Consumer medicine information

Dasatinib ARX

Dasatinib

BRAND INFORMATION

Brand name

Dasatinib ARX

Active ingredient

Dasatinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Dasatinib ARX.

SUMMARY CMI

DASATINIB ARX

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 DASATINIB ARX?

DASATINIB ARX contains the active ingredient dasatinib. DASATINIB ARX is used to treat adults aged 18 years and older with:

  • Newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia in the chronic phase.
  • Chronic, accelerated or myeloid or lymphoid blast phase chronic myeloid leukaemia with resistance or intolerance to prior therapy including imatinib.
  • Philadelphia chromosome positive acute lymphoblastic leukaemia with resistance or intolerance to prior therapy.

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

2. What should I know before I use DASATINIB ARX?

Do not use if you have ever had an allergic reaction to dasatinib 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 DASATINIB ARX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DASATINIB ARX 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 DASATINIB ARX?

  • Your doctor will decide the dose that is most appropriate for you.
  • Please follow your doctor's instructions about how and when to take DASATINIB ARX.

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

5. What should I know while using DASATINIB ARX?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using DASATINIB ARX.
  • Have any tests recommended by your doctor done as soon as possible.
Things you should not do
  • Do not give DASATINIB ARX to anyone else, even if they have the same condition as you.
  • Do not stop taking DASATINIB ARX, or lower the dosage, without checking with your doctor.
  • Do not stop taking DASATINIB ARX tablets because you are feeling better unless advised to do so by your doctor.
  • Do not take DASATINIB ARX with grapefruit or grapefruit juice.
Driving or using machines
  • DASATINIB ARX has been known to cause dizziness or light-headedness in some people. Make sure that you know how you may react to DASATINIB ARX before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy.
Looking after your medicine
  • Store it in a cool dry place away from moisture, heat or sunlight.
  • Keep the pack in a cool dry place where the temperature stays below 25°C.
  • Keep this medicine out of the sight and reach of children.

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

6. Are there any side effects?

Like all medicines, this medicine can cause side effects, although not everybody gets them. Your doctor will discuss these with you and will explain the risks and benefits of your treatment. Sometimes they may be serious and you may require medical attention. 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

DASATINIB ARX

Active ingredient(s): dasatinib (duh-sat-in-ib)

Consumer Medicine Information (CMI)

This leaflet provides important information about using DASATINIB ARX. 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 DASATINIB ARX.

Where to find information in this leaflet:

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

1. Why am I using DASATINIB ARX?

DASATINIB ARX contains the active ingredient dasatinib. DASATINIB ARX works by inhibiting the activity of proteins within the leukaemia cells of patients with CML or Ph+ ALL. These proteins are responsible for the uncontrolled growth of the leukaemia cells. By inhibiting these proteins dasatinib kills the leukaemia cells in the bone marrow and allows normal red cell, white cell and platelet production to resume.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

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

DASATINIB ARX is used to treat adults aged 18 years or over with:

  • Newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia in the chronic phase.
  • Chronic, accelerated or myeloid or lymphoid blast phase chronic myeloid leukaemia with resistance or intolerance to prior therapy including imatinib.
  • Philadelphia chromosome positive acute lymphoblastic leukaemia with resistance or intolerance to prior therapy.

It belongs to a group of medicines called protein-tyrosinekinase inhibitors.

2. What should I know before I use DASATINIB ARX?

Warnings

Do not use DASATINIB ARX if:

  • you are allergic to dasatinib, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • The expiry date printed on the pack has passed
  • The packaging is torn or shows signs of tampering.

Do not give this medicine to a child under the age of 18 years.

Check with your doctor if you:

  • have or have had any of the following medical conditions:
    - problems with your immune system
    - liver problem
    - heart problem
    - lactose intolerant
    - hepatitis B infection.
  • are pregnant or plan to become pregnant or are breastfeeding. Women who are taking dasatinib should not breast-feed. (See section Pregnancy and breastfeeding)
  • are a sexually active man. Men who take dasatinib are advised to use a condom to avoid pregnancy in their partner.
  • have allergies to any other medicines, foods, preservatives or dyes
  • have recently been vaccinated or plan to get a vaccination
  • are planning to have surgery or an anaesthetic
  • are currently receiving or are planning to receive dental treatment.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

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

Do not take this medicine if you are pregnant or plan to become pregnant.

DASATINIB ARX can cause harm to the unborn baby if it is given to a pregnant woman.

Tell your doctor if you are a sexually active man.

Men who take DASATINIB ARX are advised to use a condom to avoid pregnancy in their partner.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Women who are taking DASATINIB ARX should not breast-feed.

Where to get further information

Your doctor is the best person to answer any further questions you may have about DASATINIB ARX. Anything your doctor tells you about DASATINIB ARX should be followed even if it is different from what is in this leaflet.

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 be affected by DASATINIB ARX or they may affect how well DASATINIB ARX works.

Tell your doctor if you are taking:

  • Medicines that may increase dasatinib level in your bloodstream, such as ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, lopinavir, grapefruit juice.
  • Medicines that may decrease dasatinib level in your bloodstream, such as dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital and St John's wort.
  • Dasatinib may alter the blood levels of ciclosporin.
  • Medicines that reduce stomach acid, such as antacids and histamine-2 antagonists/proton pump inhibitors (famotidine and omeprazole).
  • Medicines that may have their plasma concentration altered by dasatinib, such as simvastatin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids.
  • Blood thinning medicines, such as warfarin, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) taken with dasatinib may increase the risk of unwanted bleeding.
  • Oral diabetes medicines from the glitazone family of mediciness may interact with dasatinib.
  • Medicines that neutralise stomach acid, such as aluminium hydroxide, magnesium hydroxide, calcium carbonate and calcium carbonate/hydroxide. These medicines may be taken up to 2 hours before or 2 hours after dasatinib.

Some medicines may interfere with DASATINIB ARX and affect how it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking DASATINIB ARX.

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

4. How do I use DASATINIB ARX?

How much to take / use

  • Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.
  • Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.
  • You should take your tablets consistently either in the morning or in the evening.
  • The usual starting dose is 100 mg once daily (either as one 100 mg tablet or two 50 mg tablets). The entire dose of 100 mg is to be taken at one time either in the morning or the evening.
  • Some patients may require an alternative starting dose (140 mg daily taken as two 70 mg tablets). The entire dose of 140 mg is to be taken at one time either in the morning or the evening.
  • Do not stop taking your medicine or change your dosage without first talking with your doctor. This medicine helps to control your condition but does not cure it. It is important to keep taking your medicine even if you feel well.
  • Depending on your response and on any side effects that you may experience, your doctor may adjust your dose of DASATINIB ARX, upward or downward, or may temporarily discontinue your medicine.

When to take DASATINIB ARX

  • Take your medicine at about the same time each day.
  • Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
  • It does not matter if you take this medicine before or after food.

How to take DASATINIB ARX

  • Swallow the tablets whole with a full glass of water.
  • Do not break, cut, chew or crush the tablet.
  • Do not take DASATINIB ARX with grapefruit or grapefruit juice.

If you forget to take DASATINIB ARX

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

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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

This may increase the chance of you getting an unwanted side effect.

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

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you use too much DASATINIB ARX

If you think that you have used too much DASATINIB ARX, 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 DASATINIB ARX?

Things you should do

  • Tell any other doctors, dentists, and pharmacists who treat you that you are taking DASATINIB ARX.
  • If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking DASATINIB ARX.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking DASATINIB ARX.
  • If you are about to have any blood tests, tell your doctor that you are taking DASATINIB ARX.
  • Have any tests recommended by your doctor done as soon as possible. Your doctor may order routine laboratory tests to evaluate your blood counts to see how well DASATINIB ARX is working.

Call your doctor straight away if you:

  • become pregnant or plan to breastfeed while taking DASATINIB ARX
  • experience bleeding or easy bruising, no matter how mild
  • develop a fever while taking DASATINIB ARX
  • experience shortness of breath and fatigue while taking DASATINIB ARX

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

Things you should not do

  • Do not give DASATINIB ARX to anyone else, even if they have the same condition as you.
  • Do not stop taking DASATINIB ARX tablets or lower the dosage, because you are feeling better unless advised to do so by your doctor.
  • Do not take DASATINIB ARX to treat any other complaints unless your doctor tells you to.

