Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Treatment with nilotinib 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).
Nilotinib has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval on the surface ECG in a concentration-dependent manner in adult and paediatric patients.
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 the QT interval, 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:
Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating nilotinib therapy and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to Tasigna administration and should be monitored periodically during therapy.
Uncommon 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.
Severe forms of drug-related 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 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 nilotinib 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).
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. 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 nilotinib. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with nilotinib 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).
Eligible patients who are confirmed to express the typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be considered for treatment discontinuation. Patients must have typical BCR-ABL transcripts to allow quantitation of BCR-ABL, evaluation of the depth of molecular response, and determination of a possible loss of molecular remission after discontinuation of treatment with nilotinib.
Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS). BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation (see sections 4.2 and 5.1).
Loss of major molecular response (MMR=BCR-ABL/ABL ≤0.1%IS) in CML patients who received nilotinib as first – or second – line therapy, or confirmed loss of MR4 (two consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4=BCR-ABL/ABL ≤0.01%IS)) in CML patients who received nilotinib as second – line therapy will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. Molecular relapse can occur during the treatment-free phase, and long-term outcome data are not yet available. It is therefore crucial to perform frequent monitoring of BCR-ABL transcript levels and complete blood count with differential in order to detect possible loss of remission (see section 4.2). For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be performed.
In 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 nilotinib, 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.
In 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.
The 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 nilotinib therapy 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 nilotinib 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 nilotinib, co-administration of alternative therapeutic agents with less potential for CYP3A4 induction should be selected (see section 4.5).
The 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 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 C max 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).
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, nilotinib therapy should be interrupted and appropriate diagnostic measures considered to exclude pancreatitis.
The 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.
Due 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 nilotinib therapy (see section 4.8).
Tasigna 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.
Laboratory abnormalities of mild to moderate transient elevations of aminotransferases and total bilirubin have been observed in children at a higher frequency than in adults, indicating a higher risk of hepatotoxicity in the paediatric population (see section 4.8). Liver function (bilirubin and hepatic transaminases levels) should be monitored monthly or as clinically indicated. Elevations of bilirubin and hepatic transaminases should be managed by withholding nilotinib temporarily, dose reduction and/or discontinuation of nilotinib (see section 4.2). The long-term effects of prolonged treatment with nilotinib in paediatric patients are unknown. In a study in the CML paediatric population, growth retardation has been documented in patients treated with nilotinib (see section 4.8). Close monitoring of growth in paediatric patients under nilotinib treatment is recommended.
Tasigna may be given in combination with haematopoietic growth factors such as erythropoietin or granulocyte colony-stimulating factor (G-CSF) if clinically indicated. It may be given with hydroxyurea or anagrelide if clinically indicated.
Nilotinib is mainly metabolised in the liver with CYP3A4 expected to be the main contributor to the oxidative metabolism. Nilotinib is also a substrate for the multi-drug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed nilotinib may be influenced by substances that affect CYP3A4 and/or P-gp.
Concomitant 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.
Rifampicin, 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 nilotinib 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 nilotinib 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.
In 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 medicinal products 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 medicinal products 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.
Nilotinib 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).
The absorption and bioavailability of nilotinib 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.
Interaction studies have only been performed in adults.
Women of childbearing potential have to use highly effective contraception during treatment with nilotinib and for up to two weeks after ending treatment.
There 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.
If a woman who is being treated with nilotinib is considering pregnancy, treatment discontinuation may be considered based on the eligibility criteria for discontinuing treatment as described in sections 4.2 and 4.4. There is a limited amount of data on pregnancies in patients while attempting treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re-initiate nilotinib treatment during pregnancy (see sections 4.2 and 4.4).
It 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). Since a risk to the newborns/infants cannot be excluded, women should not breast-feed during Tasigna treatment and for 2 weeks after the last dose.
Animal studies did not show an effect on fertility in male and female rats (see section 5.3).
Tasigna has no or negligible influence on the ability to drive and use machines. However, it is recommended that patients experiencing dizziness, fatigue, visual impairment or other undesirable effects with a potential impact on the ability to drive or use machines safely should refrain from these activities as long as the undesirable effects persist (see section 4.8).
The data described below reflect exposure to nilotinib in a total of 737 adult 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 adult 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. Safety information from two Tasigna treatment discontinuation studies is also provided.
The 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 nilotinib 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.
The data described below reflect exposure to nilotinib in 458 adult 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.
The adverse reactions are ranked under heading of frequency using the following convention: 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Non-haematological adverse reactions (excluding laboratory abnormalities) that are reported in at least 5% of the adult patients in Tasigna clinical studies that serve as the basis for the approved indications are shown in Table 3.
Table 3. Non-haematological adverse reactions (≥5% of all patients)*:
| Newly diagnosed CML-CP 300 mg twice daily n=279 | Imatinib-resistant or intolerant CML-CP and CML-AP 400 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-CP n=321 Grade 3-4 | CML-AP n=137 Grade 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 |
| Gastrointestinal disorders | ||||||||
| Nausea | Very common | 14 | <1 | Very common | 20 | <1 | <1 | <1 |
| Constipation | Common | 10 | 0 | Very common | 12 | <1 | <1 | 0 |
| Diarrhoea | Common | 9 | <1 | Very common | 11 | 2 | 2 | <1 |
| Vomiting | Common | 6 | 0 | Very common | 10 | <1 | <1 | 0 |
| Upper abdominal pain | Very common | 10 | 1 | Common | 5 | <1 | <1 | 0 |
| Abdominal pain | Common | 6 | 0 | Common | 6 | <1 | <1 | <1 |
| Dyspepsia | Common | 5 | 0 | Common | 3 | 0 | 0 | 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 |
| Alopecia | Very common | 10 | 0 | Common | 9 | 0 | 0 | 0 |
| Dry skin | Common | 10 | 0 | Common | 5 | 0 | 0 | 0 |
| Erythema | Common | 3 | 0 | Common | 5 | <1 | <1 | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Myalgia | Very common | 10 | <1 | Very common | 10 | <1 | <1 | <1 |
| Muscle spasms | Common | 9 | 0 | Common | 8 | <1 | <1 | 0 |
| Arthralgia | Common | 8 | <1 | Common | 7 | <1 | <1 | 0 |
| Bone pain | Common | 4 | 0 | Common | 6 | <1 | <1 | 0 |
| 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 |
| Asthenia | Common | 9 | <1 | Common | 6 | 0 | 0 | 0 |
| Oedema peripheral | Συχνές | 5 | <1 | Common | 6 | 0 | 0 | 0 |
* Percentages are rounded to integer for presentation in this table. However, percentages with one decimal precision are used to identify terms with a frequency of at least 5% and to classify terms according to frequency categories.
** Also includes preferred term anorexia
Adverse reactions that were reported in adult patients in the Tasigna clinical studies which serve as a basis for the approved indications at a frequency of less than 5% are shown in Table 4. For laboratory abnormalities, very common adverse reactions not included in Table 3 are also reported. These adverse reactions are included based on clinical relevance.
Table 4. Adverse reactions in adult patients in Tasigna clinical studies (<5% of all patients):
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, hepatitis B reactivation
Common: Skin papilloma
Not known: Oral papilloma, paraproteinaemia
Common: Leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia
Uncommon: Thrombocythaemia, leukocytosis
Not known: Hypersensitivity
Uncommon: Hyperthyroidism, hypothyroidism
Not known: Hyperparathyroidism secondary, thyroiditis
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
Common: Depression, insomnia, anxiety
Not known: Disorientation, confusional state, amnesia, dysphoria
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
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
Common: Vertigo
Not known: Hearing impaired, ear pain, tinnitus
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
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
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
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
Very common: Hyperbilirubinaemia (including blood bilirubin increased)
Common: Hepatic function abnormal
Uncommon: Hepatotoxicity, toxic hepatitis, jaundice
Not known: Cholestasis, hepatomegaly
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
Common: Musculoskeletal chest pain, musculoskeletal pain, back pain, flank pain, neck pain, muscular weakness
Uncommon: Musculoskeletal stiffness, joint swelling
Not known: Arthritis
Common: Pollakiuria
Uncommon: Dysuria, micturition urgency, nocturia
Not known: Renal failure, haematuria, urinary incontinence, chromaturia
Uncommon: Breast pain, gynaecomastia, erectile dysfunction
Not known: Breast induration, menorrhagia, nipple swelling
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
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 in adult patients are presented in Table 5.
Table 5. Grade 3-4 laboratory abnormalities*:
| Newly diagnosed CML-CP 300 mg twice daily | Imatinib-resistant or intolerant CML-CP and CML-AP 400 mg twice daily | ||
|---|---|---|---|
| n=279 (%) | CML-CP n=321 (%) | CML-AP n=137 (%) | |
| Haematological parameters | |||
| Myelosuppression | |||
| Neutropenia | 12 | 31 | 42 |
| Thrombocytopenia | 10 | 30 | 42 |
| Anaemia | 4 | 11 | 27 |
| Biochemistry parameters | |||
| Elevated creatinine | 0 | 1 | <1 |
| Elevated lipase | 9 | 18 | 18 |
| Elevated SGOT (AST) | 1 | 3 | 2 |
| Elevated SGPT (ALT) | 4 | 4 | 4 |
| Hypophosphataemia | 8 | 17 | 15 |
| Elevated bilirubin (total) | 4 | 7 | 9 |
| Elevated glucose | 7 | 12 | 6 |
| Elevated cholesterol (total) | 0 | ** | ** |
| Elevated triglycerides | 0 | ** | ** |
* Percentages with one decimal precision are used and rounded to integer for presentation in this table
** Parameters not collected
After discontinuation of nilotinib therapy within the framework of attempting TFR, patients may experience musculoskeletal symptoms more frequently than before treatment discontinuation, e.g., myalgia, pain in extremity, arthralgia, bone pain, spinal pain or musculoskeletal pain.
In a Phase II clinical study with newly diagnosed adult patients with Ph+ CML in chronic phase (N=190), musculoskeletal symptoms were reported within a year of Tasigna discontinuation in 24.7% versus 16.3% within the previous year on nilotinib treatment.
In a Phase II clinical study with adult patients with Ph+ CML in chronic phase on nilotinib treatment and previously treated with imatinib (N=126), musculoskeletal symptoms were reported within a year of discontinuation in 42.1% versus 14.3% within the previous year on nilotinib treatment.
Uncommon 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).
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).
The 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 very common: Growth retardation has been documented in paediatric patients treated with nilotinib.
Frequency rare: Cases of tumour lysis syndrome have been reported in patients treated with nilotinib.
The safety of nilotinib in paediatric patients (from 2 to <18 years of age) with Philadelphia chromosome positive CML in chronic phase (n=69) has been investigated in two studies (see section 5.1). In paediatric patients, the frequency, type and severity of adverse reactions observed have been generally consistent with those observed in adults, with the exception of the laboratory abnormalities hyperbilirubinaemia (Grade 3/4: 13.0%) and transaminase elevation (AST Grade 3/4: 1.4%, ALT Grade 3/4: 8.7%) which were reported at a higher frequency than in adult patients. Bilirubin and hepatic transaminase levels should be monitored during treatment (see sections 4.2 and 4.4).
In an interim analysis in a study in the CML paediatric population, with a median exposure of 33 months in each cohort (newly diagnosed and resistant or intolerant Ph+ CML-CP), growth retardation (crossing two main percentile lines from baseline) has been documented in 12.1%. Close monitoring of growth in paediatric patients under nilotinib treatment is recommended (see section 4.4).
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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