Consumer medicine information

Adenuric

Febuxostat

BRAND INFORMATION

Brand name

Adenuric

Active ingredient

Febuxostat

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Adenuric.

What is in this leaflet

This leaflet answers some common questions about ADENURIC.

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 risk of you taking ADENURIC against the benefits they expect it will 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 ADENURIC is used for

ADENURIC is used in the treatment of long-standing high uric acid levels in the blood.

High levels of uric acid in the blood lead to development of crystals which deposit in the joints causing pain, swelling and tenderness. This is known as a condition called gout.

ADENURIC contains the active ingredient febuxostat.

It works by reducing the formation and accumulation of uric acid in the blood to reduce crystal formation. ADENURIC is used to prevent gout, but is not used to treat acute attacks of gout (also called flares).

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 not addictive.

It is available only with a doctor's prescription.

There is not enough information to recommend the use of this medicine for children under the age of 18 years.

Before you use ADENURIC

When you must not take it

Do not take ADENURIC if you have an allergy to:

  • any medicine containing febuxostat
  • any of the ingredients listed at the end of this leaflet

Some 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 if you are having an acute attack of gout and are not taking ADENURIC already. Your doctor will wait until the symptoms of the acute attack of gout have passed before starting you on ADENURIC.

If you have a gout flare while you are taking ADENURIC, do not stop taking this medicine.

Do not take this medicine if you are pregnant. It is not known whether it may affect your developing baby if you take it during pregnancy.

Do not breast-feed if you are taking this medicine. It is not known if the active ingredient in ADENURIC passes into breast milk and there is a possibility that your baby may be affected.

Do not give this medicine to a child under the age of 18 years. The safety and efficacy in children younger than 18 years old has not been established.

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 any allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • heart disease, heart failure, a heart attack or a stroke
  • kidney problems
  • allergic reaction to allopurinol (a medicine used to treat gout)
  • liver problems
  • high uric acid levels as a result of cancer or Lesch-Nyhan syndrome
  • thyroid problems
  • lactose intolerance
  • organ transplant.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking ADENURIC. Your doctor will consider your cardiovascular risk factors before prescribing ADENURIC.

Taking other medicines

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

Some medicines and ADENURIC may interfere with each other. These include:

  • mercaptopurine, a medicine used to treat cancer
  • azathioprine, a medicine used to treat certain immune system problems
  • theophylline, a medicine to treat asthma and other respiratory disorders
  • tacrolimus, a medicine used to suppress the immune system after an organ transplant
  • phenytoin, a medicine used to treat epilepsy.

These medicines may be affected by ADENURIC, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines.

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

Ask your doctor or pharmacist if you are not sure if you are taking any of these medicines.

How to take ADENURIC

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

How much to take

The usual dose is 40 mg or 80 mg once daily. A starting dose of 40mg (half a tablet) is recommended and if your blood uric acid remains high after 2 to 4 weeks, the dose may be increased to 80 mg (1 whole tablet) once daily.

Your doctor will tell you how much to take. This depends on your condition and whether or not you are taking any other medicine.

How to take it

40 mg Dose:

You will need to break a tablet in half.

To break the tablet, hold the tablet between your thumbs and index fingers close to the score line.

Then, with the score line facing you, apply enough pressure to snap the tablet apart. Alternatively, use a tablet or pill cutter available from pharmacies.

Swallow one half of the tablet with a full glass of water. Keep the other half of the tablet for your next dose.

80 mg Dose:

Take one whole tablet with a full glass of water.

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.

It does not matter if you take this medicine before or after food.

How long to take it

Continue taking your medicine 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.

If you forget to take it

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 that 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 take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre on 13 11 26 (Australia) 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 ADENURIC. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using ADENURIC

Things you must do

Stop taking ADENURIC immediately and contact your doctor or go to Accident and Emergency at your nearest hospital if you develop any of the following allergy symptoms. Sometimes a serious but rare allergic reaction may follow:

  • rash, including blisters and nodules
  • shedding of the skin and inner surfaces of body cavities, e.g. mouth and genitals, painful ulcers in the mouth and/or genital areas, accompanied by fever, sore throat and fatigue
  • enlarged lymph nodes
  • generalised skin rashes
  • itchiness
  • swelling of limbs and face
  • difficulties in breathing.

These may be the first signs of a serious allergic reaction to ADENURIC. You may need urgent medical attention.

Your doctor may decide to permanently stop treatment with ADENURIC.

Tell your doctor immediately if you have an acute gout attack and you are already taking ADENURIC. Your doctor may prescribe other medicines to treat the symptoms of flares.

Keep taking ADENURIC even if you have a flare. You may experience more flares and maybe worsening pain during the initial period of treatment. This is due to the way that ADENURIC and this class of medicines work. It is important that you continue to take ADENURIC and don’t stop during a gout flare. Over time, gout flares will occur less often and be less painful if you keep taking ADENURIC.

Tell your doctor if you develop any of the following symptoms while you are taking ADENURIC. They may be signs of liver problems:

  • yellowing of skin and eyes (jaundice)
  • dark urine
  • fatigue
  • loss in appetite
  • pain in the right upper abdomen.

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

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

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

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some blood tests from time to time to make sure the medicine is working.

Things you must not do

Do not take ADENURIC 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 or operating machinery until you know how ADENURIC affects you. This medicine may cause drowsiness, dizziness, pins and needles, and blurred vision in some people.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

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

This medicine helps most people with gout, but it may have unwanted side effects in a few people. 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.

Do not be alarmed by the following 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 or pharmacist if you notice any of the following and they worry you:

  • headache
  • nausea
  • diarrhoea
  • rash
  • increase in gout symptoms
  • localised swelling (oedema).

The above list includes the more common side effects of your medicine. They are usually mild.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • signs of heart problems such as chest pain, shortness of breath, trouble breathing, dizziness, fainting, feeling lightheaded, rapid or irregular heartbeat, numbness or weakness on one side of your body, slurring of speech, sudden blurry vision or sudden severe headache.
  • sudden signs of an allergic reaction such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • severe skin reaction, with painful red areas, large blisters and peeling of layers of skin
  • pinkish, itchy swellings on the skin
  • fever
  • muscle pain, tenderness or weakness

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

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people. Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

After using ADENURIC

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 away from light where the temperature stays below 30°C.

Do not store ADENURIC 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

ADENURIC tablets are available in one strength of 80 mg.

The tablets are pale-yellow to yellow in colour and rectangular in shape. The tablets are scored on one side and marked "80" on the other side.

ADENURIC tablets are available in blister packs of 4, 8 or 28 tablets.

Not all pack sizes may be available.

Ingredients

ADENURIC contains febuxostat as the active ingredient.

Other ingredients include:

  • lactose monohydrate
  • microcrystalline cellulose
  • magnesium stearate
  • hyprolose
  • croscarmellose sodium
  • silicon dioxide.

Core tablets are coated with Opadry II Yellow 85F42129 containing:

  • polyvinyl alcohol
  • titanium dioxide
  • macrogol 3350
  • purified talc
  • iron oxide yellow

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

Supplier

ADENURIC is supplied in Australia by:

A. Menarini Australia Pty Ltd
Level 8, 67 Albert Ave,
Chatswood, NSW, 2067

Medical Information: 1800 644 542

® = Registered Trademark

Australian Registration Number:

AUST R 205556

This leaflet was revised in December 2019

For the most up to date version of this leaflet, please go to www.menarini.com.au/cmi

[vD06-0]

Published by MIMS January 2020

BRAND INFORMATION

Brand name

Adenuric

Active ingredient

Febuxostat

Schedule

S4

 

1 Name of Medicine

Febuxostat.

2 Qualitative and Quantitative Composition

Each tablet contains 80 mg of febuxostat.

Excipients with known effect.

Contains lactose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Adenuric 80 mg tablets are pale yellow to yellow, film-coated, rectangular shaped tablets, with a break line on one side and "80" engraved on the other side. They are immediate-release tablets containing 80 mg of febuxostat as the active substance.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of chronic symptomatic hyperuricaemia in conditions where urate deposition has already occurred (gouty arthritis and/or tophus formation) in adults with gout.

4.2 Dose and Method of Administration

The recommended oral dose of Adenuric is 40 mg or 80 mg once daily with or without food. The recommended starting dose of Adenuric is 40 mg once daily. If serum uric acid (sUA) is greater than 357 micromole/L (6 mg/dL) after 2-4 weeks, Adenuric 80 mg once daily is recommended. The 80 mg tablet can be split into two equal halves in order to provide a 40 mg dose. Prescribers should advise patients on how to break the tablets in half.
Testing for the target serum uric acid level of less than 357 micromole/L (6 mg/dL) may be performed as early as two weeks after initiating Adenuric therapy.
Gout flare prophylaxis of up to 6 months is recommended (see Section 4.4 Special Warnings and Precautions for Use, Acute gouty attacks (gout flares)).

Elderly.

No dose adjustment is required in the elderly.

Renal impairment.

No dosage adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30 to 89 mL/min, stages 2-3 CKD).
Caution should be exercised in patients with severe renal impairment (creatinine clearance < 30 mL/min, stage 4 CKD, see Section 5.2 Pharmacokinetic Properties). The efficacy and safety has not been fully evaluated in these patients (see Section 4.4 Special Warnings and Precautions for Use).
The maximum recommended dose of Adenuric in patients with severe renal impairment is 40 mg once daily.

Hepatic impairment.

The efficacy and safety of febuxostat has not been studied in patients with severe hepatic impairment (Child Pugh class C). Caution should be exercised in these patients (see Section 4.4 Special Warnings and Precautions for Use).
Limited information is available in patients with moderate hepatic impairment. No dosage adjustment is necessary in patients with mild hepatic impairment.

4.3 Contraindications

Hypersensitivity to febuxostat or to any other ingredients in the product.

4.4 Special Warnings and Precautions for Use

Cardiovascular disorders.

Treatment with febuxostat in patients with pre-existing major cardiovascular (CV) disease (e.g. myocardial infarction, stroke or unstable angina) is not recommended.
A numerical greater incidence of investigator reported cardiovascular APTC events (defined endpoints from the Anti-Platelet Trialists' Collaboration (APTC) including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) was observed in the febuxostat total group compared to the allopurinol group in the APEX and FACT studies (1.3 vs. 0.3 events per 100 patient years (PYs)), but not in the CONFIRMS study (see Section 5.1 Pharmacodynamic Properties, Clinical trials for detailed characteristics of the studies). The incidence of investigator reported cardiovascular APTC events in the combined phase 3 studies (APEX, FACT and CONFIRMS studies) was 0.7 vs. 0.6 events per 100 PYs. In the long-term extension studies the incidences of investigator reported APTC events were 1.2 and 0.6 events per 100 PYs for febuxostat and allopurinol, respectively. No statistically significant differences were found and no causal relationship with febuxostat was established. Identified risk factors among these patients were a medical history of atherosclerotic disease and/or myocardial infarction, or of congestive heart failure.
In a post-marketing CV outcome study (CARES study) (see Section 5.1 Pharmacodynamic Properties, Clinical trials), the rate of major adverse cardiovascular events (MACE) in patients with gout and a history of major CV disease including MI, hospitalisation for unstable angina, coronary or cerebral revascularisation procedure, stroke, hospitalised transient ischaemic attack, peripheral vascular disease, or diabetes mellitus with evidence of microvascular or macrovascular disease was similar in febuxostat versus allopurinol treated patients (hazard ratio [HR] 1.03; two-sided repeated 95% confidence interval [CI] 0.89-1.21), but a statistically significantly higher rate of CV deaths was observed with febuxostat (134 [1.5 per 100 patient years]) compared to patients treated with allopurinol (100 [1.1 per 100 patient years]) (HR 1.34; 95% CI 1.03-1.73). Sudden cardiac death was the most common cause of adjudicated CV death in the febuxostat group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%) (see Table 1).
Prescribers should consider patients' cardiovascular risk factors before initiating febuxostat. Prescribers should monitor for and counsel patients on the signs and symptoms of MI, stroke and cardiac failure.

Medicinal product allergy/ hypersensitivity.

Rare reports of serious allergic/hypersensitivity reactions, including life threatening Stevens-Johnson syndrome, toxic epidermal necrolysis and acute anaphylactic reaction/shock, have been collected in the postmarketing experience. In most cases, these reactions occurred during the first month of therapy with febuxostat. Some, but not all of these patients reported renal impairment and/or previous hypersensitivity to allopurinol. Severe hypersensitivity, including drug reaction with eosinophilia and systemic symptoms (DRESS) reactions were associated with fever, haematological, renal or hepatic involvement in some cases.
Patients should be advised of the signs and symptoms and monitored closely for symptoms of allergic/hypersensitivity reactions (see Section 4.8 Adverse Effects (Undesirable Effects)). Febuxostat treatment should be immediately stopped if serious allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, occur since early withdrawal is associated with a better prognosis. If a patient has developed allergic/hypersensitivity reactions including Stevens-Johnson syndrome and acute anaphylactic reaction/shock, febuxostat must not be re-started in this patient at any time.

Acute gouty attacks (gout flares).

Febuxostat treatment should not be started until an acute attack of gout has completely subsided. After initiation of febuxostat, an increase in gout flares is frequently observed. This increase is due to changing serum uric acid levels resulting in mobilisation of urate from tissue deposits. In order to prevent gout flares when febuxostat is initiated, concurrent prophylaxis for up to 6 months with an NSAID or colchicine is recommended.
If a gout flare occurs during febuxostat treatment, it should not be discontinued. The gout flare should be managed concurrently as appropriate for the individual patient. Continuous treatment with febuxostat decreases frequency and intensity of gout flares.

Populations with markedly increased urate production.

In patients in whom the rate of urate formation is greatly increased (e.g. malignant disease and its treatment, Lesch-Nyhan syndrome) the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. As there has been no experience with febuxostat, its use in these populations is not recommended.

Mercaptopurine/azathioprine.

Febuxostat use is not recommended in patients concomitantly treated with mercaptopurine/azathioprine as inhibition of xanthine oxidase (XO) by febuxostat may cause substantially increased plasma concentrations of mercaptopurine/azathioprine leading to severe toxicity. No interaction studies have been performed in humans. Where the combination cannot be avoided patients should be closely monitored. A reduction of the dose of mercaptopurine/azathioprine is recommended in order to reduce the risk of possible haematological effects. Data are insufficient to support a specific dose reduction of mercaptopurine/azathioprine when used concomitantly with febuxostat (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Pharmacokinetic modelling and simulation of rat data suggests that concomitant administration of oral mercaptopurine/azathioprine and febuxostat results in a ~80% decrease in the predicted population clearance, which corresponds to a ~500% increase in mercaptopurine/azathioprine AUC in humans (see Section 5.3 Preclinical Safety Data).

Organ transplant recipients.

As there has been no experience in organ transplant recipients, the use of febuxostat in such patients is not recommended.

Theophylline.

No dose adjustment is necessary for theophylline when coadministered with febuxostat. Co-administration of febuxostat 80 mg and theophylline in healthy participants showed no statistically significant interaction (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). However, the study also showed an approximately 400-fold increase in the amount of 1-methylxanthine (one of the major theophylline metabolites) excreted in urine as a result of XO inhibition by febuxostat. The safety of long-term exposure to 1-methylxanthine has not been evaluated. This should be taken into consideration when deciding to coadminister febuxostat and theophylline.

Liver disorders.

During the combined phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (see Table 5). Liver function tests are recommended prior to the initiation of therapy with febuxostat and periodically thereafter based on clinical judgement.
There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking Adenuric, although the reports contain insufficient information necessary to establish the probable cause. During randomised controlled studies, transaminase elevations greater than three times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in Adenuric and allopurinol treated patients, respectively).
Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), Adenuric treatment should be interrupted and an investigation done to establish the probable cause. Adenuric should not be restarted in these patients without another explanation for the liver test abnormalities.
Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative aetiologies are at risk for severe drug induced liver injury and should not be restarted on Adenuric. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Adenuric can be used with caution.

Thyroid disorders.

Increased TSH values (> 5.5 microIU/mL) were observed in patients on long-term treatment with febuxostat (5.5%) in the long-term open label extension studies. Caution is required when febuxostat is used in patients with alteration of thyroid function.

Lactose.

Febuxostat tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Identified precautions.

Use in Asian populations.

About 3% of patients enrolled in phase 3 studies were of Asian ethnicity. Although the clinical experience is limited, the overall incidence rates of treatment emergent adverse events were not significantly different between races within each of the treatment groups. There have been postmarketing reports of serious skin/hypersensitivity reactions in some Asian populations.

Use in hepatic impairment.

No studies have been conducted in patients with severe hepatic impairment (Child Pugh class C); therefore caution should be exercised in these patients.

Use in renal impairment.

Adenuric should be used with caution in patients with severe renal impairment (Clcr less than 30 mL/min, stage 4 CKD) as its efficacy and safety has not been fully evaluated in these patients (see Section 5.2 Pharmacokinetic Properties). There are no data in end-stage renal impairment patients who are on dialysis.
The recommended maximum dose of Adenuric in patients with severe renal impairment is 40 mg once daily (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

No dose adjustment is required in the elderly. Of the total number of participants in clinical studies of Adenuric, 16% were 65 and over, while 4% were 75 and over. Comparing subjects in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of Adenuric in geriatric subjects (≥ 65 years) were similar to those in younger subjects (18 to 40 years) (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Adenuric in children aged below the age of 18 years have not been established. No data are available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Mercaptopurine/azathioprine.

On the basis of the mechanism of action of febuxostat on xanthine oxidase (XO) inhibition, concomitant use is not recommended. Inhibition of XO by febuxostat may cause substantially increased plasma concentrations of these drugs leading to severe toxicity (see Section 4.4 Special Warnings and Precautions for Use).
Drug interaction studies of febuxostat with drugs that are metabolised by XO (except theophylline) have not been performed in humans. A reduction of the dose of mercaptopurine/azathioprine is recommended in order to reduce the risk of possible haematological effects (see Section 4.4 Special Warnings and Precautions for Use). Data are insufficient to support a specific dose reduction of mercaptopurine/azathioprine when used concomitantly with febuxostat.
Pharmacokinetic modelling and simulation of rat data suggests that concomitant administration of oral mercaptopurine/azathioprine and febuxostat results in a ~80% decrease in the predicted population clearance, which corresponds to a ~500% increase in mercaptopurine/azathioprine AUC in humans (see Section 5.3 Preclinical Safety Data).
Drug interaction studies of febuxostat with cytotoxic chemotherapeutic agents (other than azathioprine in a preclinical study) have not been conducted. No data in humans are available regarding the safety of febuxostat during cytotoxic therapy.

Rosiglitazone/CYP2C8 substrates.

Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. In a study in healthy subjects, coadministration of 120 mg febuxostat daily with a single 4 mg oral dose of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating that febuxostat is not a CYP2C8 enzyme inhibitor in vivo. Thus, coadministration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for those compounds.

Theophylline.

No dose adjustment is necessary for theophylline when coadministered with febuxostat. Administration of febuxostat (80 mg once daily) with theophylline resulted in an increase of 6% in Cmax and 6.5% in AUC of theophylline. These changes were not considered statistically significant. However, the study also showed an approximately 400-fold increase in the amount of 1-methylxanthine (one of the major theophylline metabolites) excreted in urine as a result of XO inhibition by febuxostat. The safety of long-term exposure to 1-methylxanthine has not been evaluated. This should be taken into consideration when deciding to coadminister febuxostat and theophylline.

Naproxen and other inhibitors of glucuronidation.

Febuxostat metabolism depends on uridine glucuronosyl transferase (UGT) enzymes. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. In healthy subjects concomitant use of febuxostat and naproxen 250 mg twice daily was associated with an increase in febuxostat exposure (Cmax 28%, AUC 41% and t1/2 26%). In clinical studies the use of naproxen or other NSAIDs/COX-2 inhibitors was not related to any clinically significant increase in adverse events.
Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxen being necessary.

Inducers of glucuronidation.

Potent inducers of UGT enzymes such as phenytoin might possibly lead to increased metabolism and decreased efficacy of febuxostat. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. Conversely, cessation of treatment of an inducer might lead to increased plasma levels of febuxostat.

Colchicine/ indomethacin/ hydrochlorothiazide/ warfarin.

Febuxostat can be coadministered with colchicine or indomethacin with no dose adjustment of febuxostat or the coadministered active substance being necessary.
No dose adjustment is necessary for febuxostat when administered with hydrochlorothiazide.
No dose adjustment is necessary for warfarin when administered with febuxostat. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and factor VII activity were also not affected by the coadministration of febuxostat.

Desipramine/CYP2D6 substrates.

Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. In a study in healthy subjects, 120 mg Adenuric daily resulted in a mean 22% increase in AUC of desipramine, a CYP2D6 substrate indicating a potential weak inhibitory effect of febuxostat on the CYP2D6 enzyme in vivo. Thus, coadministration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds.

Antacids.

Concomitant ingestion of an antacid containing magnesium hydroxide and aluminium hydroxide has been shown to delay absorption of febuxostat (approximately 1 hour) and to cause a 32% decrease in Cmax, but no significant change in AUC was observed. Therefore, febuxostat may be taken without regard to antacid use.

Tacrolimus.

Attention should be paid when introducing febuxostat in patients taking tacrolimus: although no specific interaction study between tacrolimus and febuxostat has been performed, a documented increase in tacrolimus plasma levels has been reported after febuxostat administration in some postmarketing cases concerning renal transplanted patients.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In rats, reproduction studies up to 48 mg/kg/day (20 to 25 times human exposure at the maximum recommended human dose [MRHD] based on AUC) showed no dose dependent adverse effects on male or female fertility. The effect of Adenuric on human fertility is unknown.
(Category B1)
Data on a very limited number of exposed pregnancies have not indicated any adverse effects of febuxostat on pregnancy or on the health of the foetus/newborn child. Studies in rats and rabbits found no evidence of foetal abnormalities at doses up to 48 mg/kg/day (25 to 33 times the clinical exposure at the MRHD based on AUC), consistent with the minimal placental transfer of febuxostat found in pharmacokinetic studies. As the potential risk of foetal harm in humans is unknown, febuxostat is not recommended for use during pregnancy.
It is unknown whether febuxostat is excreted in human breast milk. Febuxostat is readily excreted in breast milk in rats (milk:plasma ratio of 7.9 at 4 h postmaternal dose). Rats exposed to febuxostat during the lactation period at 48 mg/kg/day (25 times the clinical exposure at the MRHD based on AUC) showed maternal toxicity accompanied by a reduction in weaning index and reduced development of offspring. At the no-observed-adverse-effect-level [NOAEL] for maternal and pup developmental effects of 3 mg/kg/day the AUC based relative exposure was similar to that anticipated clinically at the maximum daily dose. A risk to a breastfeeding infant cannot be excluded. Febuxostat should not be used while breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

Somnolence, dizziness, paraesthesia and blurred vision have been reported with the use of febuxostat. Patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that Adenuric does not adversely affect performance.

4.8 Adverse Effects (Undesirable Effects)

A total of 2757 subjects with hyperuricaemia and gout were treated with febuxostat 40 mg or 80 mg daily in clinical studies. For febuxostat 40 mg, 559 patients were treated for ≥ 6 months. For febuxostat 80 mg, 1377 subjects were treated for ≥ 6 months, 674 patients were treated for ≥ 1 year and 515 patients were treated for ≥ 2 years.
The most commonly reported adverse reactions in clinical trials (4,072 subjects treated at least with a dose from 10 mg to 300 mg), post-authorisation safety studies (FAST study) and post-marketing experience are gout flares, liver function abnormalities, diarrhoea, nausea, headache, dizziness, dyspnoea, rash, pruritus, arthralgia, myalgia, pain in extremity, oedema and fatigue. These adverse reactions were mostly mild or moderate in severity. Rare serious hypersensitivity reactions to febuxostat, some of which were associated to systemic symptoms and rare events of sudden cardiac death, have occurred in the post-marketing experience.
Table 2 summarises the adverse events from the three placebo controlled clinical trials that occurred with a frequency of ≥ 1% in the febuxostat, placebo and allopurinol groups.
The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of febuxostat 40 mg, 1.2% of febuxostat 80 mg and in 0.9% of allopurinol treated subjects.

Tabulated list of adverse reactions.

Common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100) and rare (≥ 1/10,000 to < 1/1000) adverse reactions occurring in patients treated with febuxostat are listed in Table 3 and Table 4.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Post-marketing experience.

See Table 4.

Description of selected adverse reactions.

Rare serious hypersensitivity reactions to febuxostat, including Stevens-Johnson syndrome, toxic epidermal necrolysis and anaphylactic reaction/shock, have occurred in the postmarketing experience. Stevens-Johnson syndrome and toxic epidermal necrolysis are characterised by progressive skin rashes associated with blisters or mucosal lesions and eye irritation. Hypersensitivity reactions to febuxostat can be associated with the following symptoms: skin reactions characterised by infiltrated maculopapular eruption, generalised or exfoliative rashes, but also skin lesions, facial oedema, fever, haematologic abnormalities such as thrombocytopenia and eosinophilia, and single or multiple organ involvement (liver and kidney including tubulointerstitial nephritis).
Gout flares were commonly observed soon after the start of treatment and during the first months. Thereafter, the frequency of gout flare decreases in a time dependent manner. Gout flare prophylaxis is recommended.

Cardiovascular safety.

Cardiovascular events and deaths were adjudicated to one of the predefined endpoints from the Anti-Platelet Trialists' Collaborations (APTC) (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in the randomised, controlled and long-term extension studies. In the phase 3 randomised, controlled studies, the incidences of adjudicated APTC events per 100 patient years of exposure were: placebo 0 (95% CI 0.00-6.16), febuxostat 40 mg 0 (95% CI 0.00-1.08), febuxostat 80 mg 1.09 (95% CI 0.44-2.24) and allopurinol 0.60 (95% CI 0.16-1.53).
In the long-term extension studies, the incidence of adjudicated APTC events were: febuxostat 80 mg 0.97 (95% CI 0.57-1.56) and allopurinol 0.58 (95% CI 0.02-3.24).
Overall, a higher rate of APTC events was observed in febuxostat than in allopurinol treated patients. A causal relationship with febuxostat has not been established. Monitor for signs and symptoms of myocardial infarction and stroke (see Section 4.4 Special Warnings and Precautions for Use).

Abnormal haematologic and clinical chemistry findings.

During the 3 randomised controlled studies, transaminase elevations greater than 3 times the upper limit of normal were observed. The clinically important abnormalities in liver function tests reported in the controlled studies are shown in Table 5.

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.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia). Patients with an overdose should be managed by symptomatic and supportive care.

5 Pharmacological Properties

Febuxostat belongs to the pharmacotherapeutic group: Antigout preparation, preparations inhibiting uric acid production (ATC code: M04AA03).

5.1 Pharmacodynamic Properties

Mechanism of action.

Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine → xanthine → uric acid. Both steps in the above transformations are catalysed by xanthine oxidase (XO). Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO. Febuxostat is a nonpurine selective inhibitor of XO which inhibits human xanthine oxidase under in vitro conditions with a dissociation constant (Ki) of 10 nanoM. Febuxostat has been shown to inhibit both the oxidised and reduced forms of XO. At therapeutic concentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, namely, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase.

Effect on QTc interval.

The effect of febuxostat on cardiac repolarisation as assessed by the QTc interval was evaluated in normal healthy participants and in patients with gout. Adenuric in doses up to 300 mg daily, at steady-state, did not demonstrate an effect on the QTc interval.

Clinical trials.

The efficacy of Adenuric was demonstrated in one phase 2 clinical trial (TMX-00-004) and subsequently confirmed in three phase 3 pivotal studies (APEX, FACT and CONFIRMS studies). Studies were conducted in 4101 patients with hyperuricaemia and gout. Hyperuricaemia was defined as a baseline serum uric acid level (sUA) ≥ 476 micromole/L (8 mg/dL).
Subjects who completed the APEX and FACT studies were eligible to enrol in the EXCEL trial, a long-term extension study in which patients received treatment with Adenuric for a 3-year period.

TMX-00-004 and FOCUS (TMX-01-005) studies.

The efficacy of Adenuric was evaluated in a four week dose ranging study which randomised patients to: placebo, febuxostat 40 mg daily, 80 mg daily, or 120 mg daily. At the end of treatment (day 28), the proportion of participants who achieved sUA < 357 micromole/L (6 mg/dL) was 0%, 56% and 76% in the placebo, febuxostat 40 mg and 80 mg groups, respectively.
Subjects who completed this study were eligible to enrol in the FOCUS study (TMX-01-005), a long-term extension study in which subjects received treatment with Adenuric for up to five years. The proportion of patients with sUA of < 357 micromole/L (6.0 mg/dL) at the final visit was greater than 80% (81-100%) at each febuxostat dose.

CONFIRMS, APEX and FACT studies.

The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients whose last 3 monthly serum uric acid levels were < 357 micromole/L (6.0 mg/dL). In the phase 3 CONFIRMS study, the primary efficacy endpoint was the proportion of patients whose serum urate level was < 357 micromole/L (6.0 mg/dL) at the final visit. No patients with organ transplant have been included in these studies. Patients were excluded if they had secondary hyperuricaemia, history of excessive alcohol intake, malignancy within the last 5 years, severe renal or hepatic impairment, active peptic ulcer disease, history of myocardial infarction or stroke, paediatric patients, pregnant and nursing women. Noninferiority of febuxostat to the active control allopurinol specified a 10 percentage point margin (the lower limit of the confidence interval for the difference) of noninferiority for differences in response rates.
In all three studies, subjects received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In the APEX and FACT studies the duration of prophylaxis was eight weeks. In the CONFIRMS study the duration of prophylaxis was six months.

CONFIRMS study.

The CONFIRMS study was a phase 3, randomised, controlled, 26 week study to evaluate the safety and efficacy of febuxostat 40 mg and 80 mg, in comparison with allopurinol 300 mg or 200 mg, in patients with gout and hyperuricaemia. Two thousand and two hundred sixty nine (2269) patients were randomised: Adenuric 40 mg daily (n = 757), Adenuric 80 mg daily (n = 756), or allopurinol 300/200 mg daily (n = 756). At least 65% of the patients had mild-moderate renal impairment (with creatinine clearance of 30-89 mL/min, stages 2-3 CKD). Prophylaxis against gout flares was obligatory over the 26-week period.
The proportion of patients with sUA < 357 micromole/L (6.0 mg/dL) at the final visit, was 45% for 40 mg febuxostat, 67% for febuxostat 80 mg and 42% for allopurinol 300/200 mg, respectively.

APEX study.

The Allopurinol and Placebo Controlled Efficacy study of Febuxostat (APEX) was a phase 3, randomised, double blind, multicenter, 28 week study. One thousand and seventy two (1072) patients were randomised: placebo (n = 134), Adenuric 80 mg daily (n = 267), Adenuric 120 mg daily (n = 269), Adenuric 240 mg daily (n = 134) or allopurinol (300 mg daily [n = 258] for patients with a baseline serum creatinine ≤ 1.5 mg/dL or 100 mg daily [n = 10] for patients with a baseline serum creatinine > 1.5 mg/dL and ≤ 2.0 mg/dL). Two hundred and forty mg febuxostat (2 times the recommended highest dose) was used as a safety evaluation dose.
The APEX study showed statistically significant superiority of the Adenuric 80 mg daily treatment arm versus the conventionally used doses of allopurinol 300 mg (n = 258)/100 mg (n = 10) treatment arm in reducing the sUA below 357 micromole/L (6 mg/dL). See Table 6.

FACT study.

The Febuxostat Allopurinol Controlled Trial (FACT) study was a phase 3, randomised, double blind, multicenter, 52 week study. Seven hundred and sixty (760) patients were randomised: Adenuric 80 mg daily (n = 256), Adenuric 120 mg daily (n = 251), or allopurinol 300 mg daily (n = 253).
The FACT study showed the statistically significant superiority of the Adenuric 80 mg daily treatment arm versus the conventionally used dose of allopurinol 300 mg treatment arm in reducing and maintaining sUA below 357 micromole/L (6 mg/dL).
Patients in all 3 studies (CONFIRMS, APEX and FACT) were representative of the patient population for which Adenuric use is intended. Table 6 summarises the demographics and baseline characteristics for the subjects enrolled in the studies.
Table 7 summarises the efficacy endpoint results in all 3 studies.
The ability of Adenuric to lower serum uric acid levels was prompt and persistent. Reduction in serum uric acid level to < 357 micromole/L (6.0 mg/dL) was noted by the week 2 visit and was maintained throughout treatment.

Primary endpoint in the subgroup of patients with renal impairment.

An analysis in patients with gout who had mild to moderate renal impairment (Clcr 30 to 89 mL/min, stages 2-3 CKD) was prospectively defined in the CONFIRMS study. As shown in Table 8, febuxostat 80 mg was significantly more effective in lowering sUA to < 357 micromole/L (6 mg/dL) compared to allopurinol 300 mg/200 mg or febuxostat 40 mg.

Primary endpoint in the subgroup of patients with sUA ≥ 595 micromole/L (10 mg/dL).

Approximately 40% of patients (combined APEX and FACT) had a baseline sUA of ≥ 595 micromole/L (10 mg/dL). In this subgroup Adenuric achieved the primary efficacy endpoint (sUA < 357 micromole/L [6.0 mg/dL] at the last 3 visits) in 41% (80 mg daily) of patients compared to 9% in the allopurinol 300 mg/100 mg daily and 0% in the placebo groups.
In the CONFIRMS study, the proportion of patients achieving the primary efficacy endpoint (sUA < 357 micromole/L [6.0 mg/dL] at the final visit) for patients with a baseline serum urate level of ≥ 595 micromole/L (10 mg/dL) treated with febuxostat 40 mg daily was 27% (66/249), with febuxostat 80 mg daily 49% (125/254) and with allopurinol 300 mg/200 mg daily 31% (72/230), respectively.

Clinical outcomes: proportion of patients requiring treatment for a gout flare.

APEX study.

During the 8 week prophylaxis period, the proportion of subjects who required treatment for gout flare was 28% febuxostat 80 mg, 23% allopurinol 300 mg, and 20% placebo treatment groups. Flares increased following the prophylaxis period and gradually decreased over time. Between 46% and 55% of subjects received treatment for gout flares from week 8 and week 28. Gout flares during the last 4 weeks of the study (weeks 24-28) were observed in 15% (febuxostat 80 mg), 14% (allopurinol 300 mg) and 20% (placebo) of subjects.

FACT study.

During the 8 week prophylaxis period, the proportion of subjects who required treatment for a gout flare was 22% and 21% for febuxostat 80 mg and allopurinol 300 mg treatment groups respectively. After the 8 week prophylaxis period, the incidence of flares increased and gradually decreased over time (64% and 70% of subjects received treatment for gout flares from week 8-52). Gout flares during the last 4 weeks of the study (weeks 49-52) were observed in 6% (febuxostat 80 mg), and 11% (allopurinol 300 mg) of subjects.
The proportion of subjects requiring treatment for a gout flare (APEX and FACT studies) was numerically lower in the groups that achieved an average postbaseline serum urate level < 357 micromole/L, < 297 micromole/L, or < 238 micromole/L compared to the group that achieved an average postbaseline serum urate level ≥ 357 micromole/L during the last 32 weeks of the treatment period (week 20-week 24 to week 49-52 intervals).

CONFIRMS study.

The percentage of patients who required treatment for gout flares (day 1 through month 6) were 31% and 25% for the febuxostat 80 mg and allopurinol groups, respectively. No difference in the proportion of patients requiring treatment for gout flares was observed between the febuxostat 80 mg and 40 mg groups.

Post marketing long term studies.

CARES study.

The Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities (CARES) study was a multicentre, randomised, double-blind, allopurinol-controlled, non-inferiority trial comparing CV outcomes with febuxostat versus allopurinol in patients with gout and a history of major CV disease including MI, hospitalisation for unstable angina, coronary or cerebral revascularisation procedure, stroke, hospitalised transient ischemic attack, peripheral vascular disease, or diabetes mellitus with evidence of microvascular or macrovascular disease. To achieve sUA less than 357 micromole/L (6 mg/dL), the dose of febuxostat was titrated from 40 mg up to 80 mg (regardless of renal function) and the dose of allopurinol was titrated in 100 mg increments from 300 to 600 mg in patients with normal renal function and mild renal impairment and from 200 to 400 mg in patients with moderate renal impairment.
The primary endpoint in CARES was the time to first occurrence of MACE; a composite of non-fatal MI, non-fatal stroke, CV death and unstable angina with urgent coronary revascularisation.
The endpoints (primary and secondary) were analysed according to the intention-to-treat (ITT) analysis including all subjects who were randomised and received at least one dose of double-blind study medication.
Overall 56.6% of patients discontinued trial treatment prematurely and 45% of patients did not complete all trial visits.
In total, 6,190 patients were followed for a median of 32 months and the median duration of exposure was 728 days for patients in febuxostat group (n = 3,098) and 719 days in allopurinol group (n = 3,092).
Febuxostat was non-inferior to allopurinol for the primary endpoint of MACE (10.8% vs. 10.4% of patients, respectively; HR 1.03; CI 0.89-1.21).
In the analysis of the individual components of MACE, the rate of CV deaths was statistically significantly higher with febuxostat (134 [1.5 per 100 patient years]) than allopurinol (100 [1.1 per 100 patient years]) (HR 1.34; 95% CI 1.03-1.73). The rate of all-cause mortality was also higher with febuxostat than allopurinol (7.8% vs. 6.4% of patients; HR 1.22; 95% CI 1.01-1.47), which was mainly driven by the higher rate of CV deaths in that group (4.3% vs 3.2%). Sudden cardiac death was the most common cause of adjudicated CV deaths in the febuxostat group (83 of 3,098; 2.7%) as compared to the allopurinol (56 of 3,092; 1.8%). The rates of the other MACE events were similar in the febuxostat and allopurinol groups, i.e. non-fatal MI (3.6% vs. 3.8% of patients; HR 0.93; 95% CI 0.72-1.21), non-fatal stroke (2.3% vs. 2.3% of patients; HR 1.01; 95% CI 0.73-1.41) and urgent coronary revascularisation due to unstable angina (1.6% vs. 1.8% of patients; HR 0.86; 95% CI 0.59-1.26).
Rates of adjudicated hospitalisation for heart failure, hospital admissions for arrhythmias not associated with ischemia, venous thromboembolic events and hospitalisation for transient ischemic attacks were comparable for febuxostat and allopurinol.

5.2 Pharmacokinetic Properties

General.

In healthy subjects, maximum plasma concentrations (Cmax) and area under the concentration time curve (AUC) of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours. Febuxostat pharmacokinetic parameters for patients with hyperuricaemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy subjects.

Absorption.

Febuxostat is rapidly (tmax of 1.0-1.5 h) and well absorbed (at least 84%). After single or multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.5-1.6 microgram/mL, and 2.5-2.6 microgram/mL, respectively. Absolute bioavailability of the febuxostat tablet formulation has not been studied.
Following multiple 80 mg once daily doses with a high fat meal, there was a 49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed (58% fed vs. 51% fasting). Thus, Adenuric may be taken with or without food.

Distribution.

The mean apparent steady state volume of distribution (Vss/F) of febuxostat was approximately 50 L (CV ~ 40%). The plasma protein binding of febuxostat is approximately 99.2% (primarily to albumin), and is constant over the concentration range achieved with 40 mg and 80 mg doses.

Metabolism.

Febuxostat is metabolised by conjugation via uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and oxidation via the cytochrome P450 (CYP) system. Four pharmacologically active hydroxyl metabolites have been identified, of which three occur in plasma of humans. In vitro studies with human liver microsomes showed that those oxidative metabolites were formed primarily by CYP1A1, CYP1A2, CYP2C8 or CYP2C9 and febuxostat glucuronide was formed mainly by UGT 1A1, 1A8, and 1A9.

Excretion.

Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-labelled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the active substance (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the faeces as unchanged febuxostat (12%), the acyl glucuronide of the active substance (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%).

Pharmacokinetics in special patient groups.

Renal impairment.

In a dedicated Phase 1 pharmacokinetics study, following multiple doses of 80 mg of Adenuric in patients with mild (Clcr 60-89 mL/min, stage 2 chronic kidney disease (CKD)), moderate (Clcr 30 to 59 mL/min, stage 3 CKD) or severe renal impairment (Clcr 10 to 29 mL/min, stage 4 CKD), the Cmax of febuxostat did not change, relative to subjects with normal renal function. The mean total AUC of febuxostat increased by approximately 1.8-fold from 7.5 microgram.h/mL in the normal renal function group to 13.2 microgram.h/mL in the severe renal dysfunction group. The Cmax and AUC of active metabolites increased up to 2 and 4-fold, respectively. However, no dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30-89 mL/min, stages 2-3 CKD). Based on population pharmacokinetic analysis, following multiple 40 mg or 80 mg doses of Adenuric, the mean oral clearance (CL/F) values of febuxostat in patients with gout and mild (n=334), moderate (n=232) or severe (n=34) renal impairment were decreased by 14%, 34%, and 48%, respectively, compared to patients with normal (n=89) renal function. The corresponding median AUC values of febuxostat at steady-state in patients with renal impairment were increased by 18%, 49%, and 96% after 40 mg dose, and 7%, 45% and 98% after 80 mg dose, respectively, compared to patients with normal renal function.
There are insufficient data in patients with severe renal impairment (Clcr 10 to 29 mL/min, stage 4 CKD), therefore caution should be exercised in these patients (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use). There are no data in end stage renal impairment patients who are on dialysis.

Hepatic impairment.

Following multiple 80 mg doses of Adenuric in patients with mild (Child Pugh class A) or moderate (Child Pugh class B) hepatic impairment, an average of 20% to 30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child Pugh class C); caution should be exercised in those patients.

Age.

There were no significant changes observed in AUC of febuxostat or its metabolites following multiple oral doses of Adenuric in elderly as compared to younger healthy subjects. The Cmax and AUC of febuxostat and its metabolites following multiple oral doses of Adenuric in geriatric participants (≥ 65 years) were similar to those in younger participants (18 to 40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger participants. No dose adjustment is necessary in geriatric patients (see Section 4.4 Special Warnings and Precautions for Use).

Gender.

Following multiple oral doses of Adenuric, the Cmax and AUC were 24% and 12% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. In addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is needed based on gender.

5.3 Preclinical Safety Data

Pharmacokinetic modelling and simulation of rat data suggests that concomitant administration of oral mercaptopurine/azathioprine and febuxostat results in a ~80% decrease in the predicted population clearance, which corresponds to a ~500% increase in mercaptopurine/azathioprine AUC in humans (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Therefore, when orally co-administered with febuxostat, a reduction of the dose of mercaptopurine/azathioprine is recommended in order to reduce the risk of possible haematological effects.

Genotoxicity.

Febuxostat was not genotoxic in a bacterial reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, two in vivo chromosomal aberration tests in mice and rats, and an ex vivo unscheduled DNA synthesis assay in rats. While febuxostat was positive for chromosomal aberrations in Chinese hamster lung fibroblasts, the weight of evidence suggests that it does not pose a genotoxic risk.

Carcinogenicity.

In a two-year carcinogenicity study in male rats, a statistically significant increase in urinary bladder tumours (transitional cell papilloma and carcinoma) was found only in association with xanthine calculi in the high dose group, at approximately 17 times human exposure (based on AUC). In mice, these tumour types were only seen in females at approximately 8 times human exposure. Chronic irritation of bladder epithelium by the presence of calculi is believed to elicit preneoplastic and neoplastic changes. However, differences in species specific purine metabolism and urine composition mean that xanthine calculi form less readily in humans than in rodents such that urinary bladder tumours are not considered to be of likely clinical significance.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, magnesium stearate, hyprolose, croscarmellose sodium and silicon dioxide. Core tablets are coated with Opadry II Yellow, 85F42129 containing: polyvinyl alcohol, titanium dioxide, macrogol 3350, purified talc and iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

6.5 Nature and Contents of Container

Adenuric tablets are packed in clear (Aclar/PVC/Aluminium) blisters of 14 film-coated tablets. Two blisters are available in each pack of 28 tablets. Packs of 4 or 8 tablets contain either one or two blisters of 4 tablets, respectively.
Adenuric 80 mg tablets are available in packs of 4, 8 or 28 film-coated tablets*.
*Not all pack sizes may be marketed.

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

Adenuric tablet is a potent, non-purine, selective inhibitor of Xanthine Oxidase (XO) that prevents the normal oxidation of purines to uric acid. The active ingredient in Adenuric is febuxostat, a 2-arylthiazole derivative.

Chemical structure.


Chemical name: 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid.
Molecular formula: C16H16N2O3S.
Molecular weight: 316.37.

CAS number.

144060-53-7.
Febuxostat is a white, crystalline powder with a pH of 5.0 in febuxostat solution (1 in 20,000 w/v). It is practically insoluble in water, slightly soluble in methanol, freely soluble in N, N-dimethylformamide and sparingly soluble in ethanol. The solubility of febuxostat is pH dependent in a wide ranged buffer solution (i.e. Britton-Robinson buffer): at range pH 2.0-6.0 febuxostat is practically insoluble and its solubility slightly increases at range pH 8.0-10.0. Febuxostat has an aqueous pKa of 3.3 and a LogD of 1.6 at pH 7.0 in a solution of octanol/aqueous potassium chloride. Several polymorphic forms of febuxostat have been identified; however, Adenuric tablets contain febuxostat as polymorphic form A.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes