Consumer medicine information

Inlyta

Axitinib

BRAND INFORMATION

Brand name

Inlyta

Active ingredient

Axitinib

Schedule

What is in this leaflet

This leaflet answers some common questions about INLYTA.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking INLYTA against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What INLYTA is used for

What INLYTA does

INLYTA is used to treat a certain type of kidney cancer called renal cell carcinoma (RCC).

It belongs to a group of medicines called tyrosine kinase inhibitors.

How INLYTA works

INLYTA contains the active substance axitinib. It works by reducing the blood supply to the tumour and slowing down the growth of cancer.

Ask your doctor if you have any questions about why INLYTA has been prescribed for you. Your doctor may have prescribed it for another reason.

INLYTA is only available with a doctor's prescription. It is not addictive.

Use in Children

The safety and efficacy of INLYTA have not been established in children.

Before you take INLYTA

When you must not take it

Do not take INLYTA if you have an allergy to:

any medicine containing axitinib
any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

You must tell your doctor if you have or have had any of the following medical conditions:

high blood pressure
thyroid gland problems
blood clots in your veins and/or arteries (types of blood vessels) or lungs
stroke or heart attack
bleeding problems
you have an unhealed wound, or if you have surgery scheduled
liver problems
serious kidney problems (other than the kidney cancer for which you are being treated)
lactose intolerance.

Before you start treatment with INLYTA, your doctor will perform tests to check for and monitor:

blood pressure
kidney problems
thyroid levels
red blood cell count
liver enzyme levels

Before taking INLYTA your blood pressure should be well-controlled.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. INLYTA should not be taken during pregnancy. Your doctor will discuss the risks with you.

You should not breastfeed while taking INLYTA.

If you have not told your doctor about any of the above, tell him/her before you start taking INLYTA.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including:

all prescription medicines
all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by INLYTA or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

dexamethasone, a steroid medicine used to treat dermatitis, asthma and some other conditions
ketoconazole or itraconazole, medicines used to treat fungal infections
clarithromycin or telithromycin, antibiotics used to treat bacterial infections
atazanavir, indinavir, nelfinavir, ritonavir or saquinavir, medicines used to treat HIV infections/AIDS
rifampin or rifabutin, medicines used to treat tuberculosis (TB)
nefazodone, used to treat depression
phenytoin, carbamazepine or phenobarbital, anti-epileptic medicines used to stop seizures or fits
St John's wort (Hypericum perforatum), a herbal medicine used to treat depression and other conditions
theophylline, used to treat asthma or other lung diseases.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking INLYTA.

How to take INLYTA

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you which tablets you need to take each day. For kidney cancer, the usual starting dose of INLYTA is one 5 mg tablet taken 2 times a day (for a total of 2 tablets each day).

You doctor may subsequently increase or decrease your dose depending on your response to INLYTA.

While taking this medicine your blood pressure should be monitored. If you experience high blood pressure, your doctor may recommend medicine to treat it or may change your dose of INLYTA.

How to take it

Swallow the INLYTA tablets whole with a glass of water.

You can take INLYTA either with or without food.

Do not drink grapefruit juice or eat grapefruit while taking INLYTA. They may change the amount of INLYTA in your body.

When to take it

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.

How long to take it

Continue taking INLYTA for as long as your doctor tells you.

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.

Continue taking your medicine for as long as your doctor prescribes it.

If you forget to take it

Take your next dose at your regular time.

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

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 take too much (overdose)

Immediately telephone your doctor, or Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much INLYTA.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking INLYTA

Things you must do

Make sure you follow your doctor's instructions and keep all appointments.

During treatment with INLYTA, your doctor will perform regular tests to check for and monitor:

blood pressure
heart disease
stomach and bowel problems
kidney disease
thyroid levels
red blood cell count
liver enzyme levels

Regular follow up and blood tests are done to make sure the medicine is working and to check for side effects.

Men and women should use contraception to prevent pregnancy during treatment with INLYTA. Talk with your doctor about effective contraception.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking INLYTA.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

You should stop taking INLYTA 24 hours before your surgery. It may affect other medicines used during surgery.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Things you must not do

Do not take INLYTA to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert, until you know how INLYTA affects you. INLYTA may make some people feel very tired or dizzy.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking INLYTA.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

It can be difficult to tell whether side effects are the result of taking INLYTA, effects of your condition or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

Do not be alarmed by the list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if...

