Protein-kinase inhibitors

Nilotinib (as hydrochloride monohydrate)

One hard capsule contains 200 mg nilotinib (as hydrochloride monohydrate). Excipient: Lactose monohydrate: 156.11 mg per capsule.

Hard capsule White to slightly yellowish powder in light yellow opaque hard gelatin capsules, size 0 with red axial imprint “NVR/TKI”.

Tasigna is indicated for the treatment of adults with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (CML) with resistance or intolerance to prior therapy including imatinib. Efficacy data in patients with CML in blast crisis are not available.

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients with CML.

The recommended dose of Tasigna is 400 mg twice daily. Treatment should be continued as long as the patient continues to benefit.

Tasigna should be taken twice daily approximately 12 hours apart and must not be taken with food. The 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.

Tasigna may be given in combination with haematopoietic growth factors such as erythropoietin or granulocyte colony-stimulating factor (G-CSF) if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.

Dose adjustments or modifications

Tasigna may need to be temporarily withheld and/or dose reduced for haematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukaemia (see Table 1).

Table 1 Dose adjustments for neutropenia and thrombocytopenia

*ANC = absolute neutrophil count

If clinically significant moderate or severe non-haematological toxicity develops, dosing should be interrupted, and may be resumed at 400 mg once daily once the toxicity has resolved. If clinically appropriate, re-escalation of the dose to 400 mg twice daily should be considered.

Elevated serum lipase: For Grade 34 serum lipase elevations, doses should be reduced to 400 mg once daily or interrupted. Serum lipase levels should be tested monthly or as clinically indicated.

Elevated bilirubin and hepatic transaminases: For Grade 34 bilirubin elevations, doses should be reduced to 400 mg once daily or interrupted. Bilirubin and hepatic transaminases levels should be tested monthly or as clinically indicated.

If a dose is missed the patient should not take an additional dose, but take the usual prescribed next dose.

Patients with renal impairment

Clinical studies have not been performed in patients with impaired renal function.

Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment.

Patients with hepatic impairment

Tasigna has not been investigated in patients with hepatic impairment. Patients with hepatic impairment should be treated with caution.

Cardiac disorders

In 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

Tasigna is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.

Approximately 30% of subjects in clinical studies were 65 years of age or over. No major differences were observed for safety and efficacy in patients 65 years of age as compared to adults aged 18 to 65 years.

Hypersensitivity to the active substance or to any of the excipients.

Myelosuppression

Treatment with Tasigna is associated with (National Cancer Institute Common Toxicity Criteria grade 34) thrombocytopenia, neutropenia and anaemia.Occurrence is more frequent 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.

QT prolongation

Tasigna 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 II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase, the change from baseline in mean time-averaged QTcF interval at steady state was 6 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. 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.

Interactions with other medicinal products

The administration of Tasigna with agents that are strong CYP3A4 inhibitors (including, but not limited to, ketoconazole, itraconazole, voriconazole, moxifloxacin, 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. If transient interruption of treatment with Tasigna is not possible, close monitoring of the individual for prolongation of the QT interval is indicated.

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, coadministration of alternative therapeutic agents with less potential for CYP3A4 induction should be selected.

Suppression of gastric acid secretion might result in lower exposure to nilotinib. Therefore, concomitant use of antacids, H₂ blockers, or proton pump inhibitors with Tasigna is not recommended.

Food effect

The bioavailability of nilotinib is increased by food. Tasigna should not be taken in conjunction with food 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.

Hepatic impairment

Tasigna has not been investigated in patients with hepatic impairment. 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.

Serum lipase

Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis.

Lactose

Tasigna 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 concentrations

Nilotinib is mainly metabolised in the liver and is also a substrate for the multi-drug efflux pump, P-glycoprotein (Pgp). Therefore, absorption and subsequent elimination of systemically absorbed nilotinib may be influenced by substances that affect CYP3A4 and/or Pgp. 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, moxifloxacin, clarithromycin, and telithromycin, should therefore be avoided. Increased exposure to nilotinib might also be expected with moderate CYP3A4 inhibitors. Alternative concomitant medications with no or minimal CYP3A4 inhibition should be considered.

Substances that may decrease nilotinib serum concentrations

Rifampicin, a potent CYP3A4 inducer, decreases nilotinib C_max 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, therefore, absorption of nilotinib might be reduced by substances that suppress gastric acid secretion. The concomitant use of antacids, H₂ blockers, or proton pump inhibitors with Tasigna is not recommended.

Substances that may have their systemic concentration altered by nilotinib

Nilotinib is a relatively strong inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially increasing the concentrations of substances eliminated by these enzymes. The clinical relevance of these potential interactions has not been studied but caution is advised especially with concomitant use of nilotinib and medicinal products with a narrow therapeutic index. In addition, single-dose administration of Tasigna with orally administered midazolam to healthy subjects increased midazolam exposure by 30%. It cannot be excluded that the effect of nilotinib is greater at steady state. Caution should be exercised when co-administering Tasigna with substrates of these enzymes that have a narrow therapeutic index [e.g. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine)]. Since warfarin is metabolised by CYP2C9 and CYP3A4 it should be given with caution. Other medicinal products for anticoagulation should be considered.

Anti-arrhythmic medicinal products and other substances that may prolong QT

Nilotinib 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, haloperidol and methadone.

Other interactions that may affect serum concentrations

The absorption of Tasigna is increased if it is taken with food, resulting in higher serum concentration. Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided.

The data described below reflect exposure to Tasigna in 438 patients in an open-label multicentre study. At cut-off, 46% of patients in chronic-phase CML (CML-CP) had a duration of exposure of 6 to 12 months and 18% of patients had a duration of exposure of more than 12 months. 62% of patients in accelerated-phase CML (CML-AP) had a duration of exposure of 3 to 12 months and 10% of patients had a duration of exposure of more than 12 months. The dose was 400 mg twice daily. The median duration of exposure in days was 245 (1502) for the CML-CP patients and 138 (2503) for the CML-AP patients.

The most frequent non-haematological drug-related adverse events were rash, pruritus, nausea, fatigue and headache. Most of these adverse events were mild to moderate in severity. Constipation, diarrhoea, bone pain, arthralgia, muscle spasms and peripheral oedema were observed less commonly and have been of mild to moderate severity. Discontinuation for adverse events regardless of causality was observed in 16% of CP and 14% of AP patients.

Treatment emergent haematological toxicities included thrombocytopenia (27%), neutropenia (15%) and anaemia (13%). Pleural and pericardial effusions as well as complications of fluid retention occurred in <1% of patients receiving Tasigna. Congestive heart failure was observed in 1% of patients. Gastrointestinal and CNS haemorrhage were reported in 3% 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.

Non-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 using the following convention: very common (1/10) or common (1/100 to <1/10). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2 Adverse reactions (5% of all patients, n=438)

System organ class	Frequency	Adverse reaction	All grades	Grade 34	Chronic phase Grade 34	Accelerated phase Grade 34
			%	%	%	%
Nervous system disorders	Very common	Headache	15	1	2	<1
Gastrointestinal disorders	Very common	Nausea	19	<1	<1	<1
	Very common	Constipation	11	0	0	0
	Very common	Diarrhoea	10	2	2	<1
	Common	Vomiting	9	<1	<1	0
	Common	Abdominal pain	5	<1	<1	<1
Skin and subcutaneous tissue disorders	Very common	Rash	26	1	<1	0
	Very common	Pruritus	22	<1	<1	0
	Common	Alopecia	7	0<	0	0
Musculoskeletal and connective tissue disorders	Common	Myalgia	8	<1	<1	<1
	Common	Arthralgia	6	<1	<<1	0
	Common	Muscle spasms	6	0	0	0
	Common	Bone pain	6	<1	<1	0
Metabolism and nutrition disorders	Common	Anorexia	5	0	0	0
General disorders and administration site conditions	Very common	Fatigue	16	<1	<1	<1
	Common	Asthenia	6	0	0	0
	Common	Oedema peripheral	5	0	0	0

Additional data from clinical trials

The following adverse reactions were reported in patients in the Tasigna clinical studies at a frequency of less than 5% (common is 1/100 to <1/10; uncommon is>1/1,000 to <1/100; single events are captured as frequency not known [cannot be estimated from the available data]). For laboratory abnormalities, very common events (1/10) not included in Table 2 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Investigations:

Very common: lipase increased.

Common: blood amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood glucose increased, weight decreased, weight increased.

Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood creatinine increased, blood urea increased.

Not known: troponin increased, blood potassium decreased, blood bilirubin unconjugated increased.

Cardiac disorders :

Common: palpitations, electrocardiogram QT prolonged.

Uncommon: cardiac failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease, cardiomegaly, cardiac murmur, bradycardia.

Not known: myocardial infarction, ventricular dysfunction, pericarditis, cardiac flutter, extrasystoles.

Blood and lymphatic system disorders:

Common: febrile neutropenia, pancytopenia.

Uncommon: thrombocythaemia, leukocytosis.

Nervous system disorders:

Common: dizziness, paraesthesia.

Uncommon: intracranial haemorrhage, migraine, tremor, hypoaesthesia, hyperaesthesia.

Not known: brain oedema, loss of consciousness, optic neuritis, peripheral neuropathy.

Eye disorders:

Uncommon: eye haemorrhage, visual acuity reduced, periorbital oedema, conjunctivitis, eye irritation, dry eye.

Not known: papilloedema, diplopia, vision blurred, photophobia, eye swelling, blepharitis, eye pain.

Ear and labyrinth disorders:

Common: vertigo.

Not known: hearing impaired, ear pain.

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea, dyspnoea exertional, cough, dysphonia.

Uncommon: pulmonary oedema, pleural effusion, interstitial lung disease, pleuric pain, pleurisy, epistaxis, pharyngolaryngeal pain, throat irritation.

Not known: pulmonary hypertension.

Gastrointestinal disorders:

Common: abdominal discomfort, dyspepsia, flatulence.

Uncommon: pancreatitis, gastrointestinal haemorrhage, melaena, abdominal distension, mouth ulceration, gastroesophageal reflux, stomatitis, dry mouth.

Not known: gastrointestinal ulcer perforation, retroperitoneal haemorrhage, haematemesis, gastric ulcer, oesophagitis ulcerative, subileus.

Renal and urinary disorders:

Uncommon: dysuria, micturition urgency, nocturia, pollakiuria.

Not known: renal failure, haematuria, urinary incontinence.

Skin and subcutaneous tissue disorders :

Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, dry skin.

Uncommon: exfoliative rash, ecchymosis, swelling face.

Not known: erythema nodosum, skin ulcer, petechiae, photosensitivity.

Musculoskeletal and connective tissue disorders :

Common: musculoskeletal chest pain, musculoskeletal pain.

Uncommon: muscular weakness.

Not known: arthritis, joint swelling.

Endocrine disorders:

Uncommon: hyperthyroidism.

Not known: hypothyroidism, thyroiditis.

Metabolism and nutrition disorders:

Common: hypomagnesaemia, hyperkalaemia, hyperglycaemia.

Uncommon: hypokalaemia, hyponatraemia, hypocalcaemia, hypophosphataemia, dehydration, decreased appetite, increased appetite.

Not known: diabetes mellitus, hypercalcaemia, hyperphosphataemia.

Infections and infestations:

Uncommon: pneumonia, urinary tract infection, gastroenteritis, pharyngitis.

Not known: sepsis, bronchitis, herpes simplex, candidiadis.

Vascular disorders :

Common: hypertension, flushing.

Uncommon: hypertensive crisis, haematoma.

Not known: shock haemorrhagic, hypotension, thrombosis.

General disorders and administration site conditions :

Common: pyrexia.

Uncommon: chest pain, face oedema, gravitational oedema, influenza-like illness, chills, malaise.

Hepatobiliary disorders:

Uncommon: hepatitis.

Not known: hepatotoxicity, hepatomegaly, jaundice.

Reproductive system and breast disorders:

Uncommon: breast pain, gynaecomastia, erectile dysfunction.

Psychiatric disorders:

Common: insomnia.

Uncommon: depression, anxiety.

Not known: disorientation, confusional state.

Clinically relevant or severe abnormalities of routine haematological or biochemistry laboratory values are presented in Table 3.

Table 3 Grade 34 laboratory abnormalities

	CML-CP n=318 %	CML-AP n=120 %
	Grade 34	Grade 34
Haematological parameters
- Neutropenia	28%	37%
- Thrombocytopenia	28%	37%
- Anaemia	8%	23%
Biochemistry parameters
- Elevated creatinine	<1%	0%
- Elevated lipase	15%	17%
- Elevated SGOT (AST)	1%	<1%
- Elevated SGPT (ALT)	4%	2%
- Hypophosphataemia	10%	10%
- Elevated bilirubin (total)	9%	10%

Novartis Pharma

(POM)