Consumer medicine information

Tasigna

Nilotinib

BRAND INFORMATION

Brand name

Tasigna

Active ingredient

Nilotinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tasigna.

SUMMARY CMI

TASIGNA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using TASIGNA?

TASIGNA contains the active ingredient nilotinib. TASIGNA is used to treat chronic myeloid leukaemia (CML)

For more information, see Section 1. Why am I using TASIGNA? in the full CMI.

2. What should I know before I use TASIGNA?

Do not use if you have ever had an allergic reaction to TASIGNA or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use TASIGNA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TASIGNA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TASIGNA?

  • If you have been newly diagnosed with CML the usual dose of TASIGNA is two capsules of 150 mg (300 mg) twice daily. If you are no longer doing well from previous treatment for CML, the usual dose is two capsules of 200 mg (400 mg) twice daily.
  • You should take TASIGNA in the morning and evening, approximately 12 hours apart.
  • You must not take TASINGA with food. Do not eat at least 2 hours before and 1 hour after taking TASIGNA.

More instructions can be found in Section 4. How do I use TASIGNA? in the full CMI.

5. What should I know while using TASIGNA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using TASIGNA.
  • Have regular blood tests, heart and weight checks while using TASIGNA.
  • Avoid becoming pregnant while using TASIGNA and for 2 weeks after you stop using it.
Things you should not do
  • Do not stop using this medicine suddenly (unless your doctor tells you to).
  • Do not drink products and juices containing grapefruit juice, star fruit, pomegranate, seville oranges and other similar fruits while using TASIGNA.
Driving or using machines
  • It is not known if TASIGNA will influence your ability to drive and use machines.
  • Be cautious when driving or using machines in case you feel dizzy or tired while using TASIGNA.
Drinking alcohol
  • There are no known interactions between TASIGNA and alcohol.
Looking after your medicine
  • Store below 30°C.
  • Keep out of reach of children.

For more information, see Section 5. What should I know while using TASIGNA? in the full CMI.

6. Are there any side effects?

Common side effects include headache, decreased appetite, feeling sick, vomiting, constipation, diarrhoea, tummy pain, rash, hair loss, dry skin, pain in muscles or joints, tiredness.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

TASIGNA® (TAS-inn-yah)

Active ingredient(s): nilotinib

Consumer Medicine Information (CMI)

This leaflet provides important information about using TASIGNA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TASIGNA.

Where to find information in this leaflet:

1. Why am I using TASIGNA?
2. What should I know before I use TASIGNA?
3. What if I am taking other medicines?
4. How do I use TASIGNA?
5. What should I know while using TASINGA?
6. Are there any side effects?
7. Product details

1. Why am I using TASIGNA?

TASIGNA contains the active ingredient nilotinib. TASIGNA belongs to a group of medicines call tyrosine kinase inhibitors. It kills cancerous white blood cells that contain a particular kind of tyrosine kinase, while leaving normal cells alone.

TASIGNA is used to treat chronic myeloid leukaemia (CML). CML is a type of leukaemia.

2. What should I know before I use TASIGNA?

Warnings

Do not use TASIGNA if:

  • you are allergic to nilotinib, or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction can include difficulty breathing, wheezing, swelling of the face, lips or tongue and rash.

Check with your doctor if you:

  • Have or have had problems with your heart, previous heart attack, or chest pain (angina)
  • Have lower than normal blood levels of potassium or magnesium
  • Have high blood cholesterol or lipid levels
  • Have high blood sugar levels
  • Have liver or kidney problems
  • Have had hepatitis B infection
  • Have had inflammation of the pancreas (pancreatitis)
  • Have had surgery to remove your entire stomach (total gastrectomy)
  • Take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Talk to your doctor if you are pregnant or intend to become pregnant. TASIGNA may harm an unborn baby. Your doctor will discuss with you what is best for you and your baby.

Talk to your doctor if you are breastfeeding or intend to breastfeed. You should not take TASIGNA if you are breastfeeding and for 2 weeks after your last dose of TASIGNA.

Contraception

You should avoid becoming pregnant while using TASIGNA and for 2 weeks after you stop using it. Ask your doctor or pharmacist for options of effective birth control.

Use in children

TASIGNA is not recommended for use in children and adolescents under 18 years of age. It may cause slower than normal growth in some children and adolescents.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with TASIGNA and affect how it works such as:

  • St John's Wort, a herbal medicine that you can buy without a prescription
  • Antibiotic medicines such as clarithromycin, moxifloxacin, rifampicin
  • Antifungal medicines such as itraconazole, ketoconazole, voriconazole
  • Antiviral medicines used to treat HIV/AIDS such as ritonavir
  • Medicines used to treat epilepsy such as carbamazepine, phenobarbital, phenytoin
  • Medicines used to relax or calm you or help you sleep (sedatives) such as midazolam
  • Medicines used to treat irregular heart beat such as amiodarone, disopyramide, sotalol
  • Medicines that may affect the function of the heart such as chloroquine, haloperidol, methadone
  • Medicines such as alfentanil and fentanyl, that are used to treat pain or as a sedative before or during surgery or a medical procedure
  • Medicines such as ciclosporin, sirolimus and tacrolimus, that decrease the body's ability to fight infection and are commonly used to prevent rejection of transplanted organs
  • Antacids, such as those containing aluminium hydroxide, magnesium hydroxide and simethicone, neutralise the high acidity of the stomach and should be taken approximately 2 hours before and approximately 2 hours after you take TASIGNA.
  • H2 blockers, such as famotidine and nizatidine, should be taken approximately 10 hours before and approximately 2 hours after you take TASIGNA.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TASIGNA.

4. How do I use TASIGNA?

How much to take

  • If you have been newly diagnosed with CML the usual dose of TASIGNA is two capsules of 150 mg (300 mg) twice daily.
  • If you are no longer doing well from previous treatment for CML, the usual dose is two capsules of 200 mg (400 mg) twice daily.
  • Follow the instructions provided and use TASIGNA until your doctor tells you to stop.

When to take TASIGNA

  • TASIGNA should be taken in the morning and evening, approximately 12 hours apart.
  • TASIGNA must not be taken with food. Do not eat for at least 2 hours before and at least 1 hour after taking TASIGNA.

How to take TASIGNA

  • Swallow TASIGNA capsules whole with a large glass of water.
  • If you are unable to swallow capsules, you may mix the content of each capsule in one teaspoon of applesauce (pureed apple). Swallow the mixture immediately. Do not use more than one teaspoon of applesauce and do not use any other food other than applesauce.

If you forget to take TASIGNA

TASIGNA should be taken regularly at the same time, twice a day. If you miss your dose at the usual time, take it as soon as you remember and then take the next capsule as usual.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take TASIGNA, keep a treatment diary, or ask your doctor or pharmacist for some hints.

Do not stop taking TASIGNA or change your dose without talking to your doctor.

If you take too much TASIGNA

If you think that you have taken too much TASIGNA, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using TASIGNA?

Things you should do

  • Have regular blood tests, heart and weight checks as directed by your doctor.
  • Avoid becoming pregnant while using TASIGNA and for 2 weeks after you stop using it.

Call your doctor straight away if you:

  • Become pregnant or think you may be pregnant.
  • Have fainted or have an irregular heart beat while using TASIGNA.
  • Develop chest pain or discomfort, numbness or weakness, problems with walking or talking, or pain, numbness, change in colour or a cool feeling in your arms or legs.

Remind any doctor, dentist or pharmacist you visit that you are using TASIGNA.

Things you should not do

  • Do not stop using this medicine unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.

Foods and drinks to avoid

  • Do not eat or drink products and juices that contain grapefruit juice, star fruit, pomegranate, seville oranges or other similar fruits while you are being treated with TASIGNA.

Additional tests

Your doctor may do some blood tests such as checking blood cells (white blood cells, red blood cells and platelets), electrolytes (e.g., potassium and magnesium), sugar levels and cholesterol or lipid levels in your body from time to time to make sure TASIGNA is working and to prevent unwanted side effects. Your kidneys, liver, heart, blood pressure will also be checked regularly.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TASIGNA affects you.

TASIGNA may cause tiredness in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

There are no known interactions between TASIGNA with alcohol.

Looking after your medicine

  • Store below 30°.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

If your doctor recommends you stop using TASIGNA

Your doctor will regularly check your treatment with specific monitoring tests.

If you have been taking TASIGNA for 3 years, have achieved a certain response to treatment for at least 1 year and have a certain type of CML, your doctor may tell you to stop taking TASIGNA.

Your doctor will continue to monitor your CML. If you get worse, you may need to start using TASIGNA again.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Tummy problems:
  • Tummy pain or discomfort
  • Feeling sick
  • Vomiting
  • Constipation
  • Diarrhoea
  • Wind or gas
Skin problems:
  • Itching
  • Rash
  • Dry skin
  • Hair loss
  • Warts
  • Acne
Eye problems:
  • Eye infection
  • Dry eye
General:
  • Headache
  • Tiredness/lack of energy
  • Muscle, bone or joint pain
  • Pain in hands or feet
  • Muscle spasms/weakness
  • Tingling feeling or loss of sensation
  • Swelling of arms, legs, hands or feet
  • Upper respiratory tract infections
  • Depression
  • Anxiety
  • Trouble sleeping
  • Dizziness or light-headed
  • Hot flushes or night sweats
  • Frequent wee
Speak to your doctor if you have any of these less serious side effects and they worry you.
If these side effects become severe, please tell your doctor, pharmacist or healthcare provider.

Serious side effects

Serious side effectsWhat to do
Heart problems:
  • Chest pain or discomfort
  • Irregular heart beat or fast heart beat
Lung problems:
  • Difficult or painful breathing
  • Change in colour (blue) of lips, gums or skin
General:
  • Fever, severe or frequent infections, unexplained bleeding or weakness
  • Weakness, numbness or paralysis of face, limbs, fingers or toes
  • Swelling and pain in one part of the body
  • Severe upper tummy pain
  • Blurred vision, double vision, decreased sharpness of vision, flashes of light in the eye, swelling or blood in the eye
  • Vomiting blood, black or bloody poo, pale poo
  • Yellowing of the skin and eyes
  • Difficulty or pain when you wee, need to wee frequently, blood in wee, abnormal wee colour or cloudy wee
  • Painful red lumps or blisters on the skin, reddening or peeling of skin, increased sensitivity of the skin to light, changes in skin colour
  • Weight gain, loss of appetite, or increased appetite with weight loss, tiredness
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What TASIGNA contains

Active ingredient
(main ingredient)		Nilotinib
Other ingredients
(inactive ingredients)		Lactose
Colloidal anhydrous silica
Crospovidone
Magnesium stearate
Poloxamer
Gelatin
Iron oxide red
Iron oxide yellow
Titanium dioxide
Printing ink (150 mg: black; 200 mg: red)
Potential allergensGalactose
Milk
Sugars as lactose
Sulfites

Do not take this medicine if you are allergic to any of these ingredients.

What TASIGNA looks like

TASIGNA is supplied as capsules in blister packs.

TASIGNA 150 mg capsules contain a white to slightly yellowish powder in red opaque hard gelatin capsules, size 1 with black axial imprint "NVR/BCR" (AUST R 171498).

TASIGNA 200 mg capsules contain a white to slightly yellowish powder in light yellow opaque hard gelatin capsules, size 0 with red axial imprint "NVR/TKI" (AUST R 133086).

TASIGNA 150 mg and 200 mg capsules are available in packs of 28 capsules (weekly)* and 120 capsules (monthly). The weekly pack contains 14 capsules on 2 calendar cards (day time and night time). The monthly pack contains 3 packs of 40 capsules.

*Not all pack sizes may be marketed.

Who distributes TASIGNA

TASIGNA is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203
Web site: www.novartis.com.au

TASIGNA is supplied in New Zealand by:

NOVARTIS New Zealand Ltd
PO Box 99102, Newmarket
Auckland 1149, New Zealand
Telephone: 0800 354 335

® = Registered Trademark
© Copyright 2021.

This leaflet was prepared in March 2024.

Internal document code:
(tas211022c_v2.doc based on PI tas211022i.doc)

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Tasigna

Active ingredient

Nilotinib

Schedule

S4

 

1 Name of Medicine

Nilotinib hydrochloride monohydrate.

2 Qualitative and Quantitative Composition

Active substance.

Tasigna capsules contain 150 mg or 200 mg nilotinib (as nilotinib hydrochloride monohydrate).

Excipients with known effect.

Sugars as lactose, galactose, milk and sulfites. Tasigna contains lactose and may not be suitable for patients that are intolerant to this ingredient (see Section 4.4).
For the list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard capsules.

Tasigna 150 mg.

White to yellowish powder in red opaque hard gelatin size 1 capsules, with black axial imprint NVR/BCR.

Tasigna 200 mg.

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

4 Clinical Particulars

4.1 Therapeutic Indications

Tasigna is indicated for the:
treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML) in chronic phase;
treatment of adults with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukaemia (CML) resistant to or intolerant of prior therapy including imatinib.

4.2 Dose and Method of Administration

Therapy should be initiated by a physician experienced in the treatment of patients with CML and should continue as long as the patient continues to benefit.

Dose.

Patients with newly diagnosed Ph+ CML-CP.

The recommended dose of Tasigna is 300 mg twice daily (see Section 5.2 Pharmacokinetic Properties).

Dosage in newly diagnosed Ph+ CML-CP patients who have achieved a sustained deep molecular response (MR 4.5).

Discontinuation of treatment may be considered in eligible Ph+ CML-CP patients who have been treated with Tasigna at 300 mg twice daily for a minimum of 3 years if a deep molecular response is sustained for a minimum of one year immediately prior to discontinuation of therapy. Discontinuation of Tasigna should be initiated by a physician experienced in the treatment of patients with CML (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).
Patients who are eligible to discontinue Tasigna therapy must have their BCR-ABL transcript levels and complete blood count with differential monitored monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be performed with a quantitative diagnostic test validated to measure molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5 (BCR ABL/ABL ≤ 0.0032% IS).
For patients who lose MR4.0 (MR4 = BCR ABL/ABL ≤ 0.01% IS) but not Major Molecular Response (MMR; BCR ABL/ABL ≤ 0.1% IS) during the treatment-free phase, BCR-ABL transcript levels should be monitored every 2 weeks until BCR-ABL levels return to a range between MR4.0 and MR4.5. Patients who maintain BCR-ABL levels between MMR and MR4.0 for a minimum of 4 consecutive measurements can return to the original monitoring schedule.
Patients who lose MMR must re-initiate treatment within 4 weeks of when loss of remission is known to have occurred. Tasigna therapy should be re-initiated at 300 mg twice daily or at a reduced dose level of 400 mg once daily if the patient had a dose reduction prior to discontinuation of therapy. Patients who re-initiate Tasigna therapy should have their BCR-ABL transcript levels monitored monthly until MMR is re-established (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Patients with Ph+ CML-CP and CML-accelerated phase (AP) resistant to or intolerant to at least one prior therapy including imatinib.

The recommended dose of Tasigna is 400 mg twice daily (see Section 5.2 Pharmacokinetic Properties).

Dosage in Ph+ CML-CP patients who have achieved a sustained deep molecular response (MR 4.5) on Tasigna following prior imatinib therapy.