Driving or using machines

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

DASATINIB ARX has been known to cause dizziness or lightheadedness in some people. Make sure that you know how you react to DASATINIB ARX before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy.

Looking after your medicine

  • Keep DASATINIB ARX tablets in the pack until it is time to take them. If you take the tablets out of the bottle they may not keep well.
  • Keep the pack in a cool dry place where the temperature stays below 25°C.

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.

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.

Serious side effects

Serious side effectsWhat to do
  • swelling, weight gain, shortness of breath or chest pain
  • swelling around your eyes
  • skin infection - folliculitis, herpes
  • shortness of breath and fatigue
  • dark coloured urine or yellowing of your skin and eyes, nausea, loss of appetite, light-coloured bowel movements
  • changes in the way your heart beats, for example - if you notice it beating faster
  • bleeding - for example from: gastrointestinal tract; eye; nose; gums; serious bruising or excessive menstrual bleeding
  • infections - urinary tract; eye infection; difficulty breathing; coughing
  • fever
  • painful rash with blisters
  • a reduction in red blood cells, which may result in fatigue or dizziness
  • a reduction in white blood cells, which are used to fight infection
  • a reduction in cells that help your blood to clot after injury
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.

Other side effects

Common side effectsWhat to do
  • headache; dizziness; numbness or tingling in arms, legs, fingers or toes; altered taste
  • diarrhoea, nausea, vomiting
  • shortness of breath, cough, accumulation of fluid in or around the lungs, pneumonia, chest pain
  • infection, fever
  • abdominal pain, bloating, flatulence, constipation, indigestion
  • high blood pressure
  • mouth ulcers
  • skin rash, dermatitis (including eczema), dry skin, itching or peeling skin, flushing
  • hair loss
  • visual disturbances: blurry or diminished vision, dry eye
  • fatigue
  • swelling of the liver, abdomen, hands, lower legs, feet or face
  • back pain, bone pain, joint pain, pain in fingers or toes, muscle aches or spasm, muscle weakness
  • weight decrease, appetite disturbance
  • gout
  • conjunctivitis
  • tinnitus (ringing in the ears)
  • accumulation of fluid, foamy urine, weight gain (also known as nephrotic syndrome)
Speak to your doctor if you have any of these side effects and they worry you.

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 DASATINIB ARX contains

Active ingredient
(main ingredient)		dasatinib
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • ethylcellulose
  • lactose monohydrate
  • croscarmellose sodium
  • magnesium stearate
  • colloidal silicon dioxide
  • hypromellose
  • hyprolose
  • triethyl citrate
  • titanium dioxide
Potential allergenslactose monohydrate

This medicine contains sugars as lactose.

This medicine does not contain gluten.

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

What DASATINIB ARX looks like

Dasatinib 20 mg tablet
(blister: AUST R 290137, bottle: AUST R 290129)

White to off-white, round, biconvex coated tablet. Engraved “APO” on one side, over “DA” over “20” on the other side.

Dasatinib 50 mg tablet
(blister: AUST R 290131, bottle: AUST R 290128)

White to off-white, oval, bevelled-edged, biconvex coated tablet. Engraved “APO” on one side, “DAS50” on the other side.

Dasatinib 70 mg tablet
(blister: AUST R 290140, bottle: AUST R 290136)

White to off-white, round, biconvex coated tablet. Engraved “APO” on one side, “DA” over “70” on the other side.

Dasatinib 100 mg tablet
(blister: AUST R 290143, bottle: AUST R 290134)

White to off-white, oval, bevelled-edged, biconvex coated tablet. Engraved “APO” on one side, “DAS100” on the other side.

Who distributes DASATINIB ARX

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 2121
www.arrotex.com.au

This leaflet was prepared in December 2023.

Published by MIMS February 2024

BRAND INFORMATION

Brand name

Dasatinib ARX

Active ingredient

Dasatinib

Schedule

S4

 

1 Name of Medicine

Dasatinib.

2 Qualitative and Quantitative Composition

Each tablet contains 20 mg, 50 mg, 70 mg or 100 mg dasatinib as the active ingredient.

Excipients with known effect.

Sugars as lactose (monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

20 mg tablet.

White to off-white, round, biconvex coated tablet. Engraved "APO" on one side, over "DA" over "20" on the other side.

50 mg tablet.

White to off-white, oval, bevelled-edged, biconvex coated tablet. Engraved "APO" on one side, "DAS50" on the other side.

70 mg tablet.

White to off-white, round, biconvex coated tablet. Engraved "APO" on one side, "DA" over "70" on the other side.

100 mg tablet.

White to off-white, oval, bevelled-edged, biconvex coated tablet. Engraved "APO" on one side, "DAS100" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Dasatinib ARX is indicated for the treatment of adults aged 18 years or over with:
newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia in the chronic phase;
chronic, accelerated or myeloid or lymphoid blast phase chronic myeloid leukaemia with resistance or intolerance to prior therapy including imatinib;
Philadelphia chromosome positive acute lymphoblastic leukaemia with resistance or intolerance to prior therapy.

4.2 Dose and Method of Administration

Method of administration.

To be administered orally. Tablets must not be crushed, cut or chewed in order to minimize risk of dermal exposure, they must be swallowed whole. Tablets can be taken with or without a meal and should be taken consistently either in the morning or the evening.
Dasatinib should not be taken with grapefruit or grapefruit juice (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Dosage.

The recommended starting dosage of dasatinib for chronic phase CML is 100 mg administered orally once daily. The recommended starting dosage of dasatinib for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg/day administered orally once daily and should be taken consistently either in the morning or the evening.
In clinical studies, treatment with dasatinib was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response (including complete cytogenetic response (CCyR) or major molecular response (MMR and MR4.5) has not been investigated.
To achieve the recommended dose, dasatinib is available as 20 mg, 50 mg, 70 mg and 100 mg tablets. Dose increase or reduction is recommended based on patient response and tolerability.
Dose escalation. In clinical studies in adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a haematological or cytogenetic response at the recommended starting dosage.
Dose adjustment for adverse reactions.

Myelosuppression.

In clinical studies, myelosuppression was managed by dose interruption, dose reduction or discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate. Haematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications are summarized in Table 1.

Non-haematological adverse reactions.

If a moderate (Grade 2) non-haematologic adverse reaction develops with dasatinib, treatment should be interrupted until the adverse reaction has resolved or returned to baseline. The same dose should be resumed if this is the first occurrence and the dose should be reduced if this is a recurrent adverse reaction. If a severe (Grade 3 or 4) non-haematologic adverse reaction develops with dasatinib use, treatment must be withheld until the event has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence of the event.
For adult patients with chronic phase CML who received 100 mg once daily, dose reduction to 80 mg once daily with further reduction from 80 mg once daily to 50 mg once daily, if needed, is recommended. For adult patients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to 100 mg once daily with further reduction from 100 mg once daily to 50 mg once daily, if needed, is recommended.
Dose reduction for concomitant use of strong CYP3A4 inhibitors. The concomitant use of strong CYP3A4 inhibitors and grapefruit juice with dasatinib should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If possible, an alternative concomitant medication with no or minimal enzyme inhibition potential should be selected. If dasatinib must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to:
40 mg daily for patients taking dasatinib 140 mg daily;
20 mg daily for patients taking dasatinib 100 mg daily;
20 mg daily for patients taking dasatinib 70 mg daily.
For patients taking dasatinib 60 mg or 40 mg daily, consider interrupting dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating dasatinib.
These reduced doses of dasatinib are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors. However, clinical data are not available with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If dasatinib is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or stop dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the dasatinib dose is increased.

Paediatric population.

The safety and efficacy of dasatinib in children and adolescents below 18 years of age have not yet been established. No data are available (see Section 4.4 Special Warnings and Precautions for Use).

Elderly population.