Tell your doctor or pharmacist if you notice any of the following:

diarrhoea
high blood pressure
tiredness
loss of appetite
hoarseness, change in your voice
tingling or rash on palms of hands or soles of feet
nausea (feeling sick) or vomiting
weight loss
weakness
constipation
low thyroid hormone levels, symptoms include being more sensitive to cold, unintentional weight gain and lack of energy
soreness or burning of the mouth, tongue or throat
shortness of breath, cough
stomach ache, indigestion
headache
pain in hands or feet
muscle pain, joint pain
change in sense of taste
rash, dry skin, skin redness, scaly skin, itchy skin
dizziness
dehydration
nose bleeding
piles, or bleeding from the back passage
hair loss
unusual urine colour
ringing or sound in the ears

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if...

Tell your doctor as soon as possible if you notice any of the following:

high blood pressure, symptoms may include headaches, dizziness, blurred vision, nausea and vomiting
foamy and frothy urine with swelling of abdomen, legs or eyes
swelling of feet or legs, leg pain, cough.

The above list includes serious side effects that may require medical attention.

Go to hospital if...

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

chest pain or pressure, pain in your arms, back, neck or jaw; shortness of breath
numbness or weakness on one side of your body, loss of co-ordination
trouble speaking or swallowing
headache, confusion, trouble seeing, seizures or fits
severe stomach pain with vomiting and fever

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Some of these side effects (for example, changes in blood pressure, thyroid levels, liver enzymes and red blood cell count) can only be found when your doctor does tests from time to time to check your progress.

After using INLYTA

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store INLYTA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

INLYTA 1 mg are red, oval, film-coated tablets debossed with "Pfizer" on one side and "1 XNB" on the other.

INLYTA 5 mg are red, triangular, film-coated tablets debossed with "Pfizer" on one side and "5 XNB" on the other.

INLYTA tablets are available in blister packs of 28 tablets (2 blister cards of 14 tablets each)

Ingredients

INLYTA tablets contain 1 mg or 5 mg of axitinib as the active ingredient.

The tablets also contain:

lactose monohydrate
cellulose - microcrystalline
croscarmellose sodium
magnesium stearate
Opadry II RED 32K154441 film coating
glycerol triacetinHPMC 2910/Hypromellose 15cP
titanium dioxide
iron oxide red CI77491

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier

INLYTA is supplied in Australia by:

Pfizer Australia Pty Ltd
ABN 50 008 422 348
Sydney NSW 2000
Toll Free number: 1800 675 229
www.pfizer.com.au

Australian registration numbers

1 mg tablets: AUST R 184856

5 mg tablets: AUST R 184859

Date of preparation

This leaflet was prepared in October 2019.

® = Registered Trademark

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Inlyta

Active ingredient

Axitinib

Schedule

1 Name of Medicine

Axitinib.

2 Qualitative and Quantitative Composition

Inlyta is supplied as red film-coated tablets containing 1 mg, 3 mg, 5 mg, or 7 mg of axitinib.

Excipient(s) with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Inlyta 1 mg tablets.

Red, film-coated, oval tablets, debossed with "Pfizer" on one side and "1 XNB" on the other.

Inlyta 3 mg tablets.

Red, film-coated, round tablets, debossed with "Pfizer" on one side and "3 XNB" on the other.

Inlyta 5 mg tablets.

Red, film-coated, triangular tablets, debossed with "Pfizer" on one side and "5 XNB" on the other.

Inlyta 7 mg tablets.

Red, film-coated, diamond tablets, debossed with "Pfizer" on one side and "7 XNB" on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Inlyta is indicated for the treatment of patients with advanced renal cell carcinoma after failure of one prior systemic therapy.

4.2 Dose and Method of Administration

Dosage.

Recommended dose. The recommended starting oral dose of Inlyta is 5 mg twice daily. Inlyta may be taken with or without food.
If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.
Dosage adjustment. Dose increase or reduction is recommended based on individual safety and tolerability.
Patients who tolerate the Inlyta starting dose of 5 mg twice daily with no adverse reactions > grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]) for two consecutive weeks, are normotensive, and are not receiving antihypertensive medication, may have their dose increased to 7 mg twice daily. Subsequently, using the same criteria, patients who tolerate the Inlyta dose of 7 mg twice daily, may have their dose increased to a maximum of 10 mg twice daily.
Management of some adverse drug reactions may require temporary or permanent discontinuation and/or dose reduction of Inlyta therapy (see Section 4.4 Special Warnings and Precautions for Use). When dose reduction is necessary, the Inlyta dose may be reduced to 3 mg twice daily and further to 2 mg twice daily.
Dose adjustment is not required on the basis of patient age, race, gender, or body weight.

Concomitant strong CYP3A4/5 inhibitors.

Coadministration of Inlyta with strong CYP3A4/5 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) may increase axitinib plasma concentrations. Grapefruit may also increase axitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended.
Although Inlyta dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be coadministered, a dose decrease of Inlyta to approximately half the dose (e.g. from a starting dose of 5 mg twice daily to a reduced dose of 2 mg twice daily) is recommended. If coadministration of the strong inhibitor is discontinued, a return to the Inlyta dose used prior to initiation of the strong CYP3A4/5 inhibitor should be considered.

Concomitant strong CYP3A4/5 inducers.

Coadministration of Inlyta with strong CYP3A4/5 inducers (e.g. rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and Hypericum perforatum [also known as St. John's wort]) may decrease axitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal CYP3A4/5 induction potential is recommended.
Although Inlyta dose adjustment has not been studied in patients receiving strong CYP3A4/5 inducers, if a strong CYP3A4/5 inducer must be coadministered, a gradual dose increase of Inlyta is recommended. If the dose of Inlyta is increased, the patient should be monitored carefully for toxicity. If coadministration of the strong inducer is discontinued, the Inlyta dose should be immediately returned to the dose used prior to initiation of the strong CYP3A4/5 inducer.

Use in hepatic impairment.

No dose adjustment is required when administering Inlyta to patients with mild hepatic impairment (Child-Pugh class A). A dose decrease is recommended when administering Inlyta to patients with moderate hepatic impairment (Child-Pugh class B) [e.g. the starting dose should be reduced from 5 mg twice daily to 2 mg twice daily]. Inlyta has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Use in renal impairment.

No dose adjustment is required (see Section 5.2 Pharmacokinetic Properties).

Use in children.

The safety and efficacy of Inlyta in children and adolescents (< 18 years) have not been established.

Use in the elderly.

No dose adjustment is required (see Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Hypersensitivity to axitinib or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Cardiac failure events.

In a controlled clinical study with Inlyta for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiopulmonary failure, left ventricular dysfunction, and right ventricular failure) were reported in 1.7% of patients receiving Inlyta (N = 359) and 0.8% of patients receiving sorafenib (N = 355) (see Section 4.8 Adverse Effects (Undesirable Effects)). Grade 3/4 cardiac failure events were observed in 0.6% of patients receiving Inlyta and 0.3% of patients receiving sorafenib. Fatal cardiac failure was reported in 0.6% of patients receiving Inlyta and 0.3% of patients receiving sorafenib.
In clinical studies with axitinib for the treatment of patients with RCC, cardiac failure events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were reported in 1.8% of patients receiving Inlyta. Grade 3/4 cardiac failure events were reported in 1.0% and fatal cardiac failure events were reported in 0.3% of patients receiving Inlyta.
Monitor for signs or symptoms of cardiac failure periodically throughout treatment with Inlyta. Management of cardiac failure events may require temporary interruption or permanent discontinuation and/or dose reduction of Inlyta therapy.

Hypertension.

In a controlled clinical study with Inlyta for the treatment of patients with RCC, hypertension was reported in 40.4% of patients receiving Inlyta (N = 359) and 29.0% receiving sorafenib (N = 355) (see Section 4.8 Adverse Effects (Undesirable Effects)). Grade 3 hypertension was observed in 15.3% of patients receiving Inlyta and 10.7% of patients receiving sorafenib and grade 4 hypertension was observed in 0.3% of patients receiving Inlyta and 0.3% of patients receiving sorafenib. Hypertensive crisis was reported in 0.6% of patients receiving Inlyta and in none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg) was within the first month of the start of Inlyta or sorafenib treatment and blood pressure increases have been observed as early as 4 days after starting Inlyta. Hypertension was managed with standard antihypertensive therapy. Discontinuation of Inlyta treatment due to hypertension occurred in 0.3% of patients receiving Inlyta and in none of the patients receiving sorafenib (see Section 4.8 Adverse Effects (Undesirable Effects)).
In pooled clinical studies with Inlyta for the treatment of patients with RCC (N = 672), hypertension was reported in 51.2% of patients receiving Inlyta. Grade 3 hypertension was reported in 22.0% of patients receiving Inlyta. Grade 4 hypertension was reported in 1.0% of patients receiving Inlyta.
Blood pressure should be well controlled prior to initiating Inlyta. Patients should be monitored for hypertension and treated as needed with standard antihypertensive therapy. In the case of persistent hypertension despite use of antihypertensive medications, the Inlyta dose should be reduced. For patients who develop severe hypertension, temporarily interrupt Inlyta and restart at a lower dose once the patient is normotensive. If Inlyta is interrupted, patients receiving antihypertensive medications should be monitored for hypotension (see Section 4.2 Dose and Method of Administration).

Thyroid dysfunction.

In a controlled clinical study with Inlyta for the treatment of patients with RCC, hypothyroidism was reported in 19.2% of patients receiving Inlyta (N = 359) and 8.2% of patients receiving sorafenib (N = 355) (see Section 4.8 Adverse Effects (Undesirable Effects)). Hyperthyroidism was reported in 1.1% of patients receiving Inlyta and 1.1% of patients receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) < 5 microunit/mL before treatment, elevations of TSH to ≥ 10 microunit/mL occurred in 32.2% of patients receiving Inlyta and 10.8% of patients receiving sorafenib (see Section 4.8 Adverse Effects (Undesirable Effects)).
In pooled clinical studies with Inlyta for the treatment of patients with RCC (N = 672), hypothyroidism was reported in 24.6% of patients receiving Inlyta. Hyperthyroidism was reported in 1.6% of patients receiving Inlyta.
Monitor thyroid function before initiation of, and periodically throughout, treatment with Inlyta. Hypothyroidism or hyperthyroidism should be treated according to standard medical practice to maintain euthyroid state.

Arterial thromboembolic events.

In a controlled clinical study with Inlyta for the treatment of patients with RCC, grade 3/4 arterial thromboembolic events were reported in 1.1% of patients receiving Inlyta (N = 359) and 1.1% of patients receiving sorafenib (N = 355). The most frequent arterial thromboembolic event was transient ischaemic attack (1.0%) (see Section 4.8 Adverse Effects (Undesirable Effects)). Fatal cerebrovascular accident was reported in 0.3% of patients receiving Inlyta and none (0%) of the patients receiving sorafenib.
In pooled clinical studies with Inlyta for the treatment of patients with RCC (N = 672), arterial thromboembolic events were reported in 2.8% of patients receiving Inlyta. Grade 3 arterial thromboembolic events were reported in 1.2% of patients. Grade 4 arterial thromboembolic events were reported in 1.3% of patients. Fatal arterial thromboembolic events were reported in 2 patients (0.3%) receiving Inlyta.
In monotherapy studies with Inlyta (N = 699), arterial thromboembolic events (including transient ischaemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 2.3% of patients receiving Inlyta.
Inlyta should be used with caution in patients who are at risk for, or who have a history of, these events. Inlyta has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.

Venous thromboembolic events.

In a controlled clinical study with Inlyta for the treatment of patients with RCC, venous thromboembolic events were reported in 3.1% of patients receiving Inlyta (N = 359) and 0.6% of patients receiving sorafenib (N = 355). Grade 3/4 venous thromboembolic events were reported in 2.5% of patients receiving Inlyta (including pulmonary embolism, deep vein thrombosis, and retinal vein occlusion/ thrombosis) and 0.6% of patients receiving sorafenib (see Section 4.8 Adverse Effects (Undesirable Effects)). Fatal pulmonary embolism was reported in one patient (0.3%) receiving Inlyta and in none of the patients receiving sorafenib.
In pooled clinical studies with Inlyta for the treatment of patients with RCC (N = 672), venous thromboembolic events were reported in 2.8% of patients receiving Inlyta. Grade 3 venous thromboembolic events were reported in 0.9% of patients. Grade 4 venous thromboembolic events were reported in 1.2% of patients. Fatal venous thromboembolic events were reported in 1 patient (0.1%) receiving Inlyta.
Inlyta should be used with caution in patients who are at risk for, or who have a history of, these events. Inlyta has not been studied in patients who had a venous thromboembolic event within the previous 6 months.

Aneurysms and artery dissections.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Inlyta, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Elevation of haemoglobin or haematocrit.

Increases in haemoglobin or haematocrit, reflective of increases in red blood cell mass, may occur during treatment with Inlyta. An increase in red blood cell mass may increase the risk of thromboembolic events.
Elevated haemoglobin above the ULN was observed in 9.7% of patients receiving Inlyta (N = 320) and 0.9% of patients receiving sorafenib (N = 316).
Monitor haemoglobin or haematocrit before initiation of, and periodically throughout, treatment with Inlyta. If haemoglobin or haematocrit becomes elevated above the normal level, patients should be treated according to standard medical practice to decrease haemoglobin or haematocrit to an acceptable level.

Haemorrhage.

In a controlled clinical study with Inlyta for the treatment of patients with RCC, in which patients with untreated brain metastasis were excluded, haemorrhagic events were reported in 16.2% of patients receiving Inlyta (N = 359) and 18.0% of patients receiving sorafenib (N = 355). The most common haemorrhagic events in patients treated with Inlyta were epistaxis (6.1%), haematuria (3.3%), haemoptysis (2.2%), and rectal haemorrhage (2.2%) (see Section 4.8 Adverse Effects (Undesirable Effects)). Grade 3/4 haemorrhagic events were reported in 1.4% of patients receiving Inlyta (including cerebral haemorrhage, haematuria, haemoptysis, lower gastrointestinal haemorrhage, and melaena) and 3.1% of patients receiving sorafenib. Fatal haemorrhage was reported in one patient (0.3%) receiving Inlyta (gastric haemorrhage) and three patients (0.8%) receiving sorafenib.
In pooled clinical studies with Inlyta for the treatment of patients with RCC (N = 672), haemorrhagic events were reported in 25.7% of patients receiving Inlyta. Grade 3 haemorrhagic events were reported in 3.0% of patients. Grade 4 haemorrhagic events were reported in 1.0% of patients and fatal haemorrhagic events were reported in 3 patients (0.4%) receiving Inlyta.
Inlyta has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the Inlyta dose.

Gastrointestinal perforation and fistula formation.

In a controlled clinical study with Inlyta for the treatment of patients with RCC, gastrointestinal perforation was reported 0.3% of patients receiving Inlyta (N = 359) and in none of the patients receiving sorafenib (N = 355). In addition to cases of gastrointestinal perforation, fistulas were reported in 0.6% of patients receiving Inlyta and 0.3% of patients receiving sorafenib.
In pooled clinical studies with Inlyta for the treatment of patients with RCC (N = 672), gastrointestinal perforation and fistula were reported in 1.9% of patients receiving Inlyta. In monotherapy studies with Inlyta (N = 699), fatal gastrointestinal perforation was reported in one patient (0.1%).
Monitor for symptoms of gastrointestinal perforation periodically throughout treatment with Inlyta.

Wound healing complications.

No formal studies of the effect of Inlyta on wound healing have been conducted. Treatment with Inlyta should be stopped at least 24 hours prior to scheduled surgery. The decision to resume Inlyta therapy after surgery should be based on clinical judgment of adequate wound healing.

Reversible posterior leukoencephalopathy syndrome (RPLS).

In a controlled clinical study with Inlyta for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in one patient (0.3%) receiving Inlyta (N = 359) and in none of the patients receiving sorafenib (N = 355) (see Section 4.8 Adverse Effects (Undesirable Effects)).
In pooled clinical studies with Inlyta for the treatment of patients with RCC (N = 672), RPLS was reported in 0.3% of patients receiving Inlyta.
RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. In patients with signs/ symptoms of RPLS, temporarily interrupt or permanently discontinue Inlyta. The safety of reinitiating Inlyta therapy in patients previously experiencing RPLS is not known.

Proteinuria.

In a controlled clinical study with Inlyta for the treatment of patients with RCC, proteinuria was reported in 10.9% of patients receiving Inlyta (N = 359) and 7.3% of patients receiving sorafenib (N = 355) (see Section 4.8 Adverse Effects (Undesirable Effects)). Grade 3 proteinuria was reported in 3.1% of patients receiving Inlyta and 1.7% of patients receiving sorafenib.
In pooled clinical studies with Inlyta for the treatment of patients with RCC (N = 672), proteinuria was reported in 21.1% of patients receiving Inlyta. Grade 3 proteinuria was reported in 4.8% of patients receiving Inlyta. Grade 4 proteinuria was reported in 0.1% of patients receiving Inlyta.
Monitoring for proteinuria before initiation of, and periodically throughout, treatment with Inlyta is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt Inlyta treatment (see Section 4.2 Dose and Method of Administration). Inlyta should be discontinued if the patient develops nephrotic syndrome.

Elevation of liver enzymes.

In a clinical dose finding study, concurrent elevations of alanine aminotransferase (ALT) (12 times the upper limit of normal [ULN]) and bilirubin (2.3 times the ULN), considered to be drug related hepatotoxicity, were observed in 1 patient who received Inlyta at a starting dose of 20 mg twice daily (4 times the recommended starting dose). In a controlled clinical study with Inlyta for the treatment of patients with RCC, no concurrent elevations of ALT (> 3 times the ULN) and bilirubin (> 2 times the ULN) were observed for Inlyta (N = 359) or sorafenib (N = 355).
Monitor liver function tests before initiation of, and periodically throughout, treatment with Inlyta.

Lactose.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Use in hepatic impairment.

In clinical studies with Inlyta, the systemic exposure to Inlyta was approximately 2-fold higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering Inlyta to patients with moderate hepatic impairment (Child-Pugh class B) (see Section 5.2 Pharmacokinetic Properties).
Inlyta has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Use in renal impairment.

A dedicated renal impairment trial for axitinib has not been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with mild to severe renal impairment (creatinine clearance [CrCL] from 15 to 89 mL/min). No dose adjustment is needed for patients with mild to severe renal impairment. Caution should be used in patients with end stage renal disease (CrCL < 15 mL/min).

Use in the elderly.

In a controlled clinical study with Inlyta for the treatment of patients with RCC, 34.3% of patients treated with Inlyta were ≥ 65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of Inlyta between patients who were ≥ 65 years of age and younger.
No dosage adjustment is required in elderly patients (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Inlyta in children and adolescents (< 18 years) have not been studied. Physeal dysplasia was observed in immature mice and dogs given axitinib at doses ≥ 30 mg/kg/day for at least 1 month (approximately 6 times the AUC at the recommended starting dose in humans); the incidence and severity were dose related and the effects were reversible when treatment stopped. Dental caries were observed in mice treated for more than 1 month at axitinib doses ≥ 10 mg/kg/day (approximately 2 times the AUC at the recommended starting dose in humans); residual findings, indicative of partial reversibility, were observed when treatment stopped. For physeal dysplasia, no effect levels of 10 mg/kg/day in mice (approximately 1.4 times the AUC at the recommended starting dose in humans) and 10 mg/kg/day in dogs were determined in animals given axitinib for 1 month. A no effect level was not defined for caries of the incisors in mice. Other toxicities of potential concern to paediatric patients have not been evaluated in juvenile animals.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1.

CYP3A4/5 inhibitors.

Ketoconazole, a strong inhibitor of CYP3A4/5, administered at a dose of 400 mg once daily for 7 days, increased the mean AUC 2-fold and C_max 1.5-fold of a single 5 mg oral dose of Inlyta in healthy volunteers.
Coadministration of Inlyta with strong CYP3A4/5 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) may increase axitinib plasma concentrations. Grapefruit may also increase axitinib plasma concentrations.
Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, a dose adjustment of Inlyta is recommended (see Section 4.2 Dose and Method of Administration).

CYP3A4/5 inducers.

Rifampin, a strong inducer of CYP3A4/5, administered at a dose of 600 mg once daily for 9 days, reduced the mean AUC by 79% and C_max by 71% of a single 5 mg dose of Inlyta in healthy volunteers.
Coadministration of Inlyta with strong CYP3A4/5 inducers (e.g. rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and Hypericum perforatum [also known as St. John's wort]) may decrease axitinib plasma concentrations.
Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended. If a strong CYP3A4/5 inducer must be coadministered, a dose adjustment of Inlyta is recommended (see Section 4.2 Dose and Method of Administration).

In vitro studies of CYP and UGT inhibition and induction.

In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations.
In vitro studies indicated that axitinib has a potential to inhibit CYP1A2. Therefore, coadministration of Inlyta with CYP1A2 substrates may result in increased plasma concentrations of CYP1A2 substrates (e.g. theophylline).
In vitro studies also indicated that axitinib has the potential to inhibit CYP2C8. However, coadministration of Inlyta with paclitaxel, a known CYP2C8 substrate, did not result in increased plasma concentrations of paclitaxel in patients with advanced cancer, indicating lack of clinical CYP2C8 inhibition.
In vitro studies in human hepatocytes also indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5. Therefore coadministration of Inlyta is not expected to reduce the plasma concentration of coadministered CYP1A1, CYP1A2, or CYP3A4/5 substrates in vivo.

In vitro studies with P-glycoprotein.

In vitro studies indicated that axitinib inhibits P-glycoprotein. However, axitinib is not expected to inhibit P-glycoprotein at therapeutic plasma concentrations. Therefore, coadministration of Inlyta is not expected to increase the plasma concentration of digoxin, or other P-glycoprotein substrates, in vivo.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Inlyta has the potential to impair reproductive function and fertility in humans. Findings in the male reproductive tract were observed in the testes/ epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms) in mice and dogs. Axitinib did not affect mating or fertility in male mice at any dose tested up to 100 mg/kg/day. However, reduced testicular weights, sperm density and/or count were noted at ≥ 10 mg/kg/day (approximately 4 times the AUC at the recommended starting dose in humans) following at least 70 days of treatment with axitinib. Male reproductive toxicity was evident in the dog at ≥ 3 mg/kg/day, 0.2 times the AUC at the recommended starting dose in humans.
Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy. In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥ 30 mg/kg/day) following at least 15 days of treatment with axitinib (approximately 11 times the AUC at the recommended starting dose in humans). Female reproductive toxicity in the dog was observed at ≥ 10 mg/kg/day.
(Category D)
There are no studies in pregnant women using Inlyta. As angiogenesis is a critical component of embryonic and fetal development, Inlyta may cause fetal harm if administered to a pregnant woman. Axitinib has been shown to be embryotoxic and teratogenic when administered to mice and rabbits at exposures similar to or below clinical exposure.
An increase in postimplantation loss and reduced embryonic survival was observed in female mice exposed to axitinib (30 mg/kg/day, or 11 times the AUC at the recommended starting dose in humans) prior to mating and through the first week of pregnancy. Pregnant mice exposed to axitinib showed an increased occurrence of cleft palate at an oral dose level of 3 mg/kg/day (approximately half the AUC at the recommended starting dose in humans) and common variations in skeletal ossification at ≥ 1 mg/kg/day (approximately 0.15 times the AUC at the recommended starting dose in humans). Limited investigations in rabbits showed high embryo and fetal loss at exposures considerably lower than the recommended clinical dose.
Inlyta should not be used during pregnancy. Women of childbearing potential must be advised to avoid becoming pregnant while receiving treatment with Inlyta. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Adequate contraception should be used during therapy and for at least 4 weeks after completion of therapy.
No studies have been conducted in humans to assess the effect of axitinib on milk production, its presence in breast milk, or its effects of the breastfed child. It is unknown whether axitinib is excreted in human milk. Since many drugs are commonly excreted in human milk, and because of the potential for serious adverse reactions in nursing infants due to exposure to axitinib, women should discontinue breastfeeding during treatment with axitinib.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effect of Inlyta on the ability to drive and use machines have been performed. Patients should be advised that they may experience events such as dizziness and/or fatigue during treatment with Inlyta.

4.8 Adverse Effects (Undesirable Effects)

The safety of Inlyta has been evaluated in 672 patients with advanced RCC who participated in the pivotal randomised clinical study or four additional monotherapy studies with Inlyta.
In the pivotal study the median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received Inlyta and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse event occurred in 55.4% of patients receiving Inlyta and 61.9% of patients receiving sorafenib. Permanent discontinuation due to an adverse event occurred in 9.2% of patients receiving Inlyta and 13.0% of patients receiving sorafenib.
In another phase 3 study, the median duration of treatment was 9.2 months (range 0.1 to 23.7) for patients who received Inlyta and 7.0 months (range 0.03 to 22.0) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse event occurred in 52.6% of patients receiving Inlyta and 37.7% of patients receiving sorafenib. Permanent discontinuation due to an adverse event occurred in 16.3% of patients receiving Inlyta and 10.1% of patients receiving sorafenib.
The most common (≥ 20%) adverse reactions observed following treatment with Inlyta were diarrhoea, hypertension, fatigue, decreased appetite, nausea, dysphonia, weight decreased, palmar-plantar erythrodysaesthesia (hand-foot syndrome), haemorrhage, hypothyroidism, vomiting, proteinuria, cough, and constipation. Severe (grade ≥ 3) diarrhoea, hypertension and fatigue were very common (> 10%).
The following risks, including appropriate action to be taken, are discussed in greater detail (see Section 4.4 Special Warnings and Precautions for Use): cardiac failure events, hypertension, thyroid dysfunction, arterial thromboembolic events, venous thromboembolic events, elevation of haemoglobin or haematocrit, haemorrhage, gastrointestinal perforation and fistula formation, wound healing complications, reversible posterior leukoencephalopathy syndrome, proteinuria, and elevation of liver enzymes.
Table 1 presents adverse reactions reported in patients who received Inlyta. The adverse reactions are listed by system organ class, frequency category and grade of severity. Frequency categories 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), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Postmarketing experience.

The following adverse reactions have been identified during postapproval use of axitinib.

Cardiac disorders.

Cases of cardiac failure events have been reported.

Gastrointestinal disorders.

Cases of glossodynia have been reported.

Vascular disorders.

Cases of aneurysms and artery dissections, sometimes fatal, have been reported.

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

There is no specific treatment for Inlyta overdose. For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
In a controlled clinical study with Inlyta for the treatment of patients with RCC, one patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (grade 1).
In a clinical dose finding study with Inlyta, patients who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal haemoptysis.
In cases of suspected overdose, Inlyta should be withheld and supportive care instituted.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. These receptors are implicated in pathological angiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown to inhibit VEGF mediated endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumour vasculature that expressed the target in vivo and produced tumour growth delay, regression, and inhibition of metastases in many experimental models of cancer.

Pharmacodynamics.

In a randomized, 2 way crossover study, 35 healthy subjects were administered a single oral dose of Inlyta (5 mg) in the absence and presence of 400 mg ketoconazole for 7 days. Results of this study indicated that Inlyta plasma exposures up to 2-fold greater than the therapeutic levels expected following a 5 mg dose did not produce clinically significant QT interval prolongation.

Clinical trials.

The safety and efficacy of Inlyta were evaluated in a randomized, open label, multicenter phase 3 study. Patients (N = 723) with advanced renal cell carcinoma (RCC) whose disease had progressed on or after treatment with one prior systemic therapy, including sunitinib, bevacizumab, temsirolimus, or cytokine containing regimens were randomized (1:1) to receive Inlyta (n = 361) or sorafenib (n = 362). The primary endpoint, progression free survival (PFS), was assessed using a blinded independent central review. Secondary endpoints included objective response rate (ORR) and overall survival (OS).
Of the patients enrolled in this study, 389 patients (53.8%) had received one prior sunitinib based therapy, 251 patients (34.7%) had received one prior cytokine based therapy (interleukin-2 or interferon-alpha), 59 patients (8.2%) had received one prior bevacizumab based therapy, and 24 patients (3.3%) had received one prior temsirolimus based therapy. The baseline demographic and disease characteristics were similar between the Inlyta and sorafenib groups with regard to age, gender, race, Eastern Cooperative Oncology Group (ECOG) performance status, geographic region, and prior treatment.
There was a statistically significant advantage for Inlyta over sorafenib for the primary endpoint of PFS (see Table 2 and Figure 1). There was no statistically significant difference between the arms in OS.

5.2 Pharmacokinetic Properties

Absorption and distribution.

After oral administration of Inlyta tablets, the mean absolute bioavailability is 58% compared to intravenous administration. The plasma half-life of Inlyta ranges from 2.5 to 6.1 hours. Dosing of Inlyta at 5 mg twice daily resulted in < 2-fold accumulation compared to administration of a single dose. Based on the short half-life of axitinib, steady state is expected within 2 to 3 days of the initial dose.
Peak axitinib concentrations in plasma are generally reached within 4 hours following oral administration of Inlyta with the median T_max ranging from 2.5 to 4.1 hours. Administration of Inlyta with a moderate fat meal resulted in 10% lower exposure compared to overnight fasting. A high fat, high calorie meal resulted in 19% higher exposure compared to overnight fasting. Inlyta may be administered with or without food (see Section 4.2 Dose and Method of Administration).
The average C_max and area under the curve (AUC) increased proportionally over an Inlyta dosing range of 5 to 10 mg. In vitro binding of axitinib to human plasma proteins is > 99% with preferential binding to albumin and moderate binding to α₁-acid glycoprotein. At the 5 mg twice daily dose in the fed state, the geometric mean peak plasma concentration and 24 hour AUC were 27.8 nanogram/mL and 265 nanogram.h/mL, respectively in patients with advanced RCC. The geometric mean oral clearance and apparent volume of distribution were 38 L/h and 160 L, respectively.

Metabolism and elimination.

Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Following oral administration of a 5 mg radioactive dose of axitinib, 30-60% of the radioactivity was recovered in faeces and 23% of the radioactivity was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in faeces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine. In plasma, the N-glucuronide metabolite represented the predominant radioactive component (50% of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite each accounted for approximately 20% of the circulating radioactivity.
The sulfoxide and N-glucuronide metabolites show approximately 400-fold and 8000-fold less in vitro potency, respectively, against VEGFR-2 compared to axitinib.

Special populations.

Gender, ethnicity, elderly (> 65 years) patients.

Population pharmacokinetic analyses in patients with advanced cancer (including advanced RCC) and healthy volunteers indicate that there are no clinically relevant effects of age, gender, body weight, race, renal function, UGT1A1 genotype, or CYP2C19 genotype.

Children and adolescents.

Inlyta has not been studied in patients < 18 years of age.

Renal impairment.

Unchanged axitinib is not detected in the urine. Inlyta has not been studied in subjects with renal impairment. In clinical studies with Inlyta for the treatment of patients with RCC, patients with serum creatinine > 1.5 times the upper limit of normal (ULN) or calculated creatinine clearance < 60 mL/min were excluded. Population pharmacokinetic analyses have shown that axitinib clearance was not altered in subjects with renal impairment and no dose adjustment of Inlyta is recommended.

Hepatic impairment.

In vitro and in vivo data indicate that axitinib is primarily metabolized by the liver. Compared to subjects with normal hepatic function, systemic exposure following a single dose of Inlyta was similar to subjects with mild hepatic impairment (Child-Pugh class A) and higher (approximately 2-fold) in subjects with moderate hepatic impairment (Child-Pugh class B). Inlyta has not been studied in subjects with severe hepatic impairment (Child-Pugh class C) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Axitinib was tested using a series of genetic toxicology assays consisting of in vitro bacterial reverse mutation (Ames), human lymphocyte chromosome aberration, and in vivo mouse bone marrow micronucleus assays. Axitinib was not mutagenic in these assays, but induced polyploidy in human lymphocytes in vitro, and was aneugenic in the micronucleus assay at exposure levels approximately 154 times the recommended starting dose in humans.

Carcinogenicity.

Carcinogenicity studies have not been performed with axitinib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and Opadry II red 32K15441 film coating.
The Opadry II red 32K15441 film coating contains lactose monohydrate, HPMC 2910/ hypromellose 15cP, titanium dioxide, triacetin, and iron oxide red.

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 30°C.