Discontinuation of treatment may be considered in eligible Ph+ CML-CP patients who have been treated with Tasigna for a minimum of 3 years if a deep molecular response is sustained for a minimum of one year immediately prior to discontinuation of therapy. Discontinuation of Tasigna should be initiated by a physician experienced in the treatment of patients with CML (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).
Patients who are eligible to discontinue Tasigna therapy must have their BCR-ABL transcript levels and complete blood count with differential monitored monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels must be performed with a quantitative diagnostic test validated to measure molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5 (BCR ABL/ABL ≤ 0.0032% IS).
Patients with confirmed loss of MR 4.0 (two consecutive measures separated by at least 4 weeks showing loss of MR 4.0); BCR ABL/ABL ≤ 0.01% IS) or loss of MMR (BCR ABL/ABL ≤ 0.1% IS) must re-initiate treatment within 4 weeks of when loss of remission is known to have occurred. Tasigna therapy should be re-initiated at either 300 mg or 400 mg twice daily. Patients who re-initiate Tasigna therapy should have their BCR-ABL transcript levels monitored monthly until previous MMR or MR 4.0 is re-established (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Monitoring recommendations and dose adjustments.

A baseline ECG is recommended prior to initiating therapy with Tasigna and should be repeated after 7 days and as clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to Tasigna administration and potassium and magnesium blood levels should be monitored periodically during therapy, particularly in patients at risk for these electrolyte abnormalities (see Section 4.4 Special Warnings and Precautions for Use).
Increases in total serum cholesterol levels have been reported with Tasigna therapy (see Section 4.4 Special Warnings and Precautions for Use). 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 Special Warnings and Precautions for Use). Blood glucose levels should be assessed prior to initiating Tasigna therapy and monitored during treatment.
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 therapy with Tasigna (see Section 4.8 Adverse Effects (Undesirable Effects)).
Tasigna may need to be temporarily withheld and/or dose reduced for haematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukaemia (Table 1).
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 the prior dose was 400 mg once daily, treatment should be discontinued. If clinically appropriate, re-escalation of the dose to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily should be attempted.

Elevated serum lipase.

For Grade 3 or 4 lipase elevations, doses should be reduced to 400 mg once daily or interrupted. Serum lipase levels should be tested monthly or as clinically indicated (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Elevated bilirubin and hepatic transaminases.

For Grade 3 or 4 bilirubin or hepatic transaminase 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 (see Section 4.8 Adverse Effects (Undesirable Effects)).
If a dose is missed the patient should not take an additional dose, but take the usual prescribed next dose.

Method of administration.

Tasigna should be taken twice daily taken approximately 12 hours apart, and must not be taken with food. No food should be consumed for at least 2 hours before and 1 hour after the dose is taken (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
The capsules should be swallowed whole with water. For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of applesauce (pureed apple) and should be taken immediately. Not more than one teaspoon of applesauce and no food other than applesauce must be used (see Section 5.2 Pharmacokinetic Properties).
Tasigna may be given in combination with haematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.
Monitoring of response to Tasigna therapy in Ph+ CML patients should be performed both routinely and when therapy is modified, to identify suboptimal response, loss of response to therapy, poor patient compliance, or possible drug-drug interaction. Results of monitoring should guide appropriate CML management.

4.3 Contraindications

Tasigna is contraindicated in patients with a known hypersensitivity to nilotinib or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Myelosuppression.

Treatment with Tasigna is often associated with NCI CTC (National Cancer Institute Common Toxicity Criteria) Grade 3 or 4 thrombocytopenia, neutropenia and anaemia. Occurrence is more frequent in patients with imatinib-resistant or intolerant CML and in particular in patients with CML-AP. 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 Dose and Method of Administration).

QT prolongation.

In vitro data suggest that nilotinib has the potential to prolong cardiac ventricular repolarisation (QT interval).
In the Phase III study in newly diagnosed Ph+ CML-CP patients the change from baseline in mean time-averaged QTcF interval at steady state observed in the nilotinib 300 mg twice daily group was 6 msec. At the recommended dose of 300 mg twice daily no patient had an absolute QTcF of > 480 milliseconds (ms) and no events of Torsades de Pointes were observed.
In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase, treated with nilotinib 400 mg twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 6 ms and 8 ms, respectively. QTcF of > 500 ms was observed in 3 patients (< 1% of patients in the Phase II study).
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 ms. In addition, no clinically relevant arrhythmias were observed during the trial. In particular, no episodes of Torsades de pointes (either transient or sustained) were observed.
Clinically meaningful prolongation of the QT interval may occur when Tasigna is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT interval. Therefore, co-administration with food must be avoided (see Section 4.2 Dose and Method of Administration) and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The presence of hypokalaemia and hypomagnesaemia may place patients at risk of developing QT-prolongation (see Section 4.2 Dose and Method of Administration).
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 long QT syndrome;
with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia.
In clinical studies, patients with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina, or clinically significant bradycardia were excluded.
Caution should be exercised in patients with relevant cardiac disorders.

Sudden death.

In clinical trials, uncommon cases (0.1 to 1%) of sudden death have been reported in patients in imatinib-resistant or -intolerant CML patients in chronic and accelerated phase receiving Tasigna with a past medical history of cardiac disease or significant cardiac risk factors. Comorbidities in addition to the underlying malignancy were also frequently present as were concomitant medications. Ventricular repolarisation abnormalities may have been contributory factors. Based on post-marketing exposure in patient-years, the estimated reporting rate for spontaneous reports of sudden death is 0.02% per patient-year. No cases of sudden deaths have been reported in the newly diagnosed Ph+ CML-CP Phase III study.

Cardiovascular events.

Cardiovascular events were reported in the extended follow-up randomized, Phase III nilotinib trial in newly diagnosed CML patients and observed in the post-marketing reports. With a median time on therapy of 60.5 months in the clinical trial, Grade 3/4 cardiovascular events included peripheral arterial occlusive disease (1.4% and 1.1% at 300 mg and 400 mg twice a day, respectively), ischemic heart disease (2.2% and 6.1% at 300 mg and 400 mg twice a day, respectively) and ischemic cerebrovascular events (1.1% and 2.2% at 300 mg and 400 mg twice a day, respectively). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during Tasigna therapy according to standard guidelines (see Section 4.2 Dose and Method of Administration).

Fluid retention.

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 Dose and Method of Administration).

Hepatitis B reactivation.

Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving a BCR-ABL tyrosine kinase inhibitor (TKI), such as nilotinib. Some cases of hepatitis B reactivation involving drugs of the BCR-ABL TKI class resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients should be tested for hepatitis B infection before initiating treatment with nilotinib. Patients currently on nilotinib should have baseline testing for hepatitis B infection in order to identify chronic carriers of the virus. 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 hepatitis B infection during treatment. Carriers of hepatitis B virus who require treatment with nilotinib should be closely monitored for signs and symptoms of active hepatitis B infection throughout therapy and for several months following termination of therapy.

Special monitoring of Ph+ CML-CP patients who have achieved a sustained deep molecular response.

Eligibility for discontinuation of treatment.

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 levels, evaluation of the depth of molecular response, and determination of a possible loss of molecular remission after Tasigna treatment discontinuation.

Monitoring of patients who have discontinued therapy.

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 MR 4.5. BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials).
Loss of MMR or confirmed loss of MR 4.0 (two consecutive measures separated by at least 4 weeks showing loss of MR 4.0) 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 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials). For patients who fail to achieve MMR after three months of treatment re-initiation, BCR-ABL kinase domain mutation testing should be performed.

Laboratory tests and monitoring.

Blood lipids.

In a Phase III study in newly diagnosed CML patients, 1.1% of the patients treated with 400 mg nilotinib twice a day, had a Grade 3/4 elevation in total cholesterol; however, there were no Grade 3/4 elevations in the 300 mg twice a day dose group. 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 Dose and Method of Administration). If a HMG-CoA reductase inhibitor (a lipid lowering agent) is needed, please see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions before starting treatment since certain HMG-CoA reductase inhibitors are metabolized by the CYP3A4 pathway.