No clinically relevant age-related pharmacokinetic differences have been observed in these patients. No specific dose recommendation is necessary in the elderly (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose. However, caution is recommended when dasatinib is administered to patients with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

No clinical trials were conducted with dasatinib in patients with decreased renal function (the study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine > 3 times the upper limit of the normal range, and studies in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy excluded patients with serum creatinine concentration > 1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib and its metabolites is < 4%, a decrease in total body clearance is not expected in patients with renal insufficiency (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Use of dasatinib is contraindicated in patients with hypersensitivity to dasatinib or to any of the ingredients in this medicine.

4.4 Special Warnings and Precautions for Use

Myelosuppression.

Treatment with dasatinib is associated with thrombocytopenia, neutropenia and anaemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML.
In patients with chronic phase CML, complete blood counts (CBCs) should be performed every two weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated.
In patients with advanced phase CML or Ph+ ALL, CBCs should be performed weekly for the first 2 months and then monthly thereafter or as clinically indicated.
Myelosuppression is generally reversible and usually managed by withholding dasatinib temporarily or dose reduction (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests; Section 4.2 Dose and Method of Administration, Dose adjustment for adverse reactions). CTC Grade 3 or 4 (severe) cases of anaemia were managed with blood transfusions.

Bleeding.

In the pooled population of Phase III studies in patients with chronic phase CML, 5 patients (1%) receiving dasatinib at the recommended dose 100 mg daily (n = 548) had drug related Grade 3 or 4 haemorrhage. In the pooled population of clinical studies in patients with advanced phase CML or Ph+ ALL, severe (Grade 3-5) drug-related CNS haemorrhage, including fatalities, occurred in 1% of patients receiving dasatinib at the recommended dose 140 mg daily (n = 304). Eight cases were fatal and 6 of them were associated with Common Toxicity Criteria (CTC) Grade 4 thrombocytopenia. Grade 3 or 4 drug-related gastrointestinal haemorrhage, including fatalities, occurred in 6% of patients and generally required treatment interruptions and transfusions. Other cases of Grade 3 or 4 drug-related haemorrhage occurred in 2% of patients treated with dasatinib 140 mg daily dose. Most bleeding reactions in clinical studies were typically associated with Grade 3 or 4 thrombocytopenia. Additionally, in vitro and in vivo platelet assays suggest that dasatinib treatment reversibly affects platelet activation.
Caution should be exercised if patients are required to take medications that inhibit platelet function or anticoagulants.

Fluid retention.

Dasatinib is associated with fluid retention. After 5 years of follow-up in the Phase III clinical study in patients with newly diagnosed chronic phase CML (n = 258), drug-related Grade 3 or 4 fluid retention was reported in 13 patients (5%) receiving dasatinib compared to 2 patients (1%) receiving imatinib (n = 258) (see Section 4.8 Adverse Effects (Undesirable Effects)). The cumulative incidence of drug-related pleural effusion (all Grades) in dasatinib-treated subjects increased over time; 7.8% new adverse effects (AEs) of pleural effusion occurred in the first year of therapy followed by a smaller, yet consistent increase of ~5% of subjects/year after 24, 36, 48 and 60 months of treatment, respectively. The majority were low grade. In the pooled population of patients with chronic phase CML (n = 548), severe (Grade 3-4) drug-related fluid retention occurred in 32 (6%) patients receiving dasatinib at the 100 mg once daily recommended dose.
In clinical studies in patients with advanced phase CML or Ph+ ALL receiving dasatinib at the approved dose 140 mg daily (n = 304), Grade 3 or 4 drug-related fluid retention was reported in 8% of patients, including severe pleural and pericardial effusion reported in 7% and 1% of patients, respectively. Severe congestive heart failure/cardiac dysfunction was reported in 1% of patients. In these patients, severe pulmonary oedema and severe pulmonary hypertension were each reported in 1% of patients.
Patients who develop symptoms suggestive of pleural effusion or other fluid retention such as new or worsened dyspnoea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with chest X-ray or additional diagnostic imaging as appropriate. Fluid retention reactions were typically managed with dasatinib dose interruption or reduction and supportive care measures that may include diuretics or short courses of steroids. Severe pleural effusion may require thoracentesis and oxygen therapy. Dose modification should be considered. While the safety profile of dasatinib in the elderly population was similar to that in the younger population, patients aged 65 years and older are more likely to experience pleural effusion, congestive heart failure, gastrointestinal bleeding and dyspnoea, and should be monitored closely.
Cases of chylothorax have also been reported in patients presenting with pleural effusion. Some cases of chylothorax resolved upon dasatinib discontinuation, interruption or dose reduction but most cases also required additional treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

QT prolongation.

In vitro data showing inhibition of the hERG K+ channel expressed in mammalian cells and action potential prolongation in rabbit Purkinje fibres by dasatinib and a number of its metabolites suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT interval).
After 5 years of follow-up in the Phase III study in newly diagnosed chronic phase CML, 1 patient (< 1%) in each of the dasatinib (n = 258) and imatinib (n = 258) treatment groups had QTc prolongation reported as an adverse reaction. The median changes in QTcF from baseline were 3.0 msec in dasatinib-treated patients compared to 8.2 msec in imatinib-treated patients. One patient (< 1%) in each group experienced a QTcF > 500 msec. In 865 patients with leukaemia treated with dasatinib in Phase II, single-arm clinical studies, the mean QTc interval changes from baseline using Fridericia's method (QTcF) were 4-6 msec; the upper 95% confidence intervals for all mean changes from baseline were < 7 msec. Of the 2,182 patients with resistance or intolerance to prior imatinib therapy treated with dasatinib, 15 (1%) had QT prolongation reported as an adverse reaction. Twenty-one (21) of these patients (1%) experienced a QTcF > 500 msec.
Dasatinib should be administered with caution in patients who have or may develop prolongation of QTc. These include patients with hypokalaemia or hypomagnesaemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products which lead to QT prolongation and cumulative high dose anthracycline therapy. Hypokalaemia or hypomagnesaemia should be corrected prior to dasatinib administration.

Cardiac adverse reactions.

Dasatinib was studied in a randomized trial of 519 patients with newly diagnosed CML in chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of congestive heart failure/cardiac dysfunction (1.9%), pericardial effusion (4.3%), arrhythmias (1.2%), palpitations (1.9%), QT prolongation (0.4%) and myocardial infarction (0.4%) (including fatal) were reported in patients taking dasatinib (n = 258). Adverse cardiac reactions were more frequent in patients with risk factors or a previous medical history of cardiac disease. Patients with risk factors or a history of cardiac disease should be monitored carefully for signs or symptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately.
Patients with uncontrolled or significant cardiovascular disease were not included in the clinical studies.

Pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH), confirmed by right heart catheterization, has been reported in association with dasatinib treatment. In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment. Patients with PAH reported during dasatinib treatment were often taking concomitant medications or had co-morbidities in addition to the underlying malignancy.
Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib therapy. Patients who develop dyspnoea and fatigue after initiation of therapy should be evaluated for more common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. During this evaluation, guidelines for non-hematologic adverse reactions should be followed (see Section 4.2 Dose and Method of Administration, Dose adjustment for adverse reactions): if the adverse reaction is severe, treatment must be withheld until the event has resolved or improved. If no alternative diagnosis is found, the diagnosis of PAH should be considered. If PAH is confirmed, dasatinib should be permanently discontinued. Follow up should be performed according to standard practice guidelines. Improvements in hemodynamic and clinical parameters have been observed in dasatinib treated patients with PAH following cessation of dasatinib therapy.

Thrombotic microangiopathy (TMA).

BCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy (TMA), including individual case reports for dasatinib (see Section 4.8 Adverse Effects (Undesirable Effects)). If laboratory or clinical findings associated with TMA occur in a patient receiving dasatinib, treatment with dasatinib should be discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated in conjunction with low ADAMTS13 activity, treatment with dasatinib should not be resumed.

Hepatitis B virus reactivation.

BCR-ABL TKIs have been associated with hepatitis B virus (HBV) reactivation including individual case reports for dasatinib. In some instances, HBV reactivation occurring in conjunction with other BCR-ABL TKIs resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.
Screening for HBV should be considered in accordance with published guidelines before starting therapy with dasatinib. Consultation with a physician with expertise in the treatment of HBV is recommended for patients who test positive for HBV serology.
Patients who are carriers of HBV and require treatment with BCR-ABL TKIs should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop reactivation of HBV while receiving dasatinib, prompt consultation with a physician with expertise in the treatment of HBV is recommended.

Severe dermatological reactions.

Individual cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported with the use of dasatinib. Dasatinib should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified.

Lactose content.

This medicine contains 141 mg lactose in a 100 mg daily dose and 197 mg lactose in a 140 mg daily dose.

Hepatotoxicity.

Dasatinib may cause hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitor transaminases at baseline and monthly or as clinically indicated during treatment. Reduce dose, withhold, or permanently discontinue dasatinib based on severity. When dasatinib is administered in combination with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Monitor hepatic function when dasatinib is used in combination with chemotherapy.

Paediatric use.

The safety and efficacy of dasatinib in patients < 18 years of age have not been established.

Use in the elderly.

Of the 2,712 patients in clinical studies of dasatinib, 617 (23%) were 65 years of age and older and 123 (5%) were 75 years of age and older.
Patients aged 65 years and older are more likely to experience the commonly reported adverse reactions appetite disturbance (14.5% vs 8.0%), fatigue (27.4% vs 19.7%), pleural effusion (46.2 vs 28.4), cough (13.6% vs 8.4%) and dyspnoea (34.5% vs 17.7%), and more likely to experience the less frequently reported adverse events abdominal distention (3.9% vs 2.9%), dizziness (7.1% vs 4.6%), lower gastrointestinal haemorrhage (2.4% vs 0.7%), pericardial effusion (7.6% vs 4.9%), congestive heart failure (3.1% vs 0.7%) and weight decrease (7.5% vs 3.7%), and should be monitored closely.
Comparisons based on efficacy are based on limited number of subjects in specific age groups in individual studies, however similar rates of cCCyR and MMR were observed between older and younger patients.

Effects on laboratory tests.

Haematology and biochemistry in patients with newly diagnosed chronic phase CML.

The comparative frequency of Grade 3 and 4 laboratory abnormalities in patients with newly diagnosed chronic phase CML is presented in Table 2. There were no discontinuations of dasatinib therapy due to the biochemical laboratory parameters.

Haematology and biochemistry in patients with resistance or intolerance to prior imatinib therapy.

Table 3 shows laboratory findings from clinical trials in CML patients with imatinib resistance or intolerance received at 24 months of follow up.
Myelosuppression was commonly reported in all patient populations. In newly diagnosed chronic phase CML, myelosuppression was less frequently reported than in chronic phase CML patients with resistance or intolerance to prior imatinib therapy. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia and anaemia was higher in patients with advanced CML or Ph+ ALL than in chronic phase CML.
In patients who experienced Grade 3 or 4 myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of newly diagnosed chronic phase CML patients in the Phase III study and in 5% of patients with resistance or intolerance to prior imatinib therapy in the Phase III study.
Grade 3 or 4 elevations in transaminases or bilirubin and Grade 3 or 4 hypocalcaemia, hypokalaemia, and hypophosphataemia were reported in all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL. Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption. In general, decreased calcium levels were not associated with clinical symptoms. Patients developing Grade 3 or 4 hypocalcaemia often had recovery with oral calcium supplementation.

Use in hepatic impairment.

Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations). Due to the limitations of this clinical study, caution is recommended when dasatinib is administered to patients with hepatic impairment.

Use in renal impairment.

There are currently no clinical studies with dasatinib in patients with impaired renal function (the study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine > 3 times the upper limit of the normal range, and clinical studies in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy have excluded patients with serum creatinine concentration > 1.5 times the upper limit of the normal range). Dasatinib and its metabolites are minimally excreted via the kidney. Since the renal excretion of unchanged dasatinib and its metabolites is < 4%, a decrease in total body clearance is not expected in patients with renal insufficiency.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs that may increase dasatinib plasma concentrations.

CYP3A4 inhibitors.

In vitro, dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and substances that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, lopinavir, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving treatment with dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended. Selection of an alternate concomitant medication with no or minimal CYP3A4 inhibition potential is recommended. If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, the patient should be closely monitored for toxicity (see Section 4.2 Dose and Method of Administration).

Drugs that may decrease dasatinib plasma concentrations.

CYP3A4 inducers.

Drugs that induce CYP3A4 activity may increase metabolism and decrease dasatinib plasma concentration. Therefore, concomitant use of potent CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John's wort) with dasatinib is not recommended. In healthy subjects, the concomitant use of dasatinib and rifampicin, a potent CYP3A4 inducer, resulted in a five-fold decrease in dasatinib exposure. In patients for whom rifampicin or other CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be used. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is allowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use of dexamethasone, which is not likely to be clinically meaningful.

Antacids.

Non-clinical data demonstrate that the solubility of dasatinib is pH dependent. In healthy subjects, the concomitant use of aluminium hydroxide/magnesium hydroxide antacids with dasatinib reduced the AUC of a single dose of dasatinib by 55% and the Cmax by 58%. However, when antacids were administered 2 hours prior to a single dose of dasatinib, no relevant changes in dasatinib, concentration or exposure were observed. Thus, antacids may be administered up to 2 hours prior to or 2 hours following dasatinib. Simultaneous administration of dasatinib with antacids should be avoided.

Histamine-2 antagonists/proton pump inhibitors.

Long-term suppression of gastric secretion by histamine-2 antagonists or proton pump inhibitors (e.g. famotidine and omeprazole) is likely to reduce dasatinib exposure. The concomitant use of histamine-2 antagonists or proton pump inhibitors with dasatinib is not recommended. In a single-dose study in healthy subjects, the administration of famotidine 10 hours prior to a single dose of dasatinib reduced dasatinib exposure by 61%. The use of antacids should be considered in place of histamine-2 antagonists or proton pump inhibitors in patients receiving dasatinib therapy.

Drugs that may have their plasma concentration altered by dasatinib.

CYP3A4 substrates.

In a study in healthy subjects, a single 100 mg dose of dasatinib increased exposure to simvastatin, a known CYP3A4 substrate, by 20%. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving dasatinib (see Section 5.1 Pharmacodynamic Properties, Mechanism of action).

Other interactions.

In vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones.
No specific drug interaction studies between dasatinib and chemotherapy regimens routinely used in newly diagnosed Ph+ ALL patients have been performed.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Dasatinib did not affect male or female fertility in a conventional rat fertility and early embryonic development study at approximately 1x human clinical exposure (100 or 140 mg dose). However, embryolethality was evident when dams were treated at these doses. Dasatinib caused atrophy/ degeneration of the testis in rats and monkeys and an increase in the number of corpora lutea in the ovaries in rats at doses producing plasma exposure levels below or close to that anticipated in patients receiving dasatinib therapy. Data evaluating reproductive toxicity in male patients taking dasatinib is limited (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
(Category D)
Dasatinib may cause fetal harm when administered to a pregnant woman (see Section 4.6 Fertility, Pregnancy and Lactation, Embryofetal toxicity). In non-clinical studies, at exposure levels that are readily achievable in humans receiving therapeutic doses of 100 mg of dasatinib serious embryo fetal toxicity was observed in both pregnant rats and rabbits. Malformations (including skeletal alterations) and fetal death were observed in rats treated with dasatinib.
Dasatinib is therefore not recommended for use in women who are pregnant or contemplating pregnancy. Women must be advised to avoid becoming pregnant while on therapy. If dasatinib is used during pregnancy, or if the patient becomes pregnant while taking dasatinib, the patient should be apprised of the potential hazard to the fetus.
The potential effects of dasatinib on sperm have been evaluated in an oral study of fertility and early embryonic development in rats. Dasatinib is not a reproductive toxicant in male rats at clinically relevant exposures (see Section 4.6 Fertility, Pregnancy and Lactation, Effects on fertility). However, data evaluating reproductive toxicity in male patients taking dasatinib are limited.
Sexually active male or female patients of child bearing potential taking dasatinib should use adequate contraception.

Embryofetal toxicity.

Dasatinib can cause fetal harm when administered to a pregnant woman. There have been post-marketing reports of spontaneous abortion and fetal and infant anomalies from women who have taken dasatinib during pregnancy.
 It is unknown whether dasatinib is excreted in human milk. Women who are taking dasatinib should not breastfeed. In an exploratory peri- and post-natal development study in rats, dasatinib was detectable in the plasma of breast-fed pups with levels 30-40% of the maternal levels. Pleural effusion and deaths were seen in maternally-exposed rat pups, indicating indirect exposure of dasatinib was incompatible with pup survival, even at sub-therapeutic maternal exposure.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The data described below reflect exposure to dasatinib at all doses studied in 324 patients with newly diagnosed chronic phase CML and in 2,388 patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL. The median duration of therapy in 2,712 dasatinib treated patients was 19.2 months (range 0-93.2 months).
In the Phase III study of patients with newly diagnosed chronic phase CML the median duration of therapy was approximately 60 months for both dasatinib (range 0.03-72.7 months) and imatinib (range 0.3-74.6 months). The median duration of therapy in 1,618 patients with chronic phase CML was 29 months (range 0-92.9 months). In 1,094 patients with advanced phase CML or Ph+ ALL, the median duration of treatment for patients was 6.2 months (range 0-93.2 months).
The majority of patients treated with dasatinib, regardless of dose or schedule, experienced adverse reactions at some time. In the overall population of 2,712 dasatinib-treated subjects, 520 (19%) experience adverse drug reactions leading to treatment discontinuation.
In the Phase III study in patients with newly diagnosed chronic phase CML, treatment was discontinued for drug-related adverse reactions in 14% of dasatinib-treated patients and 7% of imatinib-treated patients with a minimum of 60 months follow-up. Among the pooled population of 1,618 dasatinib-treated subjects with chronic phase CML, adverse reactions leading to discontinuation were reported in 329 (20.3%) subjects, and among the 1,094 dasatinib-treated subjects with advanced phase disease, adverse drug reactions leading to discontinuation were reported in 191 (17.5%) subjects.
The majority of imatinib-intolerant patients in chronic phase CML were able to tolerate treatment with dasatinib. In clinical studies with 24 months minimum follow-up in chronic phase CML, 10 of the 215 imatinib-intolerant patients had the same Grade 3 or 4 non-haematological toxicity with dasatinib as they did with prior imatinib; 8 of the 10 patients were managed with dose reduction and were able to continue dasatinib treatment.
Adverse reactions reported in ≥ 10% of patients, and other adverse reactions of interest, in a Phase III trial of newly diagnosed chronic phase CML at a median follow-up of approximately 60 months are presented in Table 5. In this study, drug-related pleural effusion was reported in 73 patients (28%) receiving dasatinib. The median time to onset for Grade 1 or 2 pleural effusion events was 114 weeks (range 4-299 weeks). Fewer than 3% of pleural effusion events were Grade 3 or 4. The cumulative incidence of drug-related pleural effusion (all grades) in dasatinib-treated subjects increased over time; the majority are low grade. With appropriate medical care, 58 patients (80% of those with pleural effusion) were able to continue on dasatinib (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
The most frequently reported adverse reactions in dasatinib-treated patients with resistance or intolerance to prior imatinib therapy were fluid retention (including pleural effusion), diarrhoea, nausea, headache, skin rash, dyspnoea, haemorrhage, fatigue, musculoskeletal pain, infection, vomiting, cough, abdominal pain and pyrexia. In the Phase III study in patients with resistance or intolerance to prior imatinib therapy, drug-related febrile neutropenia was reported in 2.1% of dasatinib-treated patients.
Based on 2-year pooled data, the use of dasatinib is associated with fluid retention with Grade 3 and 4 cases in 11% of patients with resistance or intolerance to prior imatinib therapy. Grade 3 or 4 pleural and pericardial effusion were reported in 7% and 2% of patients. Severe congestive heart failure/cardiac dysfunction was reported in 2% of patients. Grade 3 or 4 ascites and generalised oedema were each reported in < 1%. One percent of patients experienced Grade 3 or 4 pulmonary oedema. Fluid retention reactions were typically managed by supportive care measures that include diuretics or short courses of steroids (see Section 4.4 Special Warnings and Precautions for Use).
Bleeding drug-related events, ranging from petechiae and epistaxis to Grade 3 or 4 gastrointestinal haemorrhage and CNS bleeding, were reported in patients taking dasatinib. In the Phase III study in patients with newly diagnosed chronic phase CML, 2 patients (1%) receiving dasatinib compared to 3 patients (1%) receiving imatinib had Grade 3 or 4 haemorrhage. Based on 2-year pooled data for clinical studies in patients with resistance or intolerance to prior imatinib therapy, severe CNS haemorrhage occurred in < 1% of patients. Eight cases were fatal and 6 of them were associated with CTC Grade 4 thrombocytopenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 4% of patients with resistance or intolerance to prior imatinib therapy and generally required treatment interruption and transfusions. Other Grade 3 or 4 haemorrhage occurred in 2% of patients with resistance or intolerance to prior imatinib therapy. Most bleeding related events in these patients were typically associated with Grade 3 or 4 thrombocytopenia. Additionally, in vitro and in vivo platelet assays suggest that dasatinib treatment reversibly affects platelet activation.
Treatment with dasatinib is associated with anaemia, neutropenia and thrombocytopenia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML.

QT prolongation.

In the Phase III study in patients with newly diagnosed chronic phase CML, one patient (< 1%) of the dasatinib-treated patients, and one patient (< 1%) of the imatinib-treated patients had a QTcF > 500 msec (see Section 4.4 Special Warnings and Precautions for Use).
Patients with risk factors or a history of cardiac disease should be monitored carefully for signs or symptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately (see Section 4.4 Special Warnings and Precautions for Use).
In clinical trials with patients with resistance or intolerance to prior imatinib therapy, it was recommended that treatment with imatinib be discontinued at least 7 days before starting treatment with dasatinib.
The comparative frequency of adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of the patients with newly diagnosed chronic phase CML are presented in Table 4.
A comparison of cumulative rates of selected adverse reactions in the Phase III study of newly diagnosed patients with chronic phase CML with minimum follow-up of one and five years are shown in Table 5.
In the Phase III dose-optimisation study in patients with chronic phase CML resistant or intolerant to imatinib, the overall median duration of therapy was approximately 30 months (range < 1-93 months), with a median duration in the 100 mg once daily group of 37 months (range 1-91 months). The study evaluated once daily and twice daily dosage regimens (100 mg and 140 mg once daily, and 50 mg and 70 mg twice daily). Following Year 2 analysis many patients switched to once daily dosing regimens during the subsequent extension of the study. Cumulative rates of selected adverse reactions that were reported in the 100 mg once daily recommended starting dose (n = 165) are shown in Table 6.
In the Phase III dose-optimisation study in patients with advanced phase CML and Ph+ ALL, the median duration of treatment was 14 months (range < 1-36 months) for accelerated phase CML; 3 months (range < 1-32 months) for myeloid blast CML; 4 months (< 1-22 months) for lymphoid blast CML; and 3 months (< 1-29 months) for Ph+ ALL. Selected adverse drug reactions that were reported at the recommended starting dose of 140 mg once daily are shown in Table 7. A 70 mg twice daily regimen was also studied. At Year 2 analysis, the 70 mg twice daily regimen showed a comparable efficacy profile to the 140 mg once daily regimen, but a less favourable safety profile; particularly the fluid retention (pleural effusion and pericardial effusion) was reported less frequently in patients treated with dasatinib 140 mg once daily than in those treated with 70 mg twice daily.
The following adverse reactions, excluding laboratory abnormalities, were reported in patients in dasatinib clinical trials. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Investigations.

Common: weight decreased, weight increased.
Uncommon: blood creatine phosphokinase increased, Gamma-glutamyltransferase increased.

Cardiac disorders.

Common: congestive heart failure/cardiac dysfunctionc, pericardial effusion, arrhythmia (including tachycardia), palpitations.
Uncommon: myocardial infarction (including fatal outcomes), electrocardiogram QT prolonged, pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina pectoris, cardiomegaly, electrocardiogram T wave abnormal, troponin increased.
Rare: cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis.

Blood and lymphatic system disorders.

Very common: myelosuppression (including anaemia, neutropenia, thrombocytopenia).
Common: febrile neutropenia.
Uncommon: lymphadenopathy, lymphopenia.
Rare: aplasia pure red cell.

Nervous system disorders.

Very common: headache.
Common: neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence.
Uncommon: CNS bleedingb, syncope, tremor, amnesia, balance disorder.
Rare: cerebrovascular accident, transient ischemic attack, convulsion, optic neuritis, VIIth nerve paralysis, dementia, ataxia.

Eye disorders.

Common: visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye.
Uncommon: conjunctivitis, visual impairment, photophobia, lacrimation increased.

Ear and labyrinth disorders.

Common: tinnitus.
Uncommon: hearing loss, vertigo.

Respiratory, thoracic and mediastinal disorders.

Very common: pleural effusion, dyspnoea.
Common: pulmonary oedema, pulmonary hypertension, lung infiltration, pneumonitis, cough.
Uncommon: bronchospasm, asthma, dysphonia, pulmonary arterial hypertension.
Rare: acute respiratory distress syndrome, pulmonary embolism.

Gastrointestinal disorders.

Very common: diarrhoea, vomiting, nausea, abdominal pain.
Common: gastrointestinal bleeding (including fatal), colitis (including neutropenic colitis), gastritis, mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, oral soft tissue disorder.
Uncommon: pancreatitis, upper gastrointestinal ulcer, oesophagitis, ascites, anal fissure, dysphagia, gastro-oesophageal reflux disease.
Rare: protein-losing gastroenteropathy, ileus, pancreatitis acute, anal fistula.

Renal and urinary disorders.

Uncommon: renal failure, urinary frequency, proteinuria.
Rare: renal impairment.

Skin and subcutaneous tissue disorders.

Very common: skin rashe.
Common: alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, hyperhidrosis.
Uncommon: neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome, hair disorder.
Rare: leukocytoclastic vasculitis, skin fibrosis.

Musculoskeletal and connective tissue disorders.

Very common: musculoskeletal pain.
Common: arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm.
Uncommon: rhabdomyolysis, tendonitis, muscle inflammation, osteonecrosis, arthritis.
Rare: epiphyses delayed fusiong, growth retardationg.

Metabolism and nutrition disorders.

Common: appetite disturbancesa, hyperuricaemia.
Uncommon: dehydration, hypoalbuminaemia, hypercholesterolemia, tumour lysis syndrome.
Rare: diabetes mellitus.

Infections and infestations.

Very common: infection (including bacterial, viral, fungal, non-specified).
Common: pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including uncommon reports of fatal outcome).

Injury, poisoning, and procedural complications.

Common: contusion.

Vascular disorders.

Very common: haemorrhaged.
Common: hypertension, flushing.
Uncommon: hypotension, thrombophlebitis, thrombosis.
Rare: deep vein thrombosis, embolism, livedo reticularis.
Not known: thrombotic microangiopathy.

General disorders and administration site conditions.

Very common: peripheral oedemag, fatigue, face oedemah, pyrexia.
Common: asthenia, pain, chest pain, generalised oedemai, chills.
Uncommon: malaise, other superficial oedemaj.
Rare: gait disturbance.

Immune system disorders.

Uncommon: hypersensitivity (including erythema nodosum).
Rare: anaphylactic shockk.

Endocrine disorders.

Uncommon: hypothyroidism.
Rare: hyperthyroidism, thyroiditis.

Hepatobiliary disorders.

Uncommon: hepatitis, cholecystitis, cholestasis.

Reproductive system and breast disorders.

Uncommon: gynecomastia, menstrual disorder.

Pregnancy, puerperium and perinatal conditions.

Rare: abortion.

Psychiatric disorders.

Common: depression, insomnia.
Uncommon: anxiety, confusional state, affect lability, libido decreased.
a Includes decreased appetite, early satiety, increased appetite.
b Includes central nervous system haemorrhage, cerebral haematoma, cerebral haemorrhage, extradural haematoma, haemorrhage intracranial, haemorrhagic stroke, subarachnoid haemorrhage, subdural haematoma, and subdural haemorrhage.
c Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular dysfunction, right ventricular dysfunction, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, ventricular failure, left ventricular failure, right ventricular failure and ventricular hypokinesis.
d Excludes gastrointestinal bleeding and CNS bleeding; these ADRs are reported under the gastrointestinal disorders system organ class and the nervous system disorders system organ class, respectively.
e Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalised erythema, genital rash, heat rash, milia, miliaria, pustular psoriasis, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, toxic skin eruption, urticaria vesiculosa and vasculitic rash.
f Reported only in paediatric studies. Frequency reported as common in paediatric studies vs rare in overall monotherapy population.
g Includes gravitational oedema, localised oedema, oedema peripheral.
h Includes conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, lip oedema, macular oedema, oedema mouth, orbital oedema, periorbital oedema, swelling face.
i Includes fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, peripheral swelling (reported only in paediatric studies), oedema, oedema due to cardiac disease, perinephric effusion, postprocedural oedema, visceral oedema.
j Includes genital swelling, incision site oedema, oedema genital, penile oedema, penile swelling, scrotal oedema, skin swelling, testicular swelling, vulvovaginal swelling.
k Reported only in paediatric studies.

Postmarketing experience.

The following additional adverse events have been identified during postapproval use of dasatinib. 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 drug exposure.

Infections and infestations.

Hepatitis B reactivation.

Cardiac disorders.

Atrial fibrillation/atrial fluttera.

Respiratory, thoracic and mediastinal disorders.

Interstitial lung disease, pleural effusion, chylothorax.

Skin and subcutaneous tissue disorders.

Stevens-Johnson syndromeb.

Renal and urinary disorders.

Nephrotic syndrome.

Hepatobiliary disorders.

Hepatotoxicity.
a Typically reported in elderly patients or in patients with confounding factors including significant underlying or concurrent cardiac or cardiovascular disorders, or other significant comorbidities (e.g. severe infection/sepsis, electrolyte abnormalities).
b In the post-marketing setting, individual cases of Stevens-Johnson syndrome have been reported. It could not be determined whether these mucocutaneous adverse reactions were directly related to dasatinib or to concomitant medications.

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 http://www.tga.gov.au/reporting-problems and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Experience with overdose of dasatinib in clinical studies is limited to isolated cases. The highest overdosage of 280 mg per day for one week was reported in two patients and both developed a significant decrease in platelet counts. Since dasatinib is associated with severe myelosuppression, patients who ingest more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment.

Treatment.

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Dasatinib is a potent inhibitor of multiple oncogenic kinases, cellular enzymes involved in the transmission of growth signals from the cell membrane to the nucleus. Dasatinib inhibits the activity of the BCR-ABL kinase and SRC-family kinases at low nanomolar or subnanomolar concentrations. Dasatinib also inhibits a number of other kinases including c-KIT, the EPHA2 receptor and the PDGFβ receptor. Unlike imatinib, it binds not only to the inactive but also to the active conformation of the BCR-ABL kinase. This suggests a reduced propensity for acquired drug resistance due to the emergence of mutations that promote the adoption of kinase's active conformation.
Dasatinib has been demonstrated to inhibit the survival/proliferation of human leukaemic cell lines in vitro and to inhibit the growth of human chronic myeloid leukaemia (CML) xenografts in SCID mice, in both imatinib-sensitive and resistant models of the disease. Antileukaemic activity was seen in dasatinib-treated mice in a model of CML with CNS involvement. Non-clinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL independence, most BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving SRC-family kinases (LYN and FYN) and P-glycoprotein (multi-drug resistance protein 1) overexpression.

Clinical trials.

In the Phase I study, haematological and cytogenetic responses were observed in all phases of CML and in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) (Ph+ ALL) in the first 84 patients treated and followed for up to 27 months. Responses were durable across all phases of CML and Ph+ ALL.
Four single-arm, uncontrolled, open-label Phase II clinical trials were conducted to determine the safety and efficacy of dasatinib in patients with CML in chronic, accelerated or myeloid blast phase, who were either resistant or intolerant to imatinib.
One randomized, comparative trial was conducted in chronic phase patients who failed initial treatment with 400 or 600 mg imatinib. The starting dose of dasatinib was 70 mg twice daily. Dose modifications were allowed for improving activity or management of toxicity.
Two randomized, open-label Phase III trials were conducted to evaluate the efficacy of dasatinib administered once daily compared with dasatinib administered twice daily. In addition, one open-label, randomized, comparative Phase III study was conducted in adult patients with newly diagnosed chronic phase CML.
The efficacy of dasatinib is based on haematological and cytogenetic response rates. Durability of response and estimated survival rates provide additional evidence of dasatinib clinical benefit.
A total of 2,712 patients were evaluated in clinical trials of CML; of these 23% were ≥ 65 years of age and 5% were ≥ 75 years of age.

Chronic phase CML - newly diagnosed.

An international open-label, multi-centre, randomized, comparative Phase III study was conducted in adult patients with newly diagnosed chronic phase CML. Patients were randomized to receive either dasatinib 100 mg once daily or imatinib 400 mg once daily. The primary end-point was the rate of confirmed complete cytogenetic response (cCCyR) within 12 months. Secondary endpoints included time in cCCyR (measure of durability of response), time to cCCyR, major molecular response (MMR) rate, time to MMR, progression free survival (PFS) and overall survival (OS). Other relevant efficacy results included CCyR and complete molecular response (CMR) rates.
A total of 519 patients were randomized to a treatment group: 259 to dasatinib and 260 to imatinib. Baseline characteristics were well balanced between the two treatment groups with respect to age (median age was 46 years for the dasatinib group and 49 years for the imatinib group with 10% and 11% of patients 65 years of age or older, respectively), gender (women 44% and 37%, respectively), and race (Caucasian 51% and 55%; Asian 42% and 37%, respectively). At baseline, the distribution of Hasford Scores was similar in the dasatinib and imatinib treatment groups (low risk, 33% and 34%; intermediate risk, 48% and 47%; high risk, 19% and 19%; respectively).
With a minimum of 12 months follow-up, 85% of patients randomized to the dasatinib group and 81% of patients randomized to the imatinib group were still receiving first-line treatment. Discontinuation due to disease progression occurred in 3% of dasatinib-treated patients and 5% of imatinib-treated patients. With a minimum of 60 months follow-up, 61% of patients randomized to the dasatinib group and 63% of patients randomized to the imatinib group were still receiving first-line treatment. Discontinuation due to disease progression occurred in 7% of dasatinib-treated patients and 9% of imatinib-treated patients.
Efficacy results are presented in Table 8. A statistically significantly greater proportion of patients in the dasatinib group achieved a cCCyR compared with patients in the imatinib group within the first 12 months of treatment. Efficacy of dasatinib was consistently demonstrated across different subgroups, including age, gender and baseline Hasford score.
For time-to cCCyR, a hazard ratio of 1.55 indicates that a patient treated with dasatinib is 55% more likely to achieve a cCCyR at any time compared to a patient treated with imatinib. Similarly, for time-to MMR, a hazard ratio of 2.01 indicates a patient treated with dasatinib is more than two times more likely to achieve a MMR at any time compared to a patient treated with imatinib. For durability of cCCyR (time-in response), a hazard ratio of 0.7 indicates a patient treated with dasatinib is 30% less likely to have disease progression after achieving a cCCyR (or never achieving a cCCyR) compared to a patient treated with imatinib.
After 60 months follow-up, median time to cCCyR was 3.1 months in the 214 dasatinib group responders and 5.8 months in the 204 imatinib group responders. Median time to MMR after 60 months follow-up was 9.3 months in the 196 dasatinib group responders and 15.0 months in the 163 imatinib group responders. The rates of cCCyR in the dasatinib and imatinib treatment groups, respectively, within 3 months (54% and 30%), 6 months (70% and 56%), 9 months (75% and 63%), 24 months (80% and 74%), 36 months (83% and 77%), 48 months (83% and 79%) and 60 months (83% and 79%) were consistent with the primary endpoint. The rates of MMR in the dasatinib and imatinib treatment groups, respectively, within 3 months (8% and 0.4%), 6 months (27% and 8%), 9 months (39% and 18%), 12 months (46% and 28%), 24 months (64% and 46%), 36 months (67% and 55%), 48 months (73% and 60%) and 60 months (76% and 64%) were also consistent with the primary endpoint. With a minimum of 60 months follow up, the rate of CMR (i.e. at least 4.5-log reduction from a standardised baseline value BCR-ABL ratio ≤ 0.0032%) at any time was 44% versus 34% in the dasatinib and imatinib treatment groups, respectively.
In an exploratory subgroup analysis the rate of MMR at any time in each risk group determined by Hasford score was higher in the dasatinib group compared with the imatinib group (low risk, 90% and 69%; intermediate risk, 71% and 65%; high risk, 67% and 54%; respectively).
In an exploratory analysis, more dasatinib-treated subjects (84%) achieved early molecular response (defined as BCR-ABL levels ≤ 10% at 3 months) compared with imatinib-treated subjects (64%). Subjects achieving early molecular response had a lower risk of transformation, higher rate of progression-free survival (PFS) and higher rate of overall survival (OS), as shown in Table 9 and Table 10.
The progression-free survival rate by specific timepoint is displayed graphically in Figure 1. Rate of PFS was consistently higher in dasatinib-treated patients who achieved BCR-ABL level ≤ 10% at 3 months than those who did not.
The overall survival rate by specific timepoint is displayed graphically in Figure 2. Rate of OS was consistently higher in dasatinib-treated patients who achieved BCR-ABL level ≤ 10% at 3 months than those who did not.
The time to MMR is displayed graphically in Figure 3. The time to MMR was consistently shorter in dasatinib-treated subjects compared with imatinib-treated subjects.
MMR rates by specific timepoint are displayed graphically in Figure 4. Rates of MMR were consistently higher in dasatinib-treated subjects compared with imatinib-treated subjects.
MR4.5 rates over time are displayed graphically in Figure 5. Rate of MR4.5 over time was consistently higher in dasatinib-treated subjects compared with imatinib-treated subjects.
Disease progression was defined as increasing white blood cells despite appropriate therapeutic management, loss of CHR (complete haematological response), partial CyR or CCyR, progression to accelerated phase or blast phase, or death. The estimated 60-month PFS rate was 88.9% (CI: 84.0%-92.4%) and 89.2% (CI: 84.3%-92.7%) for the dasatinib and imatinib treatment groups, respectively. Transformation to accelerated or blast phase occurred less frequently with dasatinib (n = 8; 3.1%) than with imatinib-treated patients (n = 15; 5.8%). The estimated 60-month survival rates for dasatinib and imatinib-treated patients were 90.9% (CI: 86.6%-93.8%) and 89.6% (CI: 85.2%-92.8%), respectively.
In a phase III trial of newly diagnosed chronic phase CML, BCR-ABL sequencing was performed on blood samples from patients who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L and V299L. Dasatinib does not appear to be active against the T315I mutation, based on in vitro data.

Phase III clinical trials in patients with CML in chronic, accelerated or myeloid blast phase, and Ph+ ALL who were resistant or intolerant to imatinib.

Two randomized, open-label studies were conducted to evaluate the efficacy of dasatinib administered once daily compared with dasatinib administered twice daily. The results described in Tables 11 and 12 are based on a minimum of 24 months and 60 months follow-up after the start of dasatinib therapy.
In the non-inferiority study in chronic phase CML, the primary endpoint was MCyR (once daily vs. twice daily) in imatinib-resistant patients. The main secondary endpoint was MCyR by total daily dose level in the imatinib-resistant patients. Other secondary endpoints included duration of MCyR, progression-free survival and overall survival. A total of 670 patients, of whom 497 were imatinib-resistant, were randomized to the dasatinib 100 mg once daily, 140 mg once daily, 50 mg twice daily or 70 mg twice daily group. The non-inferiority criteria were met for the primary efficacy endpoint at 6 months analysis. Results for each of the 4 individual regimens demonstrated comparable efficacy for MCyR and for a variety of secondary endpoints. At 2-Year analysis, the median duration of treatment was approximately 22 months (range: < 1-31 months). In patients with resistant or intolerant chronic phase CML, the median duration of treatment for patients still on therapy (n = 205) was 59 months (range: 28-66 months).
Efficacy results at 2-year analysis are presented in Tables 11 and 12. Efficacy was achieved across all dasatinib treatment groups, with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% confidence interval [-6.8%-10.6%]). However, the 100 mg once daily regimen had improved tolerability.
Efficacy was also assessed in patients who were intolerant to imatinib. In this population of patients who received 100 mg once daily, MCyR was achieved in 77% and CCyR in 67% with a minimum of 2 years follow-up.
Approximately 20% of subjects remained on study therapy through study completion (i.e. a minimum of 7 years), discontinuing study treatment due to study closure. Table 12 represents the comparative data (1-7 years), for the recommended starting dose 100 mg once daily in CML chronic phase.
In the Phase III, randomized, open-label study in patients with advanced phase CML and Ph+ ALL, whose disease was resistant to or who were intolerant to imatinib, the primary endpoint was MaHR. A total of 611 patients were randomized to either the dasatinib 140 mg once daily or 70 mg twice daily group. Median duration of treatment was approximately 6 months (range < 1-31 months).
The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MaHR 0.8%; 95% confidence interval [-7.1%-8.7%]); the response rates are presented in Table 13.
In patients with accelerated phase CML treated with the 140 mg once daily regimen, the median duration of MaHR and the median overall survival in patients with accelerated phase CML was not reached for either group; the median PFS was 25 months and 26 months for the 140 mg once daily group and the 70 mg twice daily group, respectively; and the median overall survival was not reached for the 140 mg once daily group and 31 months for the 70 mg twice daily group.
In patients with myeloid blast phase CML treated with the 140 mg once daily regimen, the median duration of MaHR was 8 months, and 9 months for the 140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was 4 months for both groups; and the median overall survival was 8 months for both groups. In patients with lymphoid blast phase CML, the median duration of MaHR was 5 months and 8 months for the 140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was 5 months for both groups, and the median overall survival was 11 months and 9 months, respectively.
In patients with Ph+ ALL treated with the 140 mg once daily regimen, the median duration of MaHR was 5 months and 12 months for the 140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was 4 months and 3 months, respectively, and the median overall survival was 7 months and 9 months, respectively.

5.2 Pharmacokinetic Properties

The pharmacokinetics of dasatinib were evaluated in 235 healthy subjects and in 84 patients with leukaemia.

Absorption.

Dasatinib is rapidly absorbed in patients following oral administration. The absolute bioavailability of dasatinib has not been determined. Peak concentrations were observed between 0.5-6 hours. Following oral administration, the increase in the mean exposure (AUCτ) is approximately proportional to the dose increment across doses ranging from 15 mg to 240 mg daily.
Data from a study of healthy subjects administered a single, 100 mg dose of dasatinib 30 minutes following consumption of a high-fat meal indicated a 14% increase in the mean AUC of dasatinib. Consumption of a low-fat meal 30 minutes prior to dasatinib resulted in a 21% increase in the mean AUC of dasatinib. The observed food effects are unlikely to be clinically significant. Dasatinib exposure variability is higher under fasted conditions (47% CV) compared to light-fat meal (39% CV) and high-fat meal (32% CV) conditions.
Based on the patient population PK analysis, variability in dasatinib exposure was estimated to be mainly due to inter-occasion variability in bioavailability (44% CV) and, to a lesser extent, due to inter-individual variability in bioavailability and inter-individual variability in clearance (30% and 32% CV, respectively). The random inter-occasion variability in exposure is not expected to affect the cumulative exposure and efficacy.

Distribution.

In patients, dasatinib has a large apparent volume of distribution (2,505 L) suggesting that the drug is extensively distributed in the extravascular space.

Metabolism.

Dasatinib is extensively metabolized in humans. In a study of 8 healthy subjects administered 100 mg [14C]-labelled dasatinib, unchanged dasatinib represented 29% of circulating radioactivity in plasma. Plasma concentration and measured in vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observed pharmacology of the drug. The overall mean terminal half-life of dasatinib is approximately 5-6 hours. CYP3A4 is a major enzyme responsible for the metabolism of dasatinib.

Excretion.

Elimination is predominantly in the faeces, mostly as metabolites. Following a single oral dose of [14C]-labelled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 85% of the administered radioactivity recovered in the urine and faeces, respectively. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and faeces, respectively, with the remainder of the dose being metabolites.

Special populations.

Age and gender.

Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of dasatinib.
The pharmacokinetics of dasatinib has not been evaluated in paediatric patients.

Hepatic impairment.

The effect of hepatic impairment on the single-dose pharmacokinetics of dasatinib was assessed in 8 moderately hepatic-impaired subjects who received a 50 mg dose and 5 severely hepatic-impaired subjects who received a 20 mg dose compared to matched healthy subjects who received a 70 mg dose of dasatinib. The mean Cmax and AUC of dasatinib adjusted for the 70 mg dose was decreased by 47% and 8%, respectively, in subjects with moderate hepatic impairment compared to subjects with normal hepatic function. In severely hepatic-impaired subjects, the mean Cmax and AUC adjusted for the 70 mg dose was decreased by 43% and 28%, respectively, compared to subjects with normal hepatic function (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Renal impairment.

There are no clinical studies of dasatinib in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Dasatinib was not mutagenic when tested in in vitro bacterial cell assays (Ames test) and was not clastogenic in an in vivo rat micronucleus study. Clastogenicity was observed with dasatinib in vitro in assays with Chinese hamster ovary cells in the absence and presence of metabolic activation.

Carcinogenicity.

In a two-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1 and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level generally equivalent to or slightly lower than calculated human exposure at the recommended range of starting doses 100 mg or 140 mg daily. A statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose female rats and of prostate adenoma in low-dose male rats was noted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose; ethylcellulose; lactose monohydrate; croscarmellose sodium; magnesium stearate; colloidal anhydrous silica; hypromellose; hyprolose; triethyl citrate; titanium dioxide.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

20 mg tablets.

Blister pack (clear PVC/Aclar/Al) of 60 tablets (AUSTR290137).
Bottle (white, round HDPE bottle with child-resistant cap and desiccant) of 60 tablets (AUSTR290129).

50 mg tablet.

Blister pack (clear PVC/Aclar/Al) of 60 tablets (AUSTR290131).
Bottle (white, round HDPE bottle with child-resistant cap and desiccant) of 60 tablets (AUSTR290128).

70 mg tablet.

Blister pack (clear PVC/Aclar/Al) of 60 tablets (AUSTR290140).
Bottle (white, round HDPE bottle with child-resistant cap and desiccant) of 60 tablets (AUSTR290136).

100 mg tablet.

Blister pack (clear PVC/Aclar/Al) of 30 tablets (AUSTR290143).
Bottle (white, round HDPE bottle with child-resistant cap and desiccant) of 30 tablets (AUSTR290134).
Not all strengths and/or pack types may be available.

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

Dasatinib is a white to off-white powder. The drug substance is insoluble in water (0.008 mg/mL) at 24 ± 4°C. The pH of a saturated solution of dasatinib in water is about 6.0. Two basic ionization constants (pKa) were determined to be 6.8 and 3.1, and one weakly acidic pKa was determined to be 10.8. The solubilities of dasatinib in various solvents at 24 ± 4°C are as follows: slightly soluble in ethanol (USP), methanol, polyethylene glycol 400, and propylene glycol; very slightly soluble in acetone and acetonitrile; and practically insoluble in corn oil.

Chemical structure.


Chemical Name: N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.
Molecular Formula: C22H26ClN7O2S.
Molecular Weight: 488.01.

CAS number.

302962-49-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes