Febuxostat Rowex 80 mg Film-coated Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Active ingredient:
Febuxostat
Available from:
Rowex Ltd
ATC code:
M04AA; M04AA03
INN (International Name):
Febuxostat
Dosage:
80 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Preparations inhibiting uric acid production; febuxostat
Authorization status:
Marketed
Authorization number:
PA0711/273/001
Authorization date:
2017-07-14

Read the complete document

Package leaflet: Information for the user

Febuxostat Rowex 80 mg Film-coated tablets

Febuxostat Rowex 120 mg Film-coated tablets

febuxostat

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Febuxostat Rowex is and what it is used for

What you need to know before you take Febuxostat Rowex

How to take Febuxostat Rowex

Possible side effects

How to store Febuxostat Rowex

Contents of the pack and other information

1.

What Febuxostat Rowex is and what it is used for

Febuxostat Rowex tablets contain the active substance febuxostat and are used to treat gout, which is

associated with an excess of a chemical called uric acid (urate) in the body. In some people, the

amount of uric acid builds up in the blood and may become too high to remain soluble. When this

happens, urate crystals may form in and around the joints and kidneys. These crystals can cause

sudden, severe pain, redness, warmth and swelling in a joint (known as a gout attack). Left untreated,

larger deposits called tophi may form in and around joints. These tophi may cause joint and bone

damage.

Febuxostat Rowex works by reducing uric acid levels. Keeping uric acid levels low by taking

Febuxostat Rowex once every day stops crystals building up, and over time it reduces symptoms.

Keeping uric acid levels sufficiently low for a long enough period can also shrink tophi.

Febuxostat Rowex 120 mg:

Febuxostat Rowex 120 mg film-coated tablets are also used to treat and prevent high blood levels of

uric acid that may occur when you start to receive chemotherapy for blood cancers.

When chemotherapy is given, cancer cells are destroyed, and uric acid levels increase in the blood

accordingly, unless the formation of uric acid is prevented.

Febuxostat Rowex is for adults.

2.

What you need to know before you take Febuxostat Rowex

Do not take Febuxostat Rowex

If you are allergic to febuxostat or any of the other ingredients of this medicine (listed in section

Warnings and precautions

Talk to your doctor before taking Febuxostat Rowex:

If you have or have had heart failure, heart problems or stroke

If you have or have had renal disease and/or serious allergic reaction to allopurinol (a medicine

used for the treatment of gout)

If you have or have had liver disease or liver function test abnormalities

If you are being treated for high uric acid levels as a result of Lesch-Nyhan syndrome (a rare

inherited condition in which there is too much uric acid in the blood)

If you have thyroid problems.

Should you experience allergic reactions to Febuxostat Rowex, stop taking this medicine (see also

section 4). Possible symptoms of allergic reactions might be:

rash including severe forms (e.g. blisters, nodules, itchy-, exfoliative rash), itchiness

swelling of limbs or face

difficulties in breathing

fever with enlarged lymph nodes

but also serious life threatening allergic conditions with cardiac and circulatory arrest.

Your doctor might decide to permanently stop treatment with Febuxostat Rowex.

There have been rare reports of potentially life-threatening skin rashes (Stevens-Johnson Syndrome)

with the use of febuxostat, appearing initially as reddish target-like spots or circular patches often with

central blister on the trunk. It may also include ulcers in the mouth, throat, nose, genitals and

conjunctivitis (red and swollen eyes). The rash may progress to widespread blistering or peeling of the

skin.

If you have developed Stevens-Johnson Syndrome with the use of febuxostat, you must not be

re-started on Febuxostat Rowex at any time. If you develop a rash or these skin symptoms, seek

immediate advice from a doctor and tell him/her that you are taking this medicine.

If you are having a gout attack at the moment (a sudden onset of severe pain, tenderness, redness,

warmth and swelling in a joint), wait for the gout attack to subside before first starting treatment with

Febuxostat Rowex.

For some people, gout attacks may flare up when starting certain medicines that control uric acid

levels. Not everyone gets flares, but you could get a flare-up even if you are taking Febuxostat Rowex,

and especially during the first weeks or months of treatment. It is important to keep taking Febuxostat

Rowex even if you have a flare, as Febuxostat Rowex is still working to lower uric acid. Over time,

gout flares will occur less often and be less painful if you keep taking Febuxostat Rowex every day.

Your doctor will often prescribe other medicines, if they are needed, to help prevent or treat the

symptoms of flares (such as pain and swelling in a joint).

In patients with very high urate levels (e.g. those undergoing cancer chemotherapy), treatment with

uric acid-lowering medicines could lead to the build-up of xanthine in the urinary tract, with possible

stones, even though this has not been observed in patients being treated with febuxostat for Tumor

Lysis Syndrome.

Your doctor may ask you to have blood tests to check that your liver is working normally.

Children and adolescents

Do not give this medicine to children under the age of 18 because the safety and efficacy have not

been established.

Other medicines and Febuxostat Rowex

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines, including medicines obtained without a prescription.

It is especially important to tell your doctor or pharmacist if you are taking medicines containing any

of the following substances as they may interact with Febuxostat Rowex and your doctor may wish to

consider necessary measures:

Mercaptopurine (used to treat cancer)

Azathioprine (used to reduce immune response)

Theophylline (used to treat asthma).

Pregnancy and breast-feeding

It is not known if Febuxostat Rowex may harm your unborn child. Febuxostat Rowex should not be

used during pregnancy. It is not known if Febuxostat Rowex may pass into human breast milk. You

should not use Febuxostat Rowex if you are breast-feeding, or if you are planning to breast-feed.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Be aware that you may experience dizziness, sleepiness, blurred vision and numbness or tingling

sensation during treatment and should not drive or operate machines if affected.

Febuxostat Rowex contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor

before taking this medicine.

Febuxostat Rowex contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’.

3.

How to take Febuxostat Rowex

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

The recommended dose is one tablet daily. The back of the blister pack is marked with the days of

the week to help you check that you have taken a dose each day. [Not for pack size 30]

The tablets should be taken by mouth and can be taken with or without food.

For gout treatment

Febuxostat Rowex is available as either an 80 mg tablet or a 120 mg tablet. Your doctor will have

prescribed the strength most suitable for you.

Continue to take Febuxostat Rowex every day even when you are not experiencing gout flare or

attack.

Febuxostat Rowex 120 mg:

For prevention and treatment of high uric acid levels in patients undergoing cancer chemotherapy

Febuxostat Rowex is available as a 120 mg tablet.

Start taking Febuxostat Rowex two days before chemotherapy and continue its use according to your

doctor’s advice. Usually treatment is short-term.

If you take more Febuxostat Rowex than you should

In the event of an accidental overdose ask your doctor what to do, or contact your nearest accident and

emergency department.

If you forget to take Febuxostat Rowex

If you miss a dose of Febuxostat Rowex take it as soon as you remember unless it is almost time for

your next dose, in which case miss out the forgotten dose and take your next dose at the normal time.

Do not take a double dose to make up for a forgotten dose.

If you stop taking Febuxostat Rowex

Do not stop taking Febuxostat Rowex without the advice of your doctor even if you feel better. If you

stop taking Febuxostat Rowex your uric acid levels may begin to rise and your symptoms may worsen

due to the formation of new crystals of urate in and around your joints and kidneys.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking this medicine and contact your doctor immediately or go to an emergency department

nearby if the following rare (may affect up to 1 in 1,000 people) side effects occur, because a serious

allergic reaction might follow:

anaphylactic reactions, hypersensitivity (see also section 2 “Warnings and precautions”)

potentially life-threatening skin rashes characterized by formation of blisters and 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 (Stevens-Johnson Syndrome/

Toxic Epidermal Necrolysis), or by enlarged lymph nodes, liver enlargement, hepatitis (up to liver

failure), raising of the white-cells count in the blood (drug reaction with eosinophilia and systemic

symptoms-DRESS) (see section 2)

generalised skin rashes.

Common side effects (may affect up to 1 in 10 people)

abnormal liver test results

diarrhoea

headache

rash (including various types of rash, please see below under “uncommon” and “rare” sections)

nausea

increase in gout symptoms

localized swelling due to retention of fluids in tissues (oedema).

Uncommon side effects (may affect up to 1 in 100 people)

decreased appetite, change in blood sugar levels (diabetes) of which a symptom may be excessive

thirst, increased blood fat levels, weight increase

loss of sex drive

difficulty in sleeping, sleepiness

dizziness, numbness, tingling, reduced or altered sensation (hypoaesthesia, hemiparesis or

paraesthesia), altered or reduced sense of taste, diminished sense of smell (hyposmia)

abnormal ECG heart tracing, irregular or rapid heartbeats, feeling your heartbeat (palpitation)

hot flushes or flushing (e.g. redness of the face or neck), increased blood pressure, bleeding

(haemorrhage, seen only in patients taking chemotherapy for blood disorders)

cough, shortness of breath, chest discomfort or pain, inflammation of nasal passage and/or throat

(upper respiratory tract infection), bronchitis

dry mouth, abdominal pain/discomfort or wind, heartburn/indigestion, constipation, more frequent

passing of stools, vomiting, stomach discomfort

itching, hives, skin inflammation, skin discolouration, small red or purple spots on the skin, small,

flat red spots on the skin, flat, red area on the skin that is covered with small confluent bumps,

rash, areas of redness and spots on the skin, other type of skin conditions

muscle cramp, muscle weakness, pain/ache in muscles/joints, bursitis or arthritis (inflammation of

joints usually accompanied by pain, swelling and/or stiffness), pain in extremity, back pain,

muscle spasm

blood in the urine, abnormal frequent urination, abnormal urine tests (increased level of proteins in

the urine), a reduction in the ability of the kidneys to function properly

fatigue, chest pain, chest discomfort

stones in the gallbladder or in bile ducts (cholelithiasis)

increase in blood thyroid stimulating hormone (TSH) level

changes in blood chemistry or amount of blood cells or platelets (abnormal blood test results)

kidney stones

erectile difficulties.

Rare side effects (may affect up to 1 in 1,000 people)

muscle damage, a condition which on rare occasions can be serious. It may cause muscle problems

and particularly, if at the same time, you feel unwell or have a high temperature it may be caused

by an abnormal muscle breakdown. Contact your doctor immediately if you experience muscle

pain, tenderness or weakness

severe swelling of the deeper layers of the skin, especially around the lips, eyes, genitals, hands,

feet or tongue, with possible sudden difficult breathing

high fever in combination with measles-like skin rash, enlarged lymph nodes, liver enlargement,

hepatitis (up to liver failure), raising of the white-cells count in the blood (leukocytosis, with or

without eosinophilia)

reddening of the skin (erythema), rash in various types (e.g. itchy, with white spots, with blisters,

with blisters containing pus, with shedding of the skin, measles-like rash), widespread erythema,

necrosis, and bullous detachment of the epidermis and mucous membranes, resulting in exfoliation

and possible sepsis (Stevens-Johnson Syndrome/Toxic epidermal necrolysis)

nervousness

feeling thirsty

ringing in the ears

blurred vision, change in vision

hair loss

mouth ulceration

inflammation of the pancreas: common symptoms are abdominal pain, nausea and vomiting

increased sweating

weight decrease, increased appetite, uncontrolled loss of appetite (anorexia)

muscle and/or joint stiffness

abnormally low blood cell counts (white or red blood cells or platelets)

urgent need to urinate

changes or decrease in urine amount due to inflammation in the kidneys (tubulointerstitial

nephritis)

inflammation of the liver (hepatitis)

yellowing of the skin (jaundice)

liver damage

increased level of creatine phosphokinase in blood (an indicator of muscle damage)

sudden cardiac death.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance;

website: www.hpra.ie. By reporting side effects, you can help provide more information on the safety

of this medicine.

5.

How to store Febuxostat Rowex

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The

expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Febuxostat Rowex contains

The active substance is febuxostat.

Febuxostat Rowex 80 mg film-coated tablet:

Each film-coated tablet contains 80 mg febuxostat (as hemihydrate).

Febuxostat Rowex 120 mg film-coated tablet:

Each film-coated tablet contains 120 mg febuxostat (as hemihydrate).

The other ingredients are:

Tablet core:

lactose monohydrate, cellulose, microcrystalline (E460), hydroxypropylcellulose (E463),

croscarmellose sodium, silica, colloidal anhydrous (E551), magnesium stearate (E470b).

Film-coating:

poly (vinyl alcohol) (E1203), talc (E553b), titanium dioxide (E171), macrogol 3350 (E1521),

methacrylic acid - ethyl acrylate copolymer (1:1) (Type A), iron oxide yellow (E172), sodium

hydrogen carbonate (E500(ii)).

What Febuxostat Rowex looks like and contents of the pack

Febuxostat Rowex 80 mg film-coated tablet:

Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with “80” on one side and plain

on the other, with dimensions 16.5 mm x 7.0 mm

Febuxostat Rowex 120 mg film-coated tablet:

Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with “120” on one side and plain

on the other, with dimensions 18.5 mm x 9.0 mm

Febuxostat Rowex 80 mg and 120 mg film-coated tablets are packed in Aluminium-OPA/Alu/PVC or

Aluminium-PVC/PE/PVDC blisters.

Febuxostat Rowex 80 mg and 120 mg is available in packs containing 14, 28, 30, 42, 56, 84 and 98

film-coated tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturers

Marketing Authorisation Holder

Rowex Ltd., Bantry, Co. Cork, Ireland.

Manufacturers

Rontis Hellas Medical and Pharmaceutical Products S.A., P.O. Box 3012 Larisa Industrial Area,

Larisa 41004, Greece.

Salutas Pharma GmbH, Otto-von-Guericke-Allee 1, Sachsen-Anhalt, Barleben 39179, Germany.

Lek Pharmaceuticals d.d., Verovškova ulica 57, 1526 Ljubljana, Slovenia.

This medicinal product is authorised in the Member States of the EEA under the following

names:

Austria

Febuxostat Sandoz 80 mg – Filmtabletten

Febuxostat Sandoz 120 mg - Filmtabletten

Belgium

Febuxostat Sandoz 80 mg filmomhulde tabletten

Febuxostat Sandoz 120 mg filmomhulde tabletten

Czech Republic

Febuxostat Sandoz

France

FEBUXOSTAT SANDOZ 80 mg, comprimé pelliculé

FEBUXOSTAT SANDOZ 120 mg, comprimé pelliculé

Germany

Febuxostat HEXAL 80 mg Filmtabletten

Febuxostat HEXAL 120 mg Filmtabletten

Greece

Febuxostat/Sandoz

Hungary

Febuxostat Sandoz 80 mg filmtabletta

Febuxostat Sandoz 120 mg filmtabletta

Ireland

Febuxostat Rowex 80 mg Film-coated tablets

Febuxostat Rowex 120 mg Film-coated tablets

Italy

Febuxostat Sandoz

The Netherlands

Febuxostat Sandoz 80 mg, filmomhulde tabletten

Febuxostat Sandoz 120 mg, filmomhulde tabletten

Spain

Febuxostat Sandoz 80 mg comprimidos recubiertos con pelicula EFG

Febuxostat Sandoz 120 mg comprimidos recubiertos con pelicula EFG

Slovakia

Febuxostat Sandoz 80 mg

Febuxostat Sandoz 120 mg

This leaflet was last revised in 01/2020.

Read the complete document

Health Products Regulatory Authority

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Febuxostat Rowex 80 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 80 mg of febuxostat (as hemihydrate).

Excipient(s) with known effect:

Each film-coated tablet contains 72.68 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with "80" on one side and plain on the other, with

dimensions 16.5 mm x 7.0 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Febuxostat Rowex is indicated for the treatment of chronic hyperuricaemia in conditions where urate deposition has already

occurred (including a history, or presence of, tophus and/or gouty arthritis).

Febuxostat Rowex is indicated in adults.

4.2 Posology and method of administration

Posology

Gout: The recommended oral dose of Febuxostat Rowex is 80 mg once daily without regard to food. If serum uric acid is > 6

mg/dL (357 micromol/L) after 2-4 weeks, Febuxostat Rowex 120 mg once daily may be considered.

Febuxostat Rowex works sufficiently quickly to allow retesting of the serum uric acid after 2 weeks. The therapeutic target is to

decrease and maintain serum uric acid below 6 mg/dL (357 micromol/L).

Gout flare prophylaxis of at least 6 months is recommended (see section 4.4).

Elderly

No dose adjustment is required in the elderly (see section 5.2).

Renal impairment

The efficacy and safety have not been fully evaluated in patients with severe renal impairment (creatinine clearance <30

mL/min, see section 5.2).

No dose adjustment is necessary in patients with mild or moderate renal impairment.

Hepatic impairment

The efficacy and safety of febuxostat has not been studied in patients with severe hepatic impairment (Child Pugh Class C).

Gout: The recommended dose in patients with mild hepatic impairment is 80 mg. Limited information is available in patients

with moderate hepatic impairment.

Paediatric population

The safety and the efficacy of febuxostat in childrenandadolescents aged below the age of 18 years have not been established.

No data are available.

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Method of administration

Oral use.

Febuxostat Rowex should be taken by mouth and can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see also section 4.8).

4.4 Special warnings and precautions for use

Cardio-vascular disorders

Treatment of chronic hyperuricaemia

Treatment with febuxostat in patients with pre-existing major cardiovascular diseases (e.g. myocardial infarction, stroke or

unstable angina) should be avoided, unless no other therapy options are appropriate. A numerical greater incidence of

investigator-reported cardiovascular APTC events (defined endpoints from the Anti-Platelet Trialists' Collaboration (APTC)

including cardiovascular death, non-fatal myocardial infarction, non-fatal 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 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 the post registrational CARES trial (see

section 5.1 for detailed characteristics of the study) the rate of MACE events was similar in febuxostat versus allopurinol treated

patients (HR 1.03; 95% CI 0.87- 1.23), but a higher rate of cardiovascular deaths was observed (4.3% vs. 3.2% of patients; HR

1.34;95% CI 1.03-1.73).

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 post-marketing 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 reactions, including Drug Reaction

with Eosinophilia and Systemic Symptoms (DRESS) 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). 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 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 flare)

Febuxostat treatment should not be started until an acute attack of gout has completely subsided. Gout flares may occur

during initiation of treatment due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits (see

sections 4.8 and 5.1). At treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or colchicine

is recommended (see section 4.2).

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.

Xanthine deposition

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 patients with Lesch-Nyhan Syndrome is not recommended.

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Mercaptopurine/azathioprine

Febuxostat use is not recommended in patients concomitantly treated with mercaptopurine/azathioprine as inhibition of

xanthine oxidase by febuxostat may cause increased plasma concentrations of mercaptopurine/azathioprine that could result

in severe toxicity. No interaction studies have been performed in humans.

Where the combination cannot be avoided, a reduction of the dose of mercaptopurine/azathioprine is recommended. Based

on modelling and simulation analysis of data from a pre-clinical study in rats, when coadministered with febuxostat, the dose

of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose in order to avoid possible

haematological effects (see section 4.5 and 5.3).

The patients should be closely monitored and the dose of mercaptopurine/azathioprine should be subsequently adjusted

based on the evaluation of the therapeutic response and the onset of eventual toxic effects.

Organ transplant recipients

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

section 5.1).

Theophylline

Co-administration of febuxostat 80 mg and theophylline 400mg single dose in healthy subjects showed absence of any

pharmacokinetic interaction (see section 4.5). Febuxostat 80 mg can be used in patients concomitantly treated with

theophylline without risk of increasing theophylline plasma levels.

No data is available for febuxostat 120 mg.

Liver disorders

During the combined phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with

febuxostat (5.0%). Liver function test is recommended prior to the initiation of therapy with febuxostat and periodically

thereafter based on clinical judgment (see section 5.1).

Thyroid disorders

Increased TSH values (>5.5 µIU/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 (see

section 5.1).

Febuxostat Rowex contains Lactose

Febuxostat tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or

glucose-galactose malabsorption should not take this medicinal product.

Febuxostat Rowex contains Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

Mercaptopurine/azathioprine

On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended. Inhibition of XO

by febuxostat may cause increased plasma concentrations of these active substances leading to toxicity.

Drug interaction studies of febuxostat with medicinal products (except theophylline) that are metabolized by XO have not been

performed in humans.

Modelling and simulation analysis of data from a pre-clinical study in rats indicates that, in case of concomitant administration

with febuxostat, the dose of mercaptopurine/azathioprine should be reduced to the 20% or less of the previously prescribed

dose (see section 4.4 and 5.3).

Drug interaction studies of febuxostat with other cytotoxic chemotherapy have not been conducted.

No data 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 QD 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,

co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment

for those compounds.

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Theophylline

An interaction study in healthy subjects has been performed with febuxostat to evaluate whether the inhibition of XO may

cause an increase in the theophylline circulating levels as reported with other XO inhibitors. The results of the study showed

that the co-administration of febuxostat 80 mg QD with theophylline 400 mg single dose has no effect on the

pharmacokinetics or safety of theophylline. Therefore no special caution is needed when febuxostat 80 mg and theophylline

are given concomitantly. No data are available for febuxostat 120 mg.

Naproxen and other inhibitors of glucuronidation

Febuxostat metabolism depends on UDP-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 (c

28%, AUC 41% and t

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 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/indometacin/hydrochlorothiazide/warfarin

Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment of febuxostat or the

co-administered 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 co- administration 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 febuxostat QD 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, co-administration 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 c

, but no significant change in AUC was

observed. Therefore, febuxostat may be taken without regard to antacid use.

4.6 Fertility, pregnancy and lactation

Pregnancy

Data on a very limited number of exposed pregnancies have not indicated any adverse reactions of febuxostat on pregnancy or

on the health of the foetus/new born child. Animal studies do not indicate direct or indirect harmful effects with respect to

pregnancy, embryonal/foetal development or parturition (see section 5.3). The potential risk for human is unknown. Febuxostat

should not be used during pregnancy.

Breastfeeding

It is unknown whether febuxostat is excreted in human breast milk. Animal studies have shown excretion of this active

substance in breast milk and an impaired development of suckling pups. A risk to a suckling infant cannot be excluded.

Febuxostat should not be used while breastfeeding.

Fertility

In animals, reproduction studies up to 48 mg/kg/day showed no dose-dependent adverse reactions on fertility (see section 5.3).

The effect of febuxostat on human fertility is unknown.

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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

Febuxostat Rowex does not adversely affect performance.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in clinical trials (4,072 subjects treated at least with a dose from 10 mg to 300

mg) and post-marketing experience in gout patients are gout flares, liver function abnormalities, diarrhoea, nausea, headache,

rash and oedema. 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.

Tabulated list of adverse reactions

Common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000) adverse reactions occurring in

patients treated with febuxostat are listed below.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions in combined phase 3, long-term extension studies and post-marketing experience in gout patients

Blood and lymphatic system disorders

Rare

Pancytopenia, thrombocytopenia, agranulocytosis*

Immune system disorders

Rare

Anaphylactic reaction*, drug hypersensitivity*

Endocrine disorders

Uncommon

Blood thyroid stimulating hormone increased

Eye disorders

Rare

Blurred vision

Metabolism and nutrition disorders

Common***

Gout flares

Uncommon

Diabetes mellitus, hyperlipidemia, decrease appetite, weight increase

Rare

Weight decrease, increase appetite, anorexia

Psychiatric disorders

Uncommon

Libido decreased, insomnia

Rare

Nervousness

Nervous system disorders

Common

Headache

Uncommon

Dizziness, paraesthesia, hemiparesis, somnolence, altered taste,

hypoaesthesia, hyposmia

Ear and labyrinth disorders

Rare

Tinnitus

Cardiac disorders

Uncommon

Atrial fibrillation, palpitations, ECG abnormal

Rare

Sudden cardiac death*

Vascular disorders

Uncommon

Hypertension, flushing, hot flush

Respiratory system disorders

Uncommon

Dyspnoea, bronchitis, upper respiratory tract infection, cough

Gastrointestinal disorders

Common Diarrhoea**, nausea Uncommon:

Abdominal pain, abdominal distension, gastro-oesophageal reflux

disease, vomiting, dry mouth, dyspepsia, constipation, frequent stools,

flatulence, gastrointestinal discomfort

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Rare

Pancreatitis, mouth ulceration

Hepato-biliary disorders

Common

Liver function abnormalities**

Uncommon

Cholelithiasis

Rare

Hepatitis, jaundice*, liver injury*

Skin and subcutaneous tissue disorders

Common

Rash (including various types of rash reported with lower frequencies,

see below)

Uncommon

Dermatitis, urticaria, pruritus, skin discolouration, skin lesion, petechiae,

rash macular, rash maculopapular, rash papular

Rare

Toxic epidermal necrolysis*, Stevens-Johnson syndrome*, angioedema*,

drug reaction with eosinophilia and systemic symptoms*, generalized

rash (serious)*, erythema, exfoliative rash, rash follicular, rash vesicular,

rash pustular, rash pruritic*, rash erythematous, rash morbillifom,

alopecia, hyperhidrosis

Musculoskeletal and connective tissue disorders

Uncommon

Arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness,

muscle spasm, muscle tightness, bursitis

Rare

Rhabdomyolysis*, joint stiffness, musculoskeletal stiffness

Renal and urinary disorders

Uncommon

Renal failure, nephrolithiasis, haematuria, pollakiuria, proteinuria

Rare

Tubulointerstitial nephritis*, micturition urgency

Reproductive system and breast disorder

Uncommon

Erectile dysfunction

General disorders and administration site conditions

Common

Oedema

Uncommon

Fatigue, chest pain, chest discomfort

Rare

Thirst

Investigations

Uncommon

Blood amylase increase, platelet count decrease, WBC decrease,

lymphocyte count decrease, blood creatine increase, blood creatinine

increase, haemoglobin decrease, blood urea increase, blood

triglycerides increase, blood cholesterol increase, haematocritic

decrease, blood lactate dehydrogenase increased, blood potassium

increase

Rare

Blood glucose increase, activated partial thromboplastin time prolonged,

red blood cell count decrease, blood alkaline phosphatase increase,

blood creatine phosphokinase increase*

* Adverse reactions coming from post-marketing experience

** Treatment-emergent non-infective diarrhoea and abnormal liver function tests in the combined Phase 3 studies are more

frequent in patients concomitantly treated with colchicine.

*** See section 5.1 for incidences of gout flares in the individual Phase 3 randomized controlled studies.

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 post-marketing 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 to the following symptoms: skin reactions characterised by infiltrated

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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) (see section 4.4).

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 (see section 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance; website: www.hpra.ie.

4.9 Overdose

Patients with an overdose should be managed by symptomatic and supportive care.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antigout preparation, preparations inhibiting uric acid production, ATC code: M04AA03.

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 catalyzed 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 potent,

non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar. Febuxostat has

been shown to potently inhibit both the oxidized 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.

Clinical efficacy and safety

Gout

The efficacy of febuxostat was demonstrated in three Phase 3 pivotal studies (the two pivotal APEX and FACT studies, and the

additional CONFIRMS study described below) that were conducted in 4101 patients with hyperuricaemia and gout. In each

phase 3 pivotal study, febuxostat demonstrated superior ability to lower and maintain serum uric acid levels compared to

allopurinol. The primary efficacy endpoint in the APEX and FACT studies was the proportion of patients whose last 3 monthly

serum uric acid levels were < 6.0 mg/dL (357 µmol/L). In the additional phase 3 CONFIRMS study, for which results became

available after the marketing authorisation for febuxostat was first issued, the primary efficacy endpoint was the proportion of

patients whose serum urate level was < 6.0 mg/dL at the final visit. No patients with organ transplant have been included in

these studies (see section 4.2).

APEX Study: The Allopurinol and Placebo-Controlled Efficacy Study of febuxostat (APEX) was a Phase 3, randomized,

double-blind, multicenter, 28-week study. One thousand and seventy-two (1072) patients were randomized into placebo

(n=134), febuxostat 80 mg QD (n=267), febuxostat 120 mg QD (n=269), febuxostat 240 mg QD (n=134) or allopurinol (300 mg

QD [n=258] for patients with a baseline serum creatinine ≤1.5 mg/dL or 100 mg QD [n=10] for patients with a baseline serum

creatinine >1.5 mg/dL and ≤2.0 mg/dL) groups. 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 both the febuxostat 80 mg QD and the febuxostat 120 mg QD

treatment arms versus the conventionally used doses of allopurinol 300 mg (n = 258) /100 mg (n = 10) treatment arm in

reducing the sUA below 6 mg/dL (357 µmol/L) (see Table 2 and Figure 1).

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FACT Study: The febuxostat Allopurinol Controlled Trial (FACT) Study was a Phase 3, randomized, double-blind, multicenter,

52-week study. Seven hundred sixty (760) patients were randomized: Febuxostat 80 mg QD (n=256), febuxostat 120 mg QD

(n=251), or allopurinol 300 mg QD (n=253).

The FACT study showed the statistically significant superiority of both febuxostat 80 mg and febuxostat 120 mg QD treatment

arms versus the conventionally used dose of allopurinol 300 mg treatment arm in reducing and maintaining sUA below 6

mg/dL (357 µmol/L).

Table 2 summarises the primary efficacy endpoint results:

Table 2

Proportion of Patients with Serum Uric Acid Levels <6.0 mg/dL (357 µmol/L)

Last Three Monthly Visits

Study

Febuxostat

80 mg QD

Febuxostat

120 mg QD

Allopurinol 300 /

100 mg QD

APEX

(28 weeks)

(n=262)

*, #

(n=269)

(n=268)

FACT

(52 weeks)

(n=255)

(n=250)

(n=251)

Combined

Results

(n=517)

*, #

(n=519)

(n=519)

results from subjects receiving either 100 mg QD (n=10: patients with serum

creatinine >1.5 and ≤2.0 mg/dL) or 300 mg QD (n=509) were pooled for

analyses.

* p < 0.001 vs allopurinol,

p < 0.001 vs 80 mg

The ability of febuxostat to lower serum uric acid levels was prompt and persistent. Reduction in serum uric acid level to <6.0

mg/dL (357 µmol/L) was noted by the Week 2 visit and was maintained throughout treatment. The mean serum uric acid levels

over time for each treatment group from the two pivotal Phase 3 studies are shown in Figure 1.

Note: 509 patients received allopurinol 300 mg QD; 10 patients with serum creatinine >1.5 and <2.0 mg/dL were dosed with

100 mg QD. (10 patients out of 268 in APEX study). 240 mg febuxostat was used to evaluate the safety of febuxostat at twice

the recommended highest dose.

CONFIRMS Study: The CONFIRMS study was a Phase 3, randomized, 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

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hyperuricaemia. Two thousand and two hundred-sixty nine (2269) patients were randomized: febuxostat 40 mg QD (n=757),

febuxostat 80 mg QD (n=756), or allopurinol 300/200 mg QD (n=756). At least 65% of the patients had mild-moderate renal

impairment (with creatinine clearance of 30-89 mL/min). Prophylaxis against gout flares was obligatory over the 26-week

period.

The proportion of patients with serum urate levels of < 6.0 mg/dL (357 µmol/L) at the final visit, was 45% for 40 mg febuxostat,

67% for febuxostat 80 mg and 42% for allopurinol 300/200 mg, respectively.

Primary endpoint in the sub-group of patients with renal impairment

The APEX Study evaluated efficacy in 40 patients with renal impairment (i.e., baseline serum creatinine > 1.5 mg/dL and ≤2.0

mg/dL). For renally impaired subjects who were randomized to allopurinol, the dose was capped at 100 mg QD. Febuxostat

achieved the primary efficacy endpoint in 44% (80 mg QD), 45% (120 mg QD), and 60% (240 mg QD) of patients compared to

0% in the allopurinol 100 mg QD and placebo groups.

There were no clinically significant differences in the percent decrease in serum uric acid concentration in healthy subjects

irrespective of their renal function (58% in the normal renal function group and 55% in the severe renal dysfunction group).

An analysis in patients with gout and renal impairment was prospectively defined in the CONFIRMS study, and showed that

febuxostat was significantly more efficacious in lowering serum urate levels to < 6 mg/dL compared to allopurinol 300 mg/200

mg in patients who had gout with mild to moderate renal impairment (65% of patients studied).

Primary endpoint in the sub group of patients with sUA ≥ 10 mg/dL

Approximately 40% of patients (combined APEX and FACT) had a baseline sUA of ≥ 10 mg/dL. In this subgroup febuxostat

achieved the primary efficacy endpoint (sUA < 6.0 mg/dL at the last 3 visits) in 41% (80 mg QD), 48% (120 mg QD), and 66%

(240 mg QD) of patients compared to 9% in the allopurinol 300 mg/100 mg QD and 0 % in the placebo groups.

In the CONFIRMS study, the proportion of patients achieving the primary efficacy endpoint (sUA <6.0 mg/dL at the final visit)

for patients with a baseline serum urate level of ≥ 10 mg/dL treated with febuxostat 40 mg QD was 27% (66/249), with

febuxostat 80 mg QD 49% (125/254) and with allopurinol 300 mg/200 mg QD 31% (72/230), respectively.

Clinical Outcomes: proportion of patients requiring treatment for a gout flare

APEX study: During the 8-week prophylaxis period, a greater proportion of subjects in the febuxostat 120 mg (36%) treatment

group required treatment for gout flare compared to febuxostat 80 mg (28%), allopurinol 300 mg (23%) and placebo (20%).

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, 120 mg), 14% (allopurinol 300 mg) and 20% (placebo) of subjects.

FACT study: During the 8-week prophylaxis period, a greater proportion of subjects in the febuxostat 120 mg (36%) treatment

group required treatment for a gout flare compared to both the febuxostat 80 mg (22%) and allopurinol 300 mg (21%)

treatment groups. After the 8-week prophylaxis period, the incidences 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 6-8% (febuxostat 80 mg, 120 mg) and 11% (allopurinol 300 mg) of subjects.

The proportion of subjects requiring treatment for a gout flare (APEX and FACT Study) was numerically lower in the groups that

achieved an average post-baseline serum urate level <6.0 mg/dL, <5.0 mg/dL, or <4.0 mg/dL compared to the group that

achieved an average post-baseline serum urate level ≥6.0 mg/dL during the last 32 weeks of the treatment period (week

20-week 24 to week 49 - 52 intervals).

During the CONFIRMS study, the percentages 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.

Long-term, open label extension studies

EXCEL Study (C02-021): The EXCEL study was a three years Phase 3, open label, multicenter, randomised, allopurinol-controlled,

safety extension study for patients who had completed the pivotal Phase 3 studies (APEX or FACT). A total of 1,086 patients

were enrolled: febuxostat 80 mg QD (n=649), febuxostat 120 mg QD (n=292) and allopurinol 300/100 mg QD (n=145). About

69 % of patients required no treatment change to achieve a final stable treatment. Patients who had 3 consecutive sUA levels >

6.0 mg/dL were withdrawn.

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Serum urate levels were maintained over time (i.e. 91% and 93% of patients on initial treatment with febuxostat 80 mg and

120 mg, respectively, had sUA <6 mg/dL at Month 36).

Three years data showed a decrease in the incidence of gout flares with less than 4% of patients requiring treatment for a flare

(i.e. more than 96% of patients did not require treatment for a flare) at Month 16-24 and at Month 30-36.

46% and 38%, of patients on final stable treatment of febuxostat 80 or 120 mg QD, respectively, had complete resolution of

the primary palpable tophus from baseline to the Final Visit.

FOCUS Study (TMX-01-005) was a 5 years Phase 2, open-label, multicenter, safety extension study for patients who had

completed the febuxostat 4 weeks of double blind dosing in study TMX-00-004. 116 patients were enrolled and received

initially febuxostat 80 mg QD. 62% of patients required no dose adjustment to maintain sUA <6 mg/dL and 38% of patients

required a dose adjustment to achieve a final stable dose.

The proportion of patients with serum urate levels of <6.0 mg/dL (357 µmol/L) at the final visit was greater than 80% (81-100%)

at each febuxostat dose.

During the phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat

(5.0%). These rates were similar to the rates reported on allopurinol (4.2%) (see section 4.4). Increased TSH values (>5.5 µIU/mL)

were observed in patients on long-term treatment with febuxostat (5.5%) and patients with allopurinol (5.8%) in the long term

open label extension studies (see section 4.4).

Post marketing long term studies

CARES Study was a multicenter, randomized, double-blind, non inferiority trial comparing CV outcomes with febuxostat versus

allopurinol in patients with gout and a history of major CV disease including MI, hospitalization for unstable angina, coronary

or cerebral revascularization procedure, stroke, hospitalized transient ischemic attack, peripheral vascular disease, or diabetes

mellitus with evidence of microvascular or macrovascular disease. To achieve sUA less than 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 revascularization. The

endpoints (primary and secondary) were analysed according to the intention-to treat (ITT) analysis including all subjects who

were randomized 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 3098) and 719 days in

allopurinol group (n 3092). The primary MACE endpoint occurred at similar rates in the febuxostat and allopurinol treatment

groups (10.8% vs. 10.4% of patients, respectively; hazard ratio [HR] 1.03; two-sided repeated 95% confidence interval [CI]

0.87-1.23). In the analysis of the individual components of MACE, the rate of CV deaths was higher with febuxostat than

allopurinol (4.3% vs. 3.2% of patients; HR 1.34; 95% CI 1.03-1.73). 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), nonfatal stroke (2.3%

vs. 2.3% of patients; HR 1.01; 95% CI 0.73-1.41) and urgent revascularization due to unstable angina (1.6% vs. 1.8% of patients;

HR 0.86; 95% CI 0.59 1.26). 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 (see section 4.4).

Rates of adjudicated hospitalization for heart failure, hospital admissions for arrhythmias not associated with ischemia, venous

thromboembolic events and hospitalization for transient ischemic attacks were comparable for febuxostat and allopurinol.

5.2 Pharmacokinetic properties

In healthy subjects, maximum plasma concentrations (c

) and area under the plasma concentration time curve (AUC) of

febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. For doses

between 120 mg and 300 mg, a greater than dose proportional increase in AUC is observed for febuxostat. There is no

appreciable accumulation when doses of 10 mg to 240 mg are administered every 24 hours. Febuxostat has an apparent

elimination half-life (t

) of approximately 5 to 8 hours.

Population pharmacokinetic/pharmacodynamic analyses were conducted in 211 patients with hyperuricaemia and gout,

treated with febuxostat 40-240 mg QD. In general, febuxostat pharmacokinetic parameters estimated by these analyses are

consistent with those obtained from healthy subjects, indicating that healthy subjects are representative for

pharmacokinetic/pharmacodynamic assessment in the patient population with gout.

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