Blood glucose.

In a Phase III study in newly diagnosed CML patients, 6.9% of the patients treated with 400 mg nilotinib twice a day had a Grade 3/4 elevation in blood glucose; and 7.2% of the patients treated with 300 mg nilotinib twice a day had a Grade 3/4 elevation in blood glucose. It is recommended that the glucose levels should be assessed before initiating treatment with Tasigna and monitored during treatment as clinically indicated (see Section 4.2 Dose and Method of Administration). If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.

Lactose.

Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or of glucose-galactose malabsorption.

Serum lipase.

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, doses should be interrupted and appropriate diagnostics should be considered in order to exclude pancreatitis (see Section 4.2 Dose and Method of Administration).

Electrolyte abnormalities.

The use of Tasigna can cause electrolyte imbalances commonly (see Section 4.8 Adverse Effects (Undesirable Effects), Metabolism and nutrition disorders). Electrolyte abnormalities must be corrected prior to initiating Tasigna and monitored periodically during therapy.

Hepatotoxicity.

Clinical studies showed a risk of increased total bilirubin, ALT and AST levels associated with nilotinib (see Section 4.8 Adverse Effects (Undesirable Effects)).

Total gastrectomy.

The bioavailability of nilotinib might be reduced in patients with total gastrectomy (see Section 5 Pharmacological Properties). More frequent follow-up of these patients should be considered.

Tumour lysis syndrome.

Cases of tumour lysis syndrome have been reported in patients treated with Tasigna. For monitoring recommendations please see Section 4.2 Dose and Method of Administration.

Special populations.

Use in patients with hepatic impairment.

Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib. Single dose administration 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. Pharmacokinetic parameters were subject to high inter-subject variability.
Clinical studies have excluded patients with ALT and/or 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 Dose and Method of Administration, Monitoring recommendations and dose adjustments).

Use in patients with renal impairment.

Clinical studies have not been performed in patients with impaired renal function. Clinical studies have excluded patients with serum creatinine concentration > 1.5 times the upper limit of the normal range.
Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment.

Paediatric use.

Safety and efficacy in children and adolescents below the age of 18 has not been established. There have been case reports of growth retardation in paediatric patients treated with Tasigna.

Use in the elderly.

Approximately 12% and 30% of subjects in the clinical studies (newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP) were 65 years of age or older. No major differences were observed for safety and efficacy in patients ≥ 65 years of age as compared to adults 18 to 65 years.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The administration of Tasigna with agents that are strong CYP3A4-inhibitors and drugs that may prolong the QT interval such as anti-arrhythmic medicines should be avoided (see Section 4.2 Dose and Method of Administration). 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 is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving Tasigna, concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected.
Nilotinib is mainly metabolised in the liver, and 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 drugs that affect CYP3A4 and/or P-gp.

Drugs that may increase nilotinib serum concentration.

The bioavailability of nilotinib in healthy subjects was increased 3-fold when co-administered with the strong CYP3A4 inhibitor, ketoconazole. Concurrent treatment with strong CYP3A4 inhibitors should, therefore, be avoided (including but not limited to ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin) (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, QT prolongation). Alternative concomitant medications with no or minimal CYP3A4 inhibition should be considered.
In a Phase I study of nilotinib given in combination with imatinib (a substrate of P-gp and CYP3A4), imatinib had a slight inhibitory effect on CYP3A4 and/or P-gp. When the two drugs were administered concomitantly, the AUC of nilotinib was increased by 18% to 40%.

Drugs that may decrease nilotinib serum concentration.

In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%.
Inducers of CYP3A4 activity could increase the metabolism of nilotinib and thereby decrease serum concentrations of nilotinib. The concomitant administration of medications that induce CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's wort) may reduce exposure to nilotinib. In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be considered.
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-∞). Tasigna 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. H2-blockers which are potent inducers of CYP3A4 should be used with caution.
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.

Drugs that may have their systemic concentrations altered by nilotinib.

Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, with Ki value being lowest for CYP2C9 (Ki = 0.13 microM).
Nilotinib is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of other drugs primarily metabolized 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, astemizole, terfenadine, cisapride, quinidine, pimozide, sirolimus and tacrolimus) when co-administered with nilotinib. Some of these drugs also prolong the QT interval, hence ECG monitoring should also be done if alternative drugs cannot be used.
A single-dose drug-drug interaction study in healthy subjects with warfarin 25 mg, a sensitive CYP2C9 substrate, and nilotinib 800 mg did not result in any changes in warfarin pharmacokinetics (Cmax, AUC0-∞) or warfarin pharmacodynamics (prothrombin time [PT] and international normalised ratio [INR]). The single dose drug-drug interaction study suggests that Tasigna can be used concurrently with warfarin (up to a dose of 25 mg) without increasing the anti-coagulant effect of warfarin. There are no steady-state pharmacokinetic or pharmacodynamic interaction data for co-administration of nilotinib and warfarin. Consequently, monitoring and control of warfarin pharmacodynamic markers (INR or PT) following initiation of nilotinib therapy (at least during the first 2 weeks) is recommended.
Single-dose administration of nilotinib 600 mg with midazolam 4 mg (a CYP3A substrate) to healthy subjects increased midazolam exposure by 30%. There are no steady-state pharmacokinetic interaction data for co-administration of nilotinib and midazolam. Consequently, it is possible that greater exposure to midazolam might occur with steady-state co-administration of nilotinib and midazolam.
Nilotinib is an inhibitor of P-glycoprotein in vitro at clinically relevant concentrations and may potentially influence the absorption/elimination and subsequent serum concentrations of concomitantly administered drugs that are substrates for this multi-drug efflux pump. Concomitant administration of nilotinib with imatinib increased the AUC of imatinib by 18% to 39%.

Anti-arrhythmic medicines and other drugs that may prolong the QT interval.

Concomitant use of anti-arrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong the QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide) should be avoided (see Section 4.4 Special Warnings and Precautions for Use).

Other interactions that may affect serum concentrations.

The absorption and the bioavailability of nilotinib are increased if it is taken with food, resulting in higher serum concentration (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Tasigna must 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 except apple sauce for patients unable to swallow capsules (see Section 4.2 Dose and Method of Administration). Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided at any time.
Solubility of nilotinib decreases with increasing pH and is practically insoluble in buffer solutions of pH 4.5 or higher. Hence, simultaneous treatment with nilotinib and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after Tasigna dosing.

4.6 Fertility, Pregnancy and Lactation

Contraception.

Females of reproductive potential must be advised to use effective method of contraception (methods that result in less than 1% pregnancy rates) while receiving Tasigna and for up to 2 weeks after ending treatment with Tasigna.

Effects on fertility.

The effect of nilotinib on male and female fertility is not known. In a fertility study in rats, no effects on sperm count/motility were noted in males and no effects on fertility were noted in males or females. The highest tested dose achieved an exposure (based on plasma AUC) of approximately 5 times that expected in humans at the recommended dose. Sexually active male or female patients taking Tasigna should use highly effective contraception.
(Category D)
Tasigna can cause foetal harm when administered to a pregnant woman. There are no adequate data on the use of Tasigna in pregnant women. It should not be used during pregnancy. If the drug is used during pregnancy or if the patient becomes pregnant while taking Tasigna, the patient must be informed of the potential risk to the foetus.
If a woman who is being treated with Tasigna is considering pregnancy, treatment discontinuation may be considered based on the eligibility criteria for discontinuing treatment. 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 Tasigna treatment during pregnancy (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
In animal studies, nilotinib crossed the placenta and induced embryofoetal toxicity at doses that also showed maternal toxicity. Increased postimplantation loss was observed in both the fertility study, which involved treatment of both males and females, and in the embryo toxicity study, which involved treatment of females. Embryo-lethality and foetal effects (mainly decreased foetal weights, and increased skeletal changes) in rats and increased resorption of foetuses and skeletal variations in rabbits were observed in the embryofoetal toxicity studies. Exposure to nilotinib in females at No-Observed-Adverse-Effect-Levels was generally less than or equal to that in humans at 400 mg/b.i.d.
In a pre- and post-natal study, oral administration of nilotinib to female rats from day 6 of gestation to day 21 or 22 postpartum resulted in maternal effects (reduced food consumption and lower body weight gains) and longer gestation period at 60 mg/kg. The maternal dose of 60 mg/kg was associated with decreased pup body weight and changes in some physical development parameters (the mean day for pinna unfolding, tooth eruption and eye opening was earlier). Adverse effects on the reproductive function of pups (lower mating and fertility indices) were also observed at the maternal dose of 60 mg/kg. The No-Observed-Adverse-Effect-Level in maternal animals and offspring was a maternal dose of 20 mg/kg (approximately 1.7 times the plasma AUC in patients at the recommended clinical dose).
Women of childbearing potential must be advised to use highly effective method of contraception while receiving Tasigna and for up to 2 weeks after ending treatment.
 It is not known whether nilotinib is excreted in human milk. Studies in animals demonstrate that nilotinib is excreted into milk. Lactating women should therefore not breast-feed while taking Tasigna and for 2 weeks after the last dose, as a risk to the infant cannot be excluded.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of nilotinib on the ability to drive and operate machines have been performed. Patients experiencing dizziness, visual impairment or other undesirable effects with a potential impact on the ability to safely drive or use machines should refrain from these activities as long as these undesirable effects persist (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The nilotinib safety profile described below is based on data from patients with newly diagnosed Ph+ CML-CP in a randomized, open label, active comparator-controlled phase-III trial and patients with resistant or intolerant Ph+ CML-CP and CML-AP which served as a basis for the listed indications (see Table 2; see Section 4.1 Therapeutic Indications). Safety information from two Tasigna treatment discontinuation studies is also provided.

In patients with newly diagnosed Ph+ CML-CP.

The data reported below reflect exposure to Tasigna from a randomised phase III study in patients with newly diagnosed Ph+ CML-CP treated at the recommended dose of 300 mg twice daily (n = 279). The median duration of treatment in new patients was 60.5 months (range 0.1 to 70.8 months).
Non-haematologic adverse drug reactions (ADRs) reported with very common frequency (≥ 10%) were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Most of these ADRs were mild to moderate in severity (Grade 1 or 2). Constipation, diarrhoea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral oedema, vomiting and asthenia were observed less commonly (< 10% and ≥ 5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. 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 in the nilotinib recommended dose of 300 mg twice daily was 6 msec. In the nilotinib 400 mg twice daily group and the imatinib 400 mg once daily group the change from baseline in mean time-averaged QTcF interval at steady state was 6 msec and 3 msec respectively. No patient had an absolute QTcF of > 500 msec while on study drug in any of the Tasigna treatment groups and no events of Torsades de Pointes were observed. QTcF increase from baseline that exceeds 60 msec was observed in 4 patients while on Tasigna (one in the 300 mg twice daily treatment group and three in the 400 mg twice daily treatment group).
No patients in any treatment group had a LVEF < 45% during treatment. Also, there were no patients with 15% or greater decrease from baseline in LVEF.
No sudden deaths have been reported in any treatment group.
In the nilotinib 300 mg twice daily group, haematologic ADRs include myelosuppression: thrombocytopenia (18%), neutropenia (15%), and anaemia (8%). Biochemistry ADRs 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%). See Table 4 for Grade 3/4 laboratory abnormalities.
Discontinuation due to adverse drug reactions was observed in 10% of patients.

In patients with resistant or intolerant Ph+ CML-CP and CML-AP.

The data reported below reflect exposure to Tasigna in 458 patients with Ph+ CML-CP (n = 321) and CML-AP (n = 137) resistant to or intolerant to at least one prior therapy including imatinib in an open-label multicentre study treated at the recommended dose of 400 mg twice daily.
Non-haematologic adverse drug reactions (ADRs) reported with very common frequency (≥ 10% in the combined CML-CP and CML-AP patient populations) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhoea, vomiting and myalgia. Most of these ADRs were mild to moderate in severity. Alopecia, muscle spasms, decreased appetite, arthralgia, bone pain, abdominal pain, peripheral oedema and asthenia were observed less frequently (< 10% and ≥ 5%) and have been of mild to moderate severity (Grade 1 or 2).
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 was reported in 1% and < 1% of patients, respectively.
QTcF exceeding 500 msec was observed in this study in 4 patients (< 1%). No episodes of Torsades de Pointes (transient or sustained) were observed.
Haematologic ADRs include myelosuppression: thrombocytopenia (31%), neutropenia (17%), and anaemia (14%). See Table 4 for grade 3/4 laboratory abnormalities.
Discontinuation due to adverse drug reactions was observed in 16% of CP and 10% of AP patients.

Most frequently reported adverse drug reactions.

Non-haematologic ADRs (excluding laboratory abnormalities) that were reported in at least 5% of the patients in any of the Tasigna clinical studies that serve as a basis for the listed indications are shown in Table 2. These are ranked under heading of frequency, the most frequent first. Within each frequency grouping adverse drug reactions are presented in order of decreasing seriousness. In addition the corresponding frequency category for each adverse drug reaction is based on the following (CIOMS III) convention: very common (≥ 1/10) or common (≥ 1/100 to < 1/10). The frequency is based on the highest for any Tasigna group in the two studies, using one decimal precision for percentages.

Comparison of common non-laboratory adverse reactions in clinical trials.

See Table 2.

Additional data from clinical trials.

The following adverse drug reactions were reported in patients in the Tasigna clinical studies which serve as a basis for the listed indications at the recommended doses at the following frequency (very common is ≥ 1/10; common is ≥ 1/100 to < 1/10; uncommon is > 1/1000 to < 1/100; single events are captured as frequency not known) in Table 3. 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, obtained from two clinical studies: 1. Newly diagnosed Ph+ CML-CP 60 months' analysis and 2. resistant or intolerant Ph+ CML-CP and CML-AP 24 months' analysis.

Comparison of severe laboratory abnormalities in clinical trials.

See Table 4.

Treatment discontinuation in Ph+ CML-CP patients who have achieved a sustained deep molecular response.

After discontinuation of Tasigna therapy within the framework of attempting treatment-free remission (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 patients with Ph+ CML-CP (N = 190), musculoskeletal symptoms within a year of Tasigna discontinuation were reported in 24.7% vs. 16.3% within the previous year on Tasigna treatment.
In a Phase II clinical study with patients with Ph+ CML-CP on Tasigna and previously treated with imatinib (N = 126), musculoskeletal symptoms within a year of discontinuation were reported in 42.1% vs. 14.3% within the previous year on Tasigna treatment.

Adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse reactions have been derived from post-marketing experience with Tasigna via spontaneous case reports, literature cases, expanded access programs, and clinical studies other than the global registration trials. Because 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 not known: Tumour lysis syndrome, thrombotic microangiopathy, facial paralysis.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

Isolated reports of intentional overdose with nilotinib were reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting and drowsiness. No ECG changes or hepatotoxicity were reported. Outcomes were reported as recovered.

Treatment.

In the event of overdose, the patient should be observed and appropriate supportive treatment given.
For information on the management of overdose contact the Poison Information Centre on 131 126.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nilotinib inhibits BCR-ABL tyrosine kinase activity in the nanomolar range by binding to the ATP-binding site. It also inhibited 32/33 imatinib-resistant mutant forms of BCR-ABL tyrosine kinase that were tested. As a consequence, nilotinib inhibited the proliferation of cell lines carrying these enzymes. Orally administered nilotinib, as a single agent, was also effective in reducing tumour burden and prolonging survival in a murine model of CML.
Nilotinib had little or no effect against the majority of other protein kinases examined except for the platelet derived growth factor receptor (PDGFRα and β) and stem cell factor receptor (KIT CSF-1R, DDR) kinases which it inhibited at concentrations within the range achieved following oral administration at therapeutic doses recommended for the treatment of CML.

Clinical trials.

Newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia in chronic phase (Ph+ CML-CP). An open label, multicentre, randomised Phase III study was conducted to determine the efficacy of Tasigna versus imatinib in adult patients with cytogenetically confirmed newly diagnosed Ph+ CML-CP. Patients were within six months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide, or a maximum of two weeks of imatinib in emergent cases. In addition, patients were stratified according to Sokal risk score at time of diagnosis.
Efficacy was based on a total of 846 patients (283 patients in the imatinib 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group).
Baseline characteristics were well balanced between the three groups. Median age was 46 years in the imatinib group and 47 years in both nilotinib groups, with 12.4%, 12.8% and 10.0% were ≥ 65 years of age in imatinib, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (55.8%, 56.0% and 62.3% in imatinib, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily, respectively). More than 60% of all patients were Caucasian, and 25% 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 and 60 months of treatment (or discontinued earlier). The median time on treatment was approximately 60 months in all three treatment groups. The median actual dose intensity was 400 mg/day in the imatinib group, 593 mg/day in the nilotinib 300 mg twice daily group and 773 mg/day in the nilotinib 400 mg twice daily group. This study is on-going.

Major molecular response (MMR).

The primary efficacy variable was MMR at 12 months after the start of study medication. MMR was defined as ≤ 0.1% BCR-ABL/ABL % by international scale 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 superior in the nilotinib 300 mg twice daily group compared to the imatinib 400 mg once daily group. The rate of MMR at 12 months was also statistically significantly higher in the nilotinib 400 mg twice daily group compared to the imatinib 400 mg once daily group, Table 5.
In the nilotinib recommended dose of 300 mg twice daily, the rate of MMR at 3, 6, 9 and 12 months were 8.9%, 33.0%, 43.3% and 44.3%. In the nilotinib 400 mg twice daily group, the rate of MMR at 3, 6, 9 and 12 months were 5.0%, 29.5%, 38.1% and 42.7%. In the imatinib 400 mg once daily group, the rate of MMR at 3, 6, 9 and 12 months were 0.7%, 12.0%, 18.0% and 22.3%.
The MMR rate at 12, 24, 36, 48 and 60 months is presented in Table 5.
MMR rates by different time points (including patients who achieved MMR at or before those time points as responders) are presented in the cumulative incidence of MMR (Figure 1).
For all Sokal risk groups, the MMR rates at all time points remained consistently higher in the two nilotinib groups than in the imatinib group.
Based on the Kaplan-Meier analyses of time to first MMR among all patients are graphically displayed in Figure 1. The probability of achieving MMR at different time points were higher in both nilotinib groups compared to the imatinib group (HR = 2.20 and stratified log-rank p < 0.0001 between nilotinib 300 mg twice daily and imatinib, HR = 1.90 and stratified log-rank p < 0.0001 between nilotinib 400 mg twice daily and imatinib). The proportions of patients who had a molecular response of ≤ 0.01% and ≤ 0.0032% by International Scale (IS) at different time-points is presented in Table 6 and by different time points are presented in Figures 2 and 3. Molecular response of ≤ 0.01% and ≤ 0.0032% by IS corresponds to a ≥ 4 log reduction and ≥ 4.5 log reduction, respectively, of BCR-ABL transcripts from a standardized baseline.

Duration of MMR.

Based on Kaplan-Meier estimates of the duration of first MMR, the proportions of patients who were maintaining response after 60 months among patients who achieved MMR were 93.4% (95% CI: 89.9% - 96.9%) in the nilotinib 300 mg twice daily group, 92.0% (95% CI: 88.2% - 95.8%) in the nilotinib 400 mg twice daily group and 89.1% (95% CI: 84.2% - 94.0%) in the imatinib 400 mg once daily group.

Complete cytogenetic response (CCyR).

CCyR was defined as 0% Ph+ metaphases in the bone marrow based on a minimum of 20 metaphases evaluated. CCyR rate by 12 months (includes patients who achieved CCyR at or before the 12 month time point as responders) was statistically higher for both the nilotinib 300 mg twice daily and 400 mg twice daily groups compared to imatinib 400 mg once daily group, 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 imatinib 400 mg once daily group.

Duration of CCyR.

Based on Kaplan-Meier estimates, the proportions of patients who were maintaining response after 60 months among patients who achieved CCyR were 99.1% (95% CI: 97.9% - 100%) in the nilotinib 300 mg twice daily group, 98.6% (95% CI: 97.1% - 100%) in the nilotinib 400 mg twice daily group and 97.5% (95% CI: 95.4% - 99.7%) in the imatinib 400 mg once daily group.

Progression to AP/BC on treatment.

Progression to AP/BC on treatment is defined as the time from the date of randomization to the first documented disease progression to AP/BC or CML-related death. Overall by the cut-off date, 17 patients progressed to AP or BC on treatment (2 in the nilotinib 300 mg twice daily group, 3 in the nilotinib 400 mg twice daily group and 12 in the imatinib 400 mg once daily group). The estimated rates of patients free from progression to AP or BC at 60 months were 99.3%, 98.7% and 95.2%, respectively (HR = 0.1599 and stratified log-rank p = 0.0059 between nilotinib 300 mg BID and imatinib, HR = 0.2457 and stratified log-rank p = 0.0185 between nilotinib 400 mg BID and imatinib).
Including clonal evolution as a criterion for progression, a total of 24 patients progressed to AP or BC on treatment by the cut-off date (2 in the nilotinib 300 mg twice daily group, 5 in the nilotinib 400 mg twice daily group and 17 in the imatinib 400 mg once daily group). The estimated rates of patients free from progression to AP or BC including clonal evolution at 60 months were 98.7%, 97.9% and 93.2%, respectively (HR = 0.1626 and stratified log-rank p = 0.0009 between nilotinib 300 mg BID and imatinib, HR = 0.2848 and stratified log-rank p = 0.0085 between nilotinib 400 mg BID and imatinib).
No new progression to AP/BC were reported since the 2-year analysis.

Overall survival (OS).

A total of 50 patients died during treatment or during the follow-up after discontinuation of treatment (18 in the nilotinib 300 mg twice daily group, 10 in the nilotinib 400 mg twice daily group and 22 in the imatinib 400 mg once daily group). Twenty-six (26) of these 50 deaths were related to CML (6 in the nilotinib 300 mg twice daily group, 4 in the nilotinib 400 mg twice daily group and 16 in the imatinib 400 mg once daily group). The estimated rates of patients alive at 60 months were 93.7%, 96.2% and 91.7%, respectively (HR = 0.8026 and stratified log-rank p = 0.4881 between nilotinib 300 mg twice daily and imatinib, HR = 0.4395 and stratified log-rank p = 0.0266 between nilotinib 400 mg twice daily and imatinib). Considering only CML related deaths as events, the estimated rates of OS at 60 months were 97.7%, 98.5% and 93.8%, respectively (HR = 0.3673 and stratified log-rank p = 0.0292 between nilotinib 300 mg twice daily and imatinib, HR = 0.2411 and stratified log-rank p = 0.0057 between nilotinib 400 mg twice daily and imatinib).
Resistant or intolerant Ph+ CML. An open label uncontrolled multicentre Phase II study was conducted to determine the efficacy of Tasigna (400 mg twice daily) in patients with imatinib resistant or intolerant CML with separate treatment arms for chronic and accelerated phase disease. The study is ongoing. Efficacy was based on 321 chronic phase (CP) patients and 137 accelerated phase (AP) patients enrolled. Median age was 58 years (range 21 - 85 years), with 31% of patients ≥ 65 years of age. There were 48% females and 52% males; 89% Caucasian, 4% Asian and 5% black patients. Tasigna was administered on a continuous basis (400 mg twice daily at least 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 where dose escalation to 600 mg twice daily was allowed. See Table 8.
The patients' CML disease history is given in Table 9. Resistance to imatinib included failure to achieve a complete haematological response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or haematological response. Imatinib intolerance included patients who discontinued imatinib because of toxicity and who were not in major cytogenetic response at time of study entry.
The majority of patients had a long history of CML that included extensive prior treatment with other antineoplastic agents including imatinib, hydroxyurea, interferon, and some who had even failed stem cell transplant (Table 9). The median highest prior imatinib dose had been 600 mg/day for both CP and AP patients, and the highest prior imatinib dose was > 600 mg/day in 74% of all patients with 40% of patients receiving imatinib doses > 800 mg/day.
The primary endpoint in the CP patients was major cytogenetic response (MCyR), defined as elimination (CCyR, complete cytogenetic response) or significant reduction to < 35% Ph+ metaphases (partial cytogenetic response) of Ph+ haematopoietic cells. Complete haematological response (CHR) in CP patients was evaluated as a secondary endpoint. For efficacy assessment, patients needed to have completed 6 months treatment or discontinued the study.
The primary endpoint in the AP patients was overall confirmed haematological response (HR), defined in this trial as either a complete haematological response, no evidence of leukaemia or return to chronic phase. For efficacy assessment, patients needed to have completed 4 months treatment, discontinued the study or achieved a complete haematological response.

Complete haematologic response (CHR) criteria.

Chronic CML: white blood cell count < 10 x 109/L, no blasts or promyelocytes in peripheral blood, platelets < 450 x 109/L, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils < 5% in bone marrow and peripheral blood, and no extramedullary involvement.
Accelerated CML: myeloblasts < 5% in bone marrow and 0% in peripheral blood, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, basophils < 5% in bone marrow and peripheral blood and no extramedullary involvement.
The rates of response for the chronic phase (CP) and accelerated phase (AP) treatment arms are reported in Table 10.
Tasigna was investigated separately in CML-CP and CML-AP patients with extensive previous treatment including a tyrosine kinase inhibitor in addition to imatinib. The majority (83% of CML-CP patients and 85% of CML-AP patients) were imatinib-resistant and the remainder imatinib-intolerant. In the 22 CML-CP patients, (32%) achieved a MCyR with Tasigna. In those without a CHR at baseline (n = 16), (50%) achieved a CHR. In the 11 CML-AP patients, (36%) achieved a confirmed HR and one (9%) a MCyR.
Treatment discontinuation in newly diagnosed Ph+ CML-CP patients who have achieved a sustained deep molecular response. In an open-label, multicentre, single-arm study, 215 adult patients with Ph+ CML-CP treated with Tasigna in first-line for ≥ 2 years who achieved MR4.5 as measured with the MolecularMD MRDx BCR-ABL Test were enrolled to continue Tasigna treatment for an additional 52 weeks (Tasigna consolidation phase). The study enrolled patient with typical BCR-ABL transcripts [b3a2 (e14a2) and/or b2a2 (e13a2)] at the time of CML-CP diagnosis i.e. prior to first start of TKI treatment which were amendable to standardized reverse transcriptase PCR. Of the 215 patients, 190 patients (88.4%) entered the Treatment-free Remission (TFR) phase after achieving a sustained deep molecular response during the consolidation phase, defined by the following criteria:
The 4 last quarterly assessments (taken every 12 weeks) were at least MR4 (BCR-ABL/ ABL ≤ 0.01% IS), and maintained for 1 year.
The last assessment being MR4.5 (BCR-ABL/ ABL ≤ 0.0032% IS).
No more than two assessments falling between MR4 and MR4.5 (0.0032% IS < BCR-ABL/ ABL ≤ 0.01% IS).
In the set of patients who entered the TFR phase, the median age was 55 years. The proportion of female patients was 49.5%, and 21.1% of the patients were ≥ 65 years of age. The median actual dose intensity during the 52-week Tasigna consolidation phase was 600 mg/day.
BCR-ABL levels were monitored every 4 weeks during the first 48 weeks of the TFR phase. Monitoring frequency was intensified to every 2 weeks upon the loss of MR4.0. Biweekly monitoring ended at one of the following time points:
Loss of MMR requiring patient to re-initiate Tasigna treatment.
When the BCR-ABL levels returned to a range between MR4.0 and MR4.5.
When the BCR-ABL levels remained lower than MMR for 4 consecutive measurements (8 weeks from initial loss of MR4.0).
Any patient with loss of MMR during the TFR phase re-initiated Tasigna treatment at 300 mg twice daily or at a reduced dose level of 400 mg once daily if required from the perspective of tolerance, within 5 weeks after the collection date of the blood sample demonstrating loss of MMR. Patients who required re-initiation of Tasigna treatment were monitored for BCR-ABL levels every 4 weeks for the first 24 weeks and then every 12 weeks thereafter in patients who regained MMR.
The primary endpoint was the percentage of patients who were in MMR at 48 weeks after starting the TFR phase (considering any patient who required re-initiation of treatment as non-responder). Of the 190 patients who entered the TFR phase, 98 patients (51.6% [95% CI: 44.2, 58.9]) were in MMR in the TFR phase at 48 weeks.
The pre-specified primary endpoint was that the lower limit of the 95% CI for the MMR rate at 48 weeks after starting the TFR phase should be greater than 50%. Thus the primary endpoint of the study was not met.
Eighty-eight patients (46.3%) discontinued from the TFR phase due to loss of MMR, and 1 (0.5%), 1 (0.5%), and 3 patients (1.6%) due to death from unknown cause, physician decision, and subject decision, respectively. Among the 88 patients who discontinued the TFR phase due to loss of MMR, 86 patients restarted Tasigna treatment and 2 patients permanently discontinued from the study.
Of the 86 patients who restarted treatment due to loss of MMR in the TFR phase, 85 patients (98.8%) regained MMR, (one patient discontinued study permanently due to subject decision) and 76 patients (88.4%) regained MR4.5 by the time of the cut-off date. Ten of the 86 patients (11.6%) did not regain MR4.5 by the time of cut-off and the long term clinical consequences of this loss of deep molecular response are unknown.
The Kaplan-Meier (KM) estimated median time on Tasigna to regain MMR and MR4.5 was 7.9 weeks (95% CI: 5.1, 8.0) and 13.1 weeks (95% CI: 12.3, 15.7), respectively. The KM estimated MMR rate at 24 weeks of re-initiation was 98.8% (95% CI: 94.2, 99.9). The KM estimated MR4.5 rate at 24 weeks of re-initiation was 90.9% (95% CI: 83.2, 96.0).
Among the 190 patients in the TFR phase, 99 patients (52.1%) did not have a treatment-free survival (TFS) event on or before the 48 month cut-off date, and were censored at the date of their last assessment prior to cut-off. The KM estimate of median TFS has not yet been reached (Figure 4).
Treatment discontinuation in Ph+ CML-CP patients who have achieved a sustained deep molecular response on Tasigna following prior imatinib therapy. In an open-label, multicentre, single-arm study, 163 adult patients with Ph+ CML-CP taking tyrosine kinase inhibitors (TKIs) for ≥ 3 years (imatinib as initial TKI therapy for more than 4 weeks without documented MR4.5 on imatinib at the time of switch to Tasigna, then switched to Tasigna for at least two years), and who achieved MR4.5 on Tasigna treatment as measured with the MolecularMD MRDx BCR-ABL Test were enrolled to continue Tasigna treatment for an additional 52 weeks (Tasigna consolidation phase). Of the 163 patients, 126 patients (77.3%) entered the TFR phase after achieving a sustained deep molecular response during the consolidation phase, defined by the following criterion:
The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS) during 1 year.
The median age of the patients who entered the TFR phase was 56 years. The proportion of female patients was 55.6%, and 27.8% of the patients were ≥ 65 years of age. The median actual dose intensity during the 52-week Tasigna consolidation phase was 771.8 mg/day with 52.4% and 29.4% of patients receiving a daily Tasigna dose of 800 mg and 600 mg just before entry into the TFR phase, respectively.
Patients who entered the TFR phase but experienced two consecutive measurements of BCR-ABL/ABL > 0.01% IS were considered having a confirmed loss of MR4.0, triggering re-initiation of Tasigna treatment. Patients with loss of MMR in the TFR phase immediately restarted Tasigna treatment without confirmation. All patients who restarted Tasigna therapy had BCR-ABL transcript levels monitored every 4 weeks for the first 24 weeks, then once every 12 weeks.
The primary endpoint was defined as the proportion of patients without confirmed loss of MR4.0 or loss of MMR within 48 weeks following discontinuation of Tasigna therapy. Of the 126 patients who entered the TFR phase, 73 patients (57.9%, [95% CI: 48.8, 66.7]) had no loss of MMR, no confirmed loss of MR4.0, and no re-initiation of Tasigna therapy within 48 weeks after the start of the TFR phase.
Among the 53 patients who discontinued from the TFR phase due to confirmed loss of MR4.0 or loss of MMR, 51 patients restarted Tasigna therapy and 2 patients permanently discontinued from the study. Of the 51 patients who restarted Tasigna treatment due to confirmed loss of MR4.0 or loss of MMR in the TFR phase, 48 patients (94.1%) regained MR4.0 and 3 patients (5.9%) did not regain MR4.0. Forty-seven patients (92.2%) regained MR4.5 and 4 patients (7.8%) did not regain MR4.5 by the time of the cut-off date.
Four of 51 patients (7.8%) did not regain MR4.5 by the time of cut-off and the long term clinical consequences of this loss of deep molecular response are unknown.
The Kaplan-Meier (KM) estimated median time on Tasigna to regain MR4.0 and MR4.5 was 12.0 weeks (95% CI: 8.3, 12.7) and 13.1 weeks (95% CI: 12.4, 16.1), respectively. The KM estimated rate of MR4.0 at 48 weeks of re-initiation was 100.0% (95% CI: not estimated). The KM estimated rate of MR4.5 at 48 weeks of re-initiation was 94.8% (95% CI: 85.1, 99.0).
Among the 126 patients in the TFR phase, 74 patients (58.7%) did not have a treatment-free survival (TFS) event on or before the 48-month cut-off date, and were censored at the date of their last assessment prior to cut-off. The other 52 patients had a TFS event (18 patients had confirmed loss of MR4.0, and 34 patients lost MMR). The median TFS has not yet been reached (Figure 5).

5.2 Pharmacokinetic Properties

Absorption.

Peak 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 Section 4.2 Dose and Method of Administration). Nilotinib absorption (relative bioavailability) might be reduced by approximately 48% and 22% in patients with total gastrectomy and partial gastrectomy, respectively.
Single-dose administration of 400 mg of nilotinib, using 2 capsules of 200 mg whereby the content of each capsule was dispersed in one teaspoon of apple sauce, was shown to be bioequivalent with a single dose administration of 2 intact capsules of 200 mg.

Distribution.

The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on the basis of in vitro experiments.

Metabolism.

Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum.
Of the nilotinib metabolites, the pyrimidine-N-oxide metabolite (BEJ866) has been found to possess inhibitory activity against the BCR-ABL kinase in transfected murine hematopoietic cells, albeit at concentrations much higher than those required by the parent drug, nilotinib. The mean serum exposure of BEJ866 is 1.0% of the exposure of nilotinib.

Excretion.

After a single dose of radiolabelled nilotinib in healthy subjects, greater than 90% of the dose was eliminated within 7 days mainly in faeces (93% of the dose). Parent drug accounted for 69% of the dose.

Other information.

Steady-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 serum exposure to nilotinib of 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 with 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. 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.

Pharmacokinetics in special patient groups.

Age, body weight, or ethnic origin do not affect the pharmacokinetics of nilotinib, whereas there is an effect of gender, with exposure to nilotinib in female patients being approximately 20% greater than in male patients.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies in bacterial and mammalian in vitro systems, with and without metabolic activation, and in a mammalian in vivo test did not reveal any evidence for a genotoxic potential of nilotinib.

Carcinogenicity.

In a 2 year carcinogenicity study, rats were administered oral doses of nilotinib up to 40 mg/kg/day. Exposures at the highest dose level were approximately 2 to 3 times the human steady state exposure (based on AUC) to nilotinib at the dose of 800 mg/day. The major target organ for drug-related lesions was the uterus (dilatation, vascular ectasia, hyperplasia endothelial cell, inflammation and/or epithelial hyperplasia). There was a dose-related increase in the severity of uterine squamous metaplasia and a non-statistically significant increase in the incidence of uterine squamous cell carcinoma at the highest dose. The clinical relevance of these findings is uncertain.
In a 26-week TgHras2 mouse carcinogenicity study, in which nilotinib was administered at 30, 100 and 300 mg/kg/day, skin papillomas/ carcinomas were detected at 300 mg/kg/day, representing approximately 24 to 34 times (based on AUC) the human exposure at the maximum approved dose of 800 mg/day (administered as 400 mg twice daily). The No-Observed-Effect-Level for the skin neoplastic lesions was 100 mg/kg/day, representing approximately 11 to 18 times the human exposure at the maximum approved dose of 800 mg/day (administered as 400 mg twice daily). The major target organs for non-neoplastic lesions were the skin (epidermal hyperplasia), the growing teeth (degeneration/atrophy of the enamel organ of upper incisors and inflammation of the gingiva/odontogenic epithelium of incisors), the thymus (increased incidence and/or severity of decreased lymphocytes), kidneys (tubular degeneration/regeneration), and epididymis (inflammation and hypospermia).

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule content: lactose, crospovidone, poloxamer, colloidal anhydrous silica, magnesium stearate.
Capsule: gelatin, titanium dioxide, iron oxide yellow, iron oxide red, Opacode monogramming ink S-1-277002 Black (ARTG PI No: 107581 - 150 mg capsule only), Opacode monogramming ink S-1-27794 Black (ARTG PI No: 12104 - 150 mg capsule only), TekPrint SW-1102 Red Ink (ARTG PI No: 107015 - 200 mg capsule only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Tasigna is available in 28's (weekly), 40's, 42's and 112's and 120's (monthly) packs.
The weekly pack contains 2 calendar cards (daytime and night time) of 14 capsules or a carton of 28 capsules.
The monthly pack consists of 4 packs of 28 capsules or 3 packs of 40 capsules.
Tasigna is available in PVC/PVDC/Al blister packs.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical name (CAS): 4-methyl-N-[3-(4-methyl- 1H-imidazol-1-yl)- 5-(trifluoromethyl) phenyl]-3-[[4-(3-pyridinyl)- 2-pyrimidinyl] amino]- benzamide, monohydrochloride, monohydrate.
Molecular formula: C28H22F3N7O.HCl.H2O.

CAS number.

641571-10-0 (nilotinib); 923288-90-8 (nilotinib hydrochloride monohydrate).
Molecular weight: 529.516 (nilotinib) 583.99 (nilotinib hydrochloride monohydrate).

Chemical structure.

Structural formula:
Nilotinib is a white to slightly yellowish or slightly greenish yellowish powder. The solubility of nilotinib in aqueous solutions strongly decreases with increasing pH, and it is practically insoluble in buffer solutions of pH 4.5 and higher pH values. It is very soluble in dimethyl sulfoxide, sparingly soluble in ethanol and methanol, very slightly soluble in acetonitrile and n-octanol.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes