ADENURIC - PACKAGE LEAFLET - LEAFLETS

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Adenuric - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Febuxostat

ADENURIC 80 mg film-coated tablets
ADENURIC 120 mg film-coated tablets

Why is Adenuric used? What is it for?

ADENURIC tablets contain the active substance febuxostat and are used to treat gout, a disease associated with too much uric acid (urate) in the body. In some people, the amount of uric acid that accumulates in the blood can become too much. elevated to remain in solution. In this case, urate crystals may form in and around the joints and kidneys. These crystals can cause sudden, intense pain, redness, warmth and swelling in a joint ( gout attack). If left untreated, larger deposits, called tophi, can form in and around the joints. Tophi can damage joints and bones.

ADENURIC works by reducing uric acid levels. Maintaining low uric acid levels by taking ADENURIC once a day prevents the accumulation of crystals, and over time decreases symptoms. If uric acid levels are kept low for a long enough time, the tophi can also be reabsorbed.

ADENURIC 120 mg tablets are also used for the treatment and prevention of high blood levels of uric acid which may occur in the case of chemotherapy for blood cancers. Cancer cells are destroyed during chemotherapy treatment and levels of uric acid in the blood increase unless the formation of this acid can be prevented.

ADENURIC is for adults.

Contraindications When Adenuric should not be used

Do not take ADENURIC:

If you are allergic to febuxostat or any of the other ingredients of this medicine

Precautions for use What you need to know before taking Adenuric

Talk to your doctor before taking ADENURIC:

If you have or have suffered from heart failure or other heart problems
If you have or have had kidney disease and / or severe allergic reactions to allopurinol (a medicine used to treat gout)
If you have or have ever had liver disease or liver function test abnormalities
If you have elevated uric acid levels due to Lesch-Nyhan syndrome (a rare inherited condition in which there is too much uric acid in the blood)
If you have any thyroid problems.

If allergic reactions to ADENURIC occur, stop taking the medicine. Possible symptoms of allergic reactions can be:

rash including severe forms (e.g. blisters, lumps, itchy rash, exfoliative rash), itching
swelling of the limbs or face
difficulty in breathing
fever with swollen lymph nodes
but also severe, life-threatening allergic conditions with cardiac and circulatory arrest.

Your doctor may decide to permanently stop your Adenuric treatment.

Rare, life-threatening skin rashes (Stevens-Johnson syndrome) have been reported with the use of ADENURIC and initially appeared on the trunk as reddish patches or circular patches often with central blisters. They 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, treatment with ADENURIC should no longer be restarted. If you have developed a rash or these skin symptoms, consult your doctor immediately and inform him that you are being treated with this medicine. .

If you are currently having a gout attack (sudden onset of severe pain, tenderness, redness, warmth and swelling of one joint), wait for the gout attack to stop before starting therapy with ADENURIC.

In some people, gout attacks can flare up at the beginning of certain therapies used to control uric acid levels. Not all people experience exacerbations, but you may also experience an exacerbation when taking ADENURIC, especially during the first few weeks or months of therapy. It is important that you continue to take ADENURIC even if you have a flare-up, as ADENURIC continues to work to lower your uric acid level. If you continue to take ADENURIC every day, over time, the flare-ups will occur less frequently and will be less and less painful.

Your doctor will often prescribe other medicines as needed to help prevent or treat the symptoms of flare-ups (such as pain and swelling in a 'joint).

In patients with very high urate levels (eg patients on chemotherapy), treatment with drugs that lower uric acid levels could cause xanthine to accumulate in the urinary tract with possible stone formation, although this has not been observed. in patients treated with ADENURIC for Tumor Lysis Syndrome.

Your doctor may order blood tests to check that your liver is functioning normally.

Children and adolescents

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

Interactions Which drugs or foods can change the effect of Adenuric

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, even those obtained without a prescription.

It is very important that you tell your doctor or pharmacist if you are taking a medicine that contains any of the following substances, as these may interact with ADENURIC and your doctor may want to consider appropriate measures:

Mercaptopurine (used to treat cancer)
Azathioprine (used to reduce the immune response)
Theophylline (used to treat asthma)

Warnings It is important to know that:

Pregnancy and breastfeeding

It is not known whether ADENURIC can harm an unborn baby. ADENURIC should not be used during pregnancy. It is not known if ADENURIC passes into breast milk. You should not take ADENURIC if you are breastfeeding or intend to do so.

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 feel dizzy, sleepy, blurred vision, numbness or tingling during treatment, and if these symptoms occur, you should not drive or operate machinery.

ADENURIC contains lactose

ADENURIC tablets contain lactose (a type of sugar). If you know you are intolerant to some sugars, talk to your doctor before taking this medicine.

Dose, Method and Time of Administration How to use Adenuric: Posology

Always take this medicine exactly as your doctor has told you. If you are unsure, you should consult your doctor or pharmacist.

The usual dose is one tablet per day. The back of the blister contains the days of the week to help you check that you have taken your dose each day.
The tablets must be taken by mouth. You can take them near or away from meals.

Chronic hyperuricemia with urate deposition ADENURIC is available as an 80 mg or 120 mg tablet. Your doctor will have prescribed the most suitable dosage for you.

Continue to take ADENURIC every day, even if you don't have a flare-up or a gout attack.

Prevention and treatment of elevated uric acid levels in patients undergoing chemotherapy ADENURIC is available as 120 mg tablets.

Start taking ADENURIC two days before chemotherapy and continue taking it according to your doctor's advice. Usage is usually short-lived.

Overdose What to do if you have taken too much Adenuric

If you take more ADENURIC than you should

In case of accidental overdose, ask your doctor what to do or contact the nearest emergency room.

If you forget to take ADENURIC

If you forget to take a dose of ADENURIC, take it as soon as you realize it, unless it is almost time for your next dose. In this case, skip the missed dose and take the next dose at the scheduled time. Do not take a double dose to make up for a forgotten dose.

If you stop taking ADENURIC

Do not stop taking ADENURIC without your doctor's consent, even if you feel better. If you stop taking ADENURIC, your uric acid levels may start to rise and your symptoms may worsen due to the formation of new urate crystals in and around your joints and kidneys.

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

Side Effects What are the side effects of Adenuric

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

Stop taking the medicine and contact your doctor immediately or go to the nearest emergency room if you experience the following rare side effects (may affect up to 1 in 1,000 people), as a severe allergic reaction could follow:

anaphylactic reactions, drug hypersensitivity (see also section "Warnings and Precautions")
life-threatening skin rashes characterized by blistering and peeling of the skin and internal surfaces of the body cavity, eg. 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 enlarged lymph nodes, enlarged liver, hepatitis (up to liver failure ), increased white blood cell count (drug reaction with eosinophilia and systemic symptoms - DRESS).
generalized rash

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

abnormalities in liver function test results
diarrhea
headache
rash (including various types of skin rashes, see below under "uncommon" and "rare")
nausea
increased symptoms of gout
localized swelling due to fluid retention in the tissues (edema)

Other side effects which are not mentioned above are listed below.

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

decreased appetite, changes in blood sugar levels (diabetes) a symptom of which may be excessive thirst, increased blood fat levels, weight gain
loss of libido (sexual desire)
difficulty sleeping, sleepiness
dizziness, numbness, tingling, reduced or altered tactile sensation (hypoesthesia, hemiparesis or paraesthesia), taste disturbance (dysgeusia), decreased sense of smell (hyposmia)
abnormalities in ECG traces, irregular or rapid heartbeat, perception of heartbeat (palpitations)
flushing or redness (e.g. redness of the face or neck), increased blood pressure, bleeding (haemorrhage, seen only in patients undergoing chemotherapy for blood disorders)
cough, shortness of breath, chest pain, inflammation of the nasal passage and / or throat (respiratory tract infection), bronchitis
dry mouth, abdominal pain or discomfort, excess gas, heartburn / indigestion, constipation, more frequent bowel movements, vomiting, stomach discomfort
itching, hives, inflammation of the skin, discolouration of the skin, small red or purple spots on the skin, small flat red spots on the skin, red area on the skin covered with small confluent bumps, rashes, areas of redness and spots on the skin, other skin disorders
muscle cramps, muscle weakness, pain in the muscles or joints, bursitis or arthritis (inflammation of the joints usually accompanied by pain, swelling and / or stiffness), pain in extremities, back pain, muscle spasms
blood in the urine, increased frequency of urination, abnormal urine test results (increased levels of protein in the urine) decreased ability of the kidneys to function properly
fatigue, chest pain, chest discomfort
stones in the gallbladder or bile duct (cholelithiasis)
increased blood levels of thyroid stimulating hormone (TSH)
changes in blood biochemical tests or red blood cell or platelet counts (changes in blood test results)
kidney stones
difficulty getting an erection

Rare side effects (may affect up to 1 in 1000 people) are:

muscle damage, a condition which on rare occasions can be serious. Muscle problems can develop and in particular, if you feel unwell or have a high fever at the same time, this could be the result of an abnormal breakdown of muscle cells. Contact your doctor immediately if you experience muscle pain, tenderness or weakness
marked swelling of the deeper layers of the skin, especially around the lips, eyes, genitals, hands, feet or tongue, with possible sudden difficulty in breathing
high fever associated with measles-like skin rash, enlarged lymph nodes, enlarged liver, hepatitis (up to liver failure), increased white blood cell count (leukocytosis, whether or not associated with eosinophilia)
redness of the skin (erythema), rash of various types (for example itchy, white patches, blisters, pus-containing blisters, peeling of the skin, measles-like rash), diffuse erythema, necrosis and blistering of the epidermis and mucous membranes, resulting in exfoliation and possible sepsis (Stevens-Johnson syndrome / toxic epidermal necrolysis)
nervousness
thirst
ringing in the ears
blurred vision, change in vision
hair loss
buccal ulceration
inflammation of the pancreas: common symptoms are abdominal pain, nausea and vomiting
increased sweating
decreased weight, increased appetite, uncontrolled loss of appetite (anorexia)
muscle and / or joint stiffness
abnormally low level of blood cells (white blood cells or red blood cells or platelets)
urge to urinate
changes or decreased amounts in the urine due to inflammation in the kidneys (tubulointerstitial nephritis)
inflammation of the liver (hepatitis)
yellowing of the skin (jaundice)
liver damage

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

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 the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

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

Do not use the medicine after the expiry date which is stated on the carton and on the foil of the tablet blister after "EXP". The expiry date refers to the last day of the month.
This medicinal product does not require any special storage conditions.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What ADENURIC contains

The active ingredient is febuxostat.

Each tablet contains 80 mg or 120 mg of febuxostat.

The excipients are:

Tablet core: lactose monohydrate, microcrystalline cellulose, magnesium stearate, hydroxypropylcellulose, croscarmellose sodium, colloidal silica hydrate.

Tablet coating: Opadry II yellow, 85F42129 containing: polyvinyl alcohol, titanium dioxide (E171), macrogol type 3350, talc, iron oxide yellow (E172).

What ADENURIC looks like and contents of the pack

ADENURIC film-coated tablets are pale yellow / yellow and capsule shaped. The 80 mg film-coated tablets are debossed with "80" on one side. The 120 mg film-coated tablets are debossed with "120" on one side.

ADENURIC 80 mg and 120 mg is packed in transparent blister (Aclar / PVC / Aluminum) containing 14 tablets.

ADENURIC 80 mg and 120 mg is available in packs of 14, 28, 42, 56, 84 and 98 film-coated tablets.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Adenuric can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

ADENURIC 80 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 80 mg of febuxostat.

Excipient (s) with known effect:

Each tablet contains 76.50 mg of lactose (as monohydrate)

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Light yellow / yellow, film-coated, capsule-shaped tablets with "80" debossed on one side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of chronic hyperuricaemia with urate deposition (including a history of, or presence of, tophi and / or gouty arthritis).

ADENURIC is indicated in adults.

04.2 Posology and method of administration

Dosage

The recommended oral dose of ADENURIC is 80 mg once daily and can be taken either near or away from meals. With serum uric acid values> 6 mg / dL (357 μmol / L) after 2-4 weeks, ADENURIC 120 mg once daily may be considered.

ADENURIC works quickly enough to allow a new determination of serum uric acid after 2 weeks. The therapeutic goal is to reduce and maintain the serum uric acid level below 6 mg / dL (357 μmol / L).

A treatment period of at least 6 months is recommended for prophylaxis of gout exacerbations (see section 4.4).

Elderly subjects

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

Renal impairment

The efficacy and safety of the medicinal product have not been fully established in patients with severe renal impairment (creatinine clearance

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

Hepatic impairment

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

The recommended dose for patients with mild hepatic impairment is 80 mg. There is limited information on the use of the medicinal product in patients with moderate hepatic impairment.

Pediatric population

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

Method of administration

Oral use

ADENURIC must be administered orally and can be taken with or without food.

04.3 Contraindications

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

04.4 Special warnings and appropriate precautions for use

Cardio-vascular disorders

Treatment with febuxostat is not recommended in patients with ischemic heart disease or congestive heart failure.

There was a numerically higher incidence of investigator-reported APTC cardiovascular events (endpoints defined by the Anti-Platelet Trialists "Collaboration) (including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) in the febuxostat group compared to that treated with allopurinol in the APEX and FACT studies (1.3 vs 0.3 events per 100 patient years), but not in the CONFIRMS study (see section 5.1 for detailed study characteristics). The incidence of investigator-reported APTC cardiovascular events in the pooled phase 3 studies (APEX, FACT, and CONFIRMS) was 0.7 vs 0.6 events per 100 patient years.

In the long-term extension studies, the incidences of investigator-reported APTC events were 1.2 and 0.6 events per 100 patient years for febuxostat and allopurinol, respectively. No statistically significant differences were observed and no causal relationship with febuxostat was established. Risk factors identified for these patients were a clinical history of atherosclerotic disease and / or myocardial infarction, or congestive heart failure.

Allergy / hypersensitivity to the drug

Rare reports of severe allergic / hypersensitivity reactions including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis and acute anaphylactic reactions / shock have been collected in the post-marketing period. In most cases, these reactions occurred during the first month of febuxostat therapy. Some, but not all, of these patients have reported renal impairment and / or previous hypersensitivity to allopurinol. In some cases, severe hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS) have been associated with fever, involvement haematological, renal or hepatic. Patients should be informed of the signs and symptoms and monitored closely for symptoms of allergic / hypersensitivity reactions (see section 4.8). Treatment with febuxostat should be discontinued immediately if severe allergic / hypersensitivity reactions occur, including Stevens-Johnson syndrome, as preventive discontinuation of treatment is associated with a better prognosis. If the patient has developed an allergic reaction / hypersensitivity, including Stevens-Johnson syndrome and acute anaphylactic reaction / shock, febuxostat should no longer be administered.

Acute attacks of gout (flare-up)

Treatment with febuxostat should not be started until the acute gout attack has completely resolved. At the start of therapy, gout flare-ups may occur due to a change in serum uric acid levels, which occur. determines following a mobilization of urates from tissue deposits (see sections 4.8 and 5.1). At the start of treatment with febuxostat, prophylaxis against flare-ups of gout for at least 6 months using an NSAID or colchicine is recommended (see section 4.2).

If a flare-up of gout occurs during treatment with febuxostat, it should not be discontinued. The exacerbation should be treated simultaneously, according to the needs of the individual patient. Continued treatment with febuxostat reduces the frequency and intensity of gout flares.

Deposition of xanthine

In patients in whom the rate at which urates are formed is increased (for example in malignant neoplasms and during their treatment or in Lesch-Nyhan syndrome), the absolute concentration of xanthine in the urine may, in rare cases, increase in measure to allow its deposit in the urinary tract. As there is no experience with febuxostat, its use in this category of patients is not recommended.

Mercaptopurine / azathioprine

The use of febuxostat is not recommended in patients treated concomitantly with mercaptopurine / azathioprine. When concomitant use cannot be avoided, patients should be carefully monitored. A dose reduction of mercaptopurine or azathioprine is recommended to avoid possible haematological effects (see section 4.5).

Subjects who have undergone an organ transplant

As there is no experience with the use of ADENURIC in organ transplant recipients, the use of febuxostat is not recommended in these patients (see section 5.1).

Theophylline

Concomitant administration of febuxostat 80 mg and theophylline 400 mg as a single dose in healthy subjects demonstrated the absence of a pharmacokinetic interaction (see section 4.5). Febuxostat 80 mg can be used in patients treated concomitantly with theophylline without the risk of increased plasma levels of theophylline There are no data available for febuxostat 120 mg.

Liver diseases

During the combined phase 3 clinical trials, mild liver function test abnormalities (5.0%) were observed in patients treated with febuxostat. Liver function tests are recommended prior to initiation of febuxostat therapy and at periodic intervals thereafter as judged by the physician (see section 5.1).

Diseases of the thyroid gland

In long-term open-label extension studies, elevated TSH values (> 5.5 mcIU / mL) were observed in long-term patients treated with febuxostat (5.5%). Caution should be used with febuxostat in patients with impaired thyroid function (see section 5.1).

Lactose

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

04.5 Interactions with other medicinal products and other forms of interaction

Mercaptopurine / azathioprine

Based on the mechanism of action of febuxostat on inhibition of xanthine oxidase (XO), concomitant use of ADENURIC with mercaptopurine / azathioprine is not recommended. Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs, leading to toxicity (see section 4.4). No interaction studies of febuxostat with XO metabolised drugs have been conducted.

No interaction studies have been performed between febuxostat and cytotoxic chemotherapy. There are no data on the safety of febuxostat used concomitantly with cytotoxic therapy.

Rosiglitazone / CYP2C8 substrates

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

Theophylline

An interaction study with febuxostat was conducted in healthy subjects to evaluate whether inhibition of XO could lead to an increase in circulating theophylline levels, as reported for other XO inhibitors. The results of the study show that concomitant administration of febuxostat, 80 mg once daily, and theophylline, 400 mg as a single dose, has no effect on the pharmacokinetics and safety of theophylline. Consequently, no particular caution is required when febuxostat 80 mg and theophylline are administered concomitantly. There are no data available for febuxostat 120 mg.

Naproxen and other glucuronidation inhibitors

The metabolism of febuxostat is dependent on uridine glucuronosyl transferase (UGT) enzymes. Drugs that inhibit glucuronidation, such as NSAIDs and probenecid, are theoretically able to affect the elimination of febuxostat. In healthy subjects, the concomitant use of febuxostat and naproxen 250 mg twice daily was associated with a increased exposure to febuxostat (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 side effects. Febuxostat can be administered concomitantly with naproxen, with no need for dose adjustment of febuxostat or naproxen.

Inducers of glucuronidation

Potent inducers of UGT enzymes may result in increased metabolism and decreased efficacy of febuxostat. A check of serum uric acid is therefore recommended 1-2 weeks after initiation of therapy with a potent glucuronidation inducer. Conversely, discontinuation of treatment with a glucuronidation inducer may result in increased plasma levels of febuxostat.

Colchicine / indomethacin / hydrochlorothiazide / warfarin

Febuxostat can be administered concurrently with colchicine or indomethacin without the need to adjust the dose of febuxostat or the other concomitantly administered active substance.

No dose adjustment of febuxostat is required when administered concomitantly with hydrochlorothiazide.

No dose adjustment of warfarin is required when administered concomitantly with febuxostat. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy patients. Furthermore, INR and activated Factor VII are not affected by the administration of febuxostat.

Desipramine / CYP2D6 substrates

Febuxostat has been shown to be a weak inhibitor of CYP2D6 in vitro. In a study in healthy subjects, 120 mg of ADENURIC once daily resulted in a mean increase of 22% in the AUC of desipramine, a CYP2D6 substrate, indicating a possible weak inhibitory action of febuxostat on the CYP2D6 enzyme. in vivo. In case of concomitant administration of febuxostat and other CYP2D6 substrates, therefore, the need for any dose adjustment for any of these compounds is not conceivable.

Antacids

It has been shown that the simultaneous intake of an antacid containing magnesium hydroxide and aluminum hydroxide delays the absorption of febuxostat (by about 1 hour) and causes a 32% decrease in Cmax, while no significant change has been observed in relation to the "AUC. It is therefore possible to take febuxostat without taking into account the use of antacid drugs.

04.6 Pregnancy and lactation

Pregnancy

Data on a very limited number of exposed pregnancies indicate no undesirable effects of febuxostat on pregnancy or on the health of the fetus / newborn. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development or parturition (see section 5.3). The potential risk for humans is unknown. Febuxostat should not be used during pregnancy.

Feeding time

It is not known whether febuxostat is excreted in human milk. Animal studies have shown an excretion of this active ingredient in breast milk accompanied by a developmental deficit in new born during lactation. A risk to the breast-fed infant cannot be excluded. Febuxostat should not be used during lactation. "breastfeeding.

Fertility

In animal reproduction studies, doses up to 48 mg / kg / day showed no dose-dependent adverse effects on fertility (see section 5.3). The effect of ADENURIC on human fertility is unknown.

04.7 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 great caution before driving, operating machinery or performing hazardous activities until they are reasonably certain that the use of ADENURIC does not impairs their performance.

04.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in clinical trials (4,072 subjects treated with at least a 10 mg to 300 mg dose) and post-marketing experience are acute gout attacks, liver function abnormalities, diarrhea, nausea, headache, rash. and edema. These adverse reactions were mostly mild or moderate in severity. Rare serious hypersensitivity reactions to febuxostat, some of which were associated with systemic symptoms, occurred in post-marketing experience.

Tabular list of adverse reactions

Common adverse reactions (≥1 / 100 -

Table 1: Adverse reactions reported in long-term combined phase III studies and post-marketing experience

Disorders of the blood and lymphatic system Rare Pancytopenia, thrombocytopenia Disorders of the immune system Rare Anaphylactic reaction *, drug hypersensitivity * Endocrine pathologies Uncommon Increased blood levels of thyroid stimulating hormone (TSH) Eye disorders Rare Blurred vision Metabolism and nutrition disorders Common*** Gout attacks Uncommon Diabetes mellitus, hyperlipidemia, decreased appetite, weight gain Rare Weight decreased, appetite increased, anorexia Psychiatric disorders Uncommon Drop in libido, insomnia Rare Nervousness Nervous system disorders Common Headache Uncommon Dizziness, paraesthesia, hemiparesis somnolence, taste disturbances, hypoesthesia, hyposmia Ear and labyrinth disorders Rare Tinnitus Cardiac pathologies Uncommon Atrial fibrillations, palpitations, abnormal ECG Vascular pathologies Uncommon Hypertension, redness of the face, hot flashes Respiratory, thoracic and mediastinal disorders Uncommon Dyspnoea, bronchitis, upper respiratory tract infection, cough Gastrointestinal disorders Common Diarrhea **, nausea Uncommon Abdominal pain, abdominal distension, gastroesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent defecation, flatulence, gastrointestinal discomfort Rare Pancreatitis, Buccal ulceration Hepatobiliary disorders Common Abnormal liver function test values ** Uncommon Cholelithiasis Rare Hepatitis, jaundice *, liver damage * Skin and subcutaneous tissue disorders Common Skin rash (including various types of rash reported with lower frequencies, see below) Uncommon Dermatitis, urticaria, pruritus, skin discolouration, skin lesions, petechiae, macular rash, maculopapular rash, papular rash Rare Toxic epidermal necrolysis *, Stevens-Johnson syndrome *, angioedema *, drug reaction with eosinophilia and systemic symptoms *, generalized (severe) rash *, erythema, exfoliative rash, follicular rash, vesicular rash, pustular rash, itchy rash *, erythematous rash, morbid rash, alopecia, hyperhidrosis Musculoskeletal and connective tissue disorders Uncommon Arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle spasms, muscle tension, bursitis Rare Rhabdomyolysis, joint stiffness, musculoskeletal stiffness Renal and urinary disorders Uncommon Renal failure, nephrolithiasis, haematuria, pollakiuria, proteinuria Rare Tubulointerstitial nephritis *, urge urgency Diseases of the reproductive system and breast Uncommon Erectile dysfunction General disorders and administration site conditions Common Edema Uncommon Fatigue, chest pain, chest discomfort Rare Thirst Diagnostic tests Uncommon Increased blood amylase, decreased platelet count, decreased white blood cell count, decreased lymphocyte count, increased blood creatine, increased blood creatinine, decreased hemoglobin, increased urea, increased blood triglycerides blood, blood cholesterol increased, hematocrit decreased, blood lactate dehydrogenase increased, blood potassium increased Rare Increased blood glucose, prolonged activated partial thromboplastin time, decreased red blood cell count, increased blood alkaline phosphatase

* Adverse reactions collected in post-marketing experience

** Emerging treatment of non-infectious diarrhea and abnormal liver function tests in the combined phase 3 studies are more frequent in patients treated concurrently with colchicine.

*** See section 5.1 for the incidence of gout attacks in the individual phase 3 randomized controlled trials.

Description of selected adverse reactions

Rare cases of severe hypersensitivity reactions to febuxostat, including Stevens-Johnson syndrome, toxic epidermal necrolysis and anaphylactic / shock reactions, have occurred in postmarketing experience. Stevens-Johnson syndrome and toxic epidermal necrolysis are characterized by eruptions progressive skin associated with blisters or mucosal lesions and eye irritation.

Hypersensitivity reactions to febuxostat may be associated with the following symptoms: skin reactions characterized by infiltrated maculopapular rash, generalized or exfoliative rashes, but also skin lesions, facial edema, fever, haematological changes such as thrombocytopenia and eosinophilia, and single or multiple organ involvement ( liver and kidneys, including tubulointerstitial nephritis) (see section 4.4).

Acute gout attacks were commonly observed soon after initiation of treatment and during the first few months. Thereafter, the frequency of gout flare-ups decreases in a time-dependent manner. Prophylaxis of acute gout attacks is recommended (see sections 4.2 and 4.4 ).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

In the event of an overdose, patients should be treated with symptomatic and supportive care.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antigout preparations, preparations inhibiting the production of uric acid.

ATC code: M04AA03

Mechanism of action

Uric acid is the final product of purine metabolism and in humans it is produced following the sequence hypoxanthine → xanthine → uric acid. Both steps of the above reaction are catalyzed by xanthine oxidase (XO). Febuxostat is a derivative 2 -arylthiazole which has the therapeutic effect of reducing serum uric acid through the selective inhibition of XO. Febuxostat is a potent, non-purine, selective inhibitor of XO (NP-SIXO) with a Ki value (constant d "inhibition) in vitro less than 1 nanomolar. Febuxostat has been shown to be able to inhibit XO with great efficacy, both in the oxidized and in the reduced form. At therapeutic concentrations, febuxostat does not inhibit the other enzymes involved in the metabolism of purines or pyrimidines, namely guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleosylase.

Clinical efficacy and safety

The efficacy of ADENURIC was demonstrated in three pivotal phase 3 studies (the two main studies APEX and FACT, and the additional CONFIRMS study described below) which were conducted in 4,101 patients with hyperuricaemia and gout. In each of the studies pivotal phase 3, ADENURIC demonstrated a greater ability than allopurinol to reduce and maintain serum uric acid levels. The primary efficacy endpoint in the APEX and FACT studies was the percentage of patients in whom uric acid levels serum in the last 3 months resulted

APEX study: APEX (Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat-Study of the efficacy of febuxostat controlled against allopurinol and placebo) was a Phase 3, randomized, double-blind, multicenter, 28-week study of duration. 1,072 were randomized. patients who received: placebo (n = 134), ADENURIC 80 mg once daily (n = 267), ADENURIC 120 mg once daily (n = 269), ADENURIC 240 mg once daily (n = 134) o allopurinol (at a dose of 300 mg once daily [n = 258] for patients with baseline serum creatinine ≤1.5 mg / dL or at a dose of 100 mg once daily [n = 10] for patients with baseline serum creatinine> 1.5 mg / dL and ≤2.0 mg / dL) The dose of 240 mg of febuxostat (equal to twice the maximum recommended dose) was used for the safety assessment.

The APEX study demonstrated statistically significant superiority of the groups treated with both ADENURIC 80 mg once daily and ADENURIC 120 mg once daily in lowering serum uric acid to levels below 6 mg / dL (357 μmol / L) compared to groups treated with conventional allopurinol doses of 300 mg (n = 258) / 100 mg (n = 10) (see Table 2 and Figure 1). FACT study: FACT (Febuxostat Allopurinol Controlled Trial) was a 52-week, randomized, double-blind, multicentre, phase 3 study. 760 patients were randomized who received: ADENURIC 80 mg once daily (n = 256), ADENURIC 120 mg once daily (n = 251), or allopurinol 300 mg once daily (n = 253).

The FACT study demonstrated statistically significant superiority of the groups treated with both ADENURIC 80 mg and ADENURIC 120 mg once daily in lowering and maintaining serum uric acid below 6 mg / dL (357 μmol / L) compared to the group treated with the conventional dose of allopurinol of 300 mg.

Table 2 summarizes the results of the primary efficacy endpoint:

Table 2

Percentage of patients with serum uric acid levels

Last three monthly visits

Study ADENURIC 80 mg once daily ADENURIC 120 mg once daily Allopurinol 300/100 mg once a day APEX (28 weeks) 48% * (n = 262) 65% *, # (n = 269) 22% (n = 268) FACT (52 weeks) 53% * (n = 255) 62% * (n = 250) 21% (n = 251) Results (Sum) 51% * (n = 517) 63% *, # (n = 519) 22% (n = 519) 1 the results obtained from subjects treated with 100 mg once daily (n = 10: patients with serum creatinine> 1.5 and 2.0 mg / dL) or with 300 mg once daily (n = 509) were collected together for analysis. * p

The ability of ADENURIC to lower serum uric acid levels was rapid and persistent. The reduction in serum uric acid levels to values

CONFIRMS Study: The CONFIRMS study was a 26-week, randomized, controlled, phase 3 study to evaluate the safety and efficacy of febuxostat 40 mg and 80 mg, compared to allopurinol 300 mg or 200 mg, in patients with gout and hyperuricaemia. 2,269 patients were randomized: ADENURIC 40 mg once daily (n = 757), ADENURIC 80 mg once daily (n = 756) or allopurinol 300/200 mg once daily (n = 756). 65% of patients had mild to moderate renal impairment (with creatinine clearance of 30-89 mL / min) Gout prophylaxis was mandatory beyond the 26-week period.

The proportion of patients with serum urate levels of μmol / L at the final visit was 45% for 40 mg of febuxostat, 67% for 80 mg of febuxostat and 42% for allopurinol 300/200 mg, respectively.

Primary endpoint in the subgroup of patients with renal impairment

The APEX study evaluated the drug's efficacy in 40 patients with renal impairment (baseline serum creatinine> 1.5 mg / dL and ≤ 2.0 mg / dL). For patients with renal impairment who were randomized to receive allopurinol, the latter dose was limited to 100 mg once a day. ADENURIC achieved the primary efficacy endpoint in 44% (80 mg once daily), 45% (120 mg once daily), and 60% (240 mg once daily) of patients respectively compared to 0 % found in the allopurinol 100 mg once daily and placebo groups.

No clinically significant differences were observed in the rate of reduction in serum uric acid concentrations in healthy subjects regardless of their renal function status (58% in the normal renal function group and 55% in the severe renal impairment group).

An "analysis in patients with gout and renal impairment was prospectively defined in the CONFIRMS study, and demonstrated that febuxostat was significantly more effective in reducing serum urate levels than

Primary endpoint in the subgroup of patients with a serum uric acid level ≥ 10 mg / dL

Approximately 40% of patients (APEX and FACT taken together) had a baseline serum uric acid value ≥ 10 mg / dL. In this subgroup ADENURIC achieved the primary efficacy endpoint (uric acid level

In the CONFIRMS study, the proportion of patients who met the primary efficacy endpoint (uric acid level

Clinical results: Percentage of patients who required treatment for a gout attack

APEX study: During the 8-week prophylaxis period, a higher proportion (36%) of patients treated with febuxostat 120 mg required treatment for a gout attack than febuxostat 80 mg (28%), allopurinol 300 mg (23%) and placebo (20%). Attacks increased following the prophylaxis period and gradually decreased over time. Between 46% and 55% of subjects received treatment for acute gout attacks from week 8 to week 28. Gout attacks 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 the patients. FACT: During the 8-week prophylