatotoxicity, toxic hepatitis, jaundice.Not known: cholestasis, hepatomegaly.
Skin and subcutaneous tissue disorders:Common: night sweats, eczema, urticaria, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform).Uncommon: exfoliative rash, drug eruption, skin pain, ecchymosis, swelling face.Not known: erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysaesthesia syndrome, petechiae, photosensitivity, blister, dermal cysts, sebaceous hyperplasia, skin atrophy, skin discolouration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis, psoriasis.
Musculoskeletal and connective tissue disorders:Common: musculoskeletal chest pain, musculoskeletal pain, back pain, flank pain, neck pain, muscular weakness.Uncommon: musculoskeletal stiffness, joint swelling.Not known: arthritis.
Renal and urinary disorders:Common: pollakiuria.Uncommon: dysuria, micturition urgency, nocturia.Not known: renal failure, haematuria, urinary incontinence, chromaturia.
Reproductive system and breast disorders:Uncommon: breast pain, gynaecomastia, erectile dysfunction.Not known: breast induration, menorrhagia, nipple swelling.
General disorders and administration site conditions:Common: chest pain (including non-cardiac chest pain), pain, pyrexia, chest discomfort, malaise.Uncommon: face oedema, gravitational oedema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold).Not known: localised oedema.
Investigations:Very common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, lipoprotein cholesterol (including low density and high density) increased, total cholesterol increased, blood triglycerides increased.Common: haemoglobin decreased, blood amylase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased, weight increased, blood insulin increased, globulins decreased.Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood urea increased.Not known: troponin increased, blood bilirubin unconjugated increased, blood insulin decreased, insulin C-peptide decreased, blood parathyroid hormone increased.Clinically relevant or severe abnormalities of routine haematological or biochemistry laboratory values are presented in Table 3.Table 3 Grade 3-4 laboratory abnormalities*
|Newly diagnosed CML-CP300 mg twice daily||Imatinib-resistant or intolerantCML-CP and CML-AP400 mg twice daily|
|- Elevated creatinine||0||1||<1|
|- Elevated lipase||9||18||18|
|- Elevated SGOT (AST)||1||3||2|
|- Elevated SGPT (ALT)||4||4||4|
|- Elevated bilirubin (total)||4||7||9|
|- Elevated glucose||7||12||6|
|- Elevated cholesterol (total)||0||**||**|
|- Elevated triglycerides||0||**||**|
Sudden deathUncommon cases (0.1 to 1%) of sudden deaths have been reported in Tasigna clinical trials and/or compassionate use programs in patients with imatinib-resistant or intolerant CML in chronic phase or accelerated phase with a past medical history of cardiac disease or significant cardiac risk factors (see section 4.4).Postmarketing experienceThe following adverse reactions have been derived from post-marketing experience with Tasigna via spontaneous case reports, literature cases, expanded access programmes, and clinical studies other than the global registration trials. Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to nilotinib exposure.Frequency rare: Cases of tumour lysis syndrome have been reported in patients treated with Tasigna.
Reporting of suspected adverse reactionsReporting 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Clinical studies in newly diagnosed CML in chronic phaseAn open-label, multicentre, randomised Phase III study was conducted to determine the efficacy of nilotinib versus imatinib in 846 adult patients with cytogenetically confirmed newly diagnosed Philadelphia chromosome positive CML in the chronic phase. Patients were within six months of diagnosis and were previously untreated, with the exception of hydroxyurea and/or anagrelide. Patients were randomised 1:1:1 to receive either nilotinib 300 mg twice daily (n=282), nilotinib 400 mg twice daily (n=281) or imatinib 400 mg once daily (n=283). Randomisation was stratified by Sokal risk score at the time of diagnosis.Baseline characteristics were well balanced between the three treatment arms. Median age was 47 years in both nilotinib arms and 46 years in the imatinib arm, with 12.8%, 10.0% and 12.4% of patients were ≥65 years of age in the nilotinib 300 mg twice daily, nilotinib 400 mg twice daily and imatinib 400 mg once daily treatment arms, respectively. There were slightly more male than female patients (56.0%, 62.3% and 55.8%, in the nilotinib 300 mg twice daily, 400 mg twice daily and imatinib 400 mg once daily arm, respectively). More than 60% of all patients were Caucasian and 25% of all patients were Asian.The primary data analysis time point was when all 846 patients completed 12 months of treatment (or discontinued earlier). Subsequent analyses reflect when patients completed 24, 36, 48, 60 and 72 months of treatment (or discontinued earlier). The median time on treatment was approximately 70 months in the nilotinib treatment groups and 64 months in the imatinib group. The median actual dose intensity was 593 mg/day for nilotinib 300 mg twice daily, 772 mg/day for nilotinib 400 mg twice daily and 400 mg/day for imatinib 400 mg once daily. This study is ongoing.The primary efficacy endpoint was major molecular response (MMR) at 12 months. MMR was defined as ≤0.1% BCR-ABL/ABL% by international scale (IS) measured by RQ-PCR, which corresponds to a ≥3 log reduction of BCR-ABL transcript from standardised baseline. The MMR rate at 12 months was statistically significantly higher for nilotinib 300 mg twice daily compared to imatinib 400 mg once daily (44.3% versus 22.3%, p<0.0001). The rate of MMR at 12 months, was also statistically significantly higher for nilotinib 400 mg twice daily compared to imatinib 400 mg once daily (42.7% versus 22.3%, p<0.0001).The rates of MMR at 3, 6, 9 and 12 months were 8.9%, 33.0%, 43.3% and 44.3% for nilotinib 300 mg twice daily, 5.0%, 29.5%, 38.1% and 42.7% for nilotinib 400 mg twice daily and 0.7%, 12.0%, 18.0% and 22.3% for imatinib 400 mg once daily.The MMR rate at 12, 24, 36, 48, 60 and 72 months is presented in Table 5.
Table 5 MMR rate
|Tasigna 300 mg twice daily n=282 (%)||Tasigna 400 mg twice daily n=281 (%)||Imatinib 400 mg once daily n=283 (%)|
|MMRat 12 months|
|Response (95% CI)||44.31 (38.4; 50.3)||42.71 (36.8; 48.7)||22.3 (17.6; 27.6)|
|MMR at 24 months|
|Response (95% CI)||61.71 (55.8; 67.4)||59.11 (53.1; 64.9)||37.5 (31.8; 43.4)|
|MMR at 36 months2|
|Response (95% CI)||58.51 (52.5; 64.3)||57.31 (51.3; 63.2)||38.5 (32.8; 44.5)|
|MMR at 48 months3|
|Response (95% CI)||59.91 (54.0; 65.7)||55.2 (49.1; 61.1)||43.8 (38.0; 49.8)|
|MMR at 60 months4|
|Response (95% CI)||62.8 (56.8; 68.4)||61.2 (55.2; 66.9)||49.1 (43.2; 55.1)|
|MMR at 72 months5|
|Response (95% CI)||52.5 (46.5; 58.4)||57.7 (51.6; 63.5)||41.7 (35.9; 47.7)|
Figure 1 Cumulative incidence of MMRFor all Sokal risk groups, the MMR rates at all time points remained consistently higher in the two nilotinib groups than in the imatinib group.In a retrospective analysis, 91% (234/258) of patients on nilotinib 300 mg twice daily achieved BCR-ABL levels ≤ 10% at 3 months of treatment compared to 67% (176/264) of patients on imatinib 400 mg once daily. Patients with BCR-ABL levels ≤ 10% at 3 months of treatment show a greater overall survival at 72 months compared to those who did not achieve this molecular response level (94.5% vs. 77.1% respectively [p=0.0005]).Based on the Kaplan-Meier analysis of time to first MMR the probability of achieving MMR at different time points was higher for both nilotinib at 300 mg and 400 mg twice daily compared to imatinib 400 mg once daily (HR=2.17 and stratified log-rank p<0.0001 between nilotinib 300 mg twice daily and imatinib 400 mg once daily, HR=1.88 and stratified log-rank p<0.0001 between nilotinib 400 mg twice daily and imatinib 400 mg once daily).The proportion of patients who had a molecular response of ≤0.01% and ≤0.0032% by IS at different time points are presented in Table 6 and the proportion of patients who had a molecular response of ≤0.01% and ≤0.0032% by IS by different time points are presented in Figures 2 and 3. Molecular responses of ≤0.01% and ≤0.0032% by IS correspond to a ≥4 log reduction and ≥4.5 log reduction, respectively, of BCR-ABL transcripts from a standardised baseline.
Table 6 Proportions of patients who had molecular response of ≤0.01% (4 log reduction) and ≤0.0032% (4.5 log reduction)
|Tasigna 300 mg twice daily n=282 (%)||Tasigna 400 mg twice daily n=281 (%)||Imatinib 400 mg once daily n=283 (%)|
|At 12 months||11.7||4.3||8.5||4.6||3.9||0.4|
|At 24 months||24.5||12.4||22.1||7.8||10.2||2.8|
|At 36 months||29.4||13.8||23.8||12.1||14.1||8.1|
|At 48 months||33.0||16.3||29.9||17.1||19.8||10.2|
|At 60 months||47.9||32.3||43.4||29.5||31.1||19.8|
|At 72 months||44.3||31.2||45.2||28.8||27.2||18.0|
Figure 2 Cumulative incidence of molecular response of ≤0.01% (4-log reduction)
Figure 3 Cumulative incidence of molecular response of ≤0.0032% (4.5 log reduction)Based on Kaplan-Meier estimates of the duration of first MMR, the proportions of patients who were maintaining response for 72 months among patients who achieved MMR were 92.5% (95% CI: 88.6-96.4%) in the nilotinib 300 mg twice daily group, 92.2% (95% CI: 88.5-95.9%) in the nilotinib 400 mg twice daily group and 88.0% (95% CI: 84.2-94.0%) in the imatinib 400 mg once daily group.Complete cytogenetic response (CCyR) was defined as 0% Ph+ metaphases in the bone marrow based on a minimum of 20 metaphases evaluated. Best CCyR rate by 12 months (including patients who achieved CCyR at or before the 12 month time point as responders) was statistically higher for both nilotinib 300 mg and 400 mg twice daily compared to imatinib 400 mg once daily, see Table 7.CCyR rate by 24 months (includes patients who achieved CCyR at or before the 24 month time point as responders) was statistically higher for both the nilotinib 300 mg twice daily and 400 mg twice daily groups compared to the imatinib 400 mg once daily group.
Table 7 Best complete cytogenetic response (CCyR) rate
|Tasigna (nilotinib) 300 mg twice daily n=282 (%)||Tasigna (nilotinib) 400 mg twice daily n=281 (%)||Glivec (imatinib) 400 mg once daily n=283 (%)|
|By 12 months|
|Response (95% CI)||80.1 (75.0; 84.6)||77.9 (72.6; 82.6)||65.0 (59.2; 70.6)|
|CMH test p-value for response rate (versus imatinib 400 mg once daily)||<0.0001||0.0005|
|By 24 months|
|Response (95% CI)||86.9 (82.4; 90.6)||84.7 (79.9; 88.7)||77.0 (71.7; 81.8)|
|CMH test p-value for response rate (versus imatinib 400 mg once daily)||0.0018||0.0160|
Clinical studies in imatinib-resistant or intolerant CML in chronic phase and accelerated phaseAn open-label, uncontrolled, multicentre Phase II study was conducted to determine the efficacy of Tasigna in patients with imatinib resistant or intolerant CML with separate treatment arms for chronic and accelerated phase disease. Efficacy was based on 321 CP patients and 137 AP patients enrolled. Median duration of treatment was 561 days for CP patients and 264 days for AP patients (see Table 8). Tasigna was administered on a continuous basis (twice daily 2 hours after a meal and with no food for at least one hour after administration) unless there was evidence of inadequate response or disease progression. The dose was 400 mg twice daily and dose escalation to 600 mg twice daily was allowed.
Table 8 Duration of exposure with Tasigna
|Chronic phase n=321||Accelerated phase n=137|
|Median duration of therapy in days (25th-75th percentiles)||561 (196-852)||264 (115-595)|
Table 9 CML disease history characteristics
|Chronic phase (n=321)||Accelerated phase (n=137)*|
|Median time since diagnosis in months (range)||58 (5275)||71 (2298)|
|Imatinib Resistant Intolerant without MCyR||226 (70%) 95 (30%)||109 (80%) 27 (20%)|
|Median time of imatinib treatment in days (25th-75th percentiles)||975 (519-1,488)||857 (424-1,497)|
|Prior bone marrow transplant||7%||8%|
|* Missing information on imatinib-resistant/intolerant status for one patient.|
Chronic PhaseThe MCyR rate in 321 CP patients was 51%. Most responders achieved their MCyR rapidly within 3 months (median 2.8 months) of starting Tasigna treatment and these were sustained. The median time to achieve CCyR was just past 3 months (median 3.4 months). Of the patients who achieved MCyR, 77% (95% CI: 70% - 84%) were maintaining response at 24 months. Median duration of MCyR has not been reached. Of the patients who achieved CCyR, 85% (95% CI: 78% - 93%) were maintaining response at 24 months. Median duration of CCyR has not been reached. Patients with a CHR at baseline achieved a MCyR faster (1.9 versus 2.8 months). Of CP patients without a baseline CHR, 70% achieved a CHR, median time to CHR was 1 month and median duration of CHR was 32.8 months. The estimated 24-month overall survival rate in CML-CP patients was 87%.
Accelerated PhaseThe overall confirmed HR rate in 137 AP patients was 50%. Most responders achieved a HR early with Tasigna treatment (median 1.0 months) and these have been durable (median duration of confirmed HR was 24.2 months). Of the patients who achieved HR, 53% (95% CI: 39% - 67%) were maintaining response at 24 months. MCyR rate was 30% with a median time to response of 2.8 months. Of the patients who achieved MCyR, 63% (95% CI: 45% - 80%) were maintaining response at 24 months. Median duration of MCyR was 32.7 months. The estimated 24-month overall survival rate in CML-AP patients was 70%.The rates of response for the two treatment arms are reported in Table 10.
Table 10 Response in CML
|(Best Response Rate)||Chronic Phase||Accelerated Phase|
|Haematological Response (%)|
|Overall (95%CI) Complete NEL Return to CP||- 87 (74-94) - -||- 65 (56-72) - -||- 701 (63-76) -||48 (29-68) 37 7 4||51 (42-61) 28 10 13||50 (42-59) 30 9 11|
|Cytogenetic Response (%)|
|Major (95%CI) Complete Partial||57 (46-67) 41 16||49 (42-56) 35 14||51 (46-57) 37 15||33 (17-54) 22 11||29 (21-39) 19 10||30 (22-38) 20 10|
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies with Tasigna in paediatric patients from birth to less than 18 years in the treatment of Philadelphia chromosome positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use).
AbsorptionPeak concentrations of nilotinib are reached 3 hours after oral administration. Nilotinib absorption following oral administration was approximately 30%. The absolute bioavailability of nilotinib has not been determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability of nilotinib capsule is approximately 50%. In healthy volunteers, Cmax and area under the serum concentration-time curve (AUC) of nilotinib are increased by 112% and 82%, respectively, compared to fasting conditions when Tasigna is given with food. Administration of Tasigna 30 minutes or 2 hours after food increased bioavailability of nilotinib by 29% or 15%, respectively (see sections 4.2, 4.4 and 4.5).Nilotinib absorption (relative bioavailability) might be reduced by approximately 48% and 22% in patients with total gastrectomy and partial gastrectomy, respectively.
DistributionThe blood-to-plasma ratio of nilotinib is 0.71. Plasma protein binding is approximately 98% on the basis of in vitro experiments.
BiotransformationMain metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. None of the metabolites contribute significantly to the pharmacological activity of nilotinib. Nilotinib is primarily metabolised by CYP3A4, with possible minor contribution from CYP2C8.
EliminationAfter a single dose of radiolabelled nilotinib in healthy subjects, more than 90% of the dose was eliminated within 7 days, mainly in faeces (94% of the dose). Unchanged nilotinib accounted for 69% of the dose.The apparent elimination half-life estimated from the multiple-dose pharmacokinetics with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib pharmacokinetics was moderate to high.
Linearity/non-linearitySteady-state nilotinib exposure was dose-dependent, with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg given as once-daily dosing. Daily systemic exposure to nilotinib with 400 mg twice-daily dosing at steady state was 35% higher than with 800 mg once-daily dosing. Systemic exposure (AUC) of nilotinib at steady state at a dose level of 400 mg twice daily was approximately 13.4% higher than at a dose level of 300 mg twice daily. The average nilotinib trough and peak concentrations over 12 months were approximately 15.7% and 14.8% higher following 400 mg twice-daily dosing compared to 300 mg twice daily. There was no relevant increase in exposure to nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily.Steady-state conditions were essentially achieved by day 8. An increase in serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice-daily dosing.
Bioavailability/bioequivalence studiesSingle-dose administration of 400 mg nilotinib, using 2 hard capsules of 200 mg whereby the content of each hard capsule was dispersed in one teaspoon of apple sauce, was shown to be bioequivalent with a single-dose administration of 2 intact hard capsules of 200 mg.
Hard capsule contentLactose monohydrateCrospovidonePoloxamer 188Silica, colloidal anhydrousMagnesium stearate
Hard capsule shellGelatinTitanium dioxide (E171)Yellow iron oxide (E172)
Printing inkShellac (E904)Red iron oxide (E172)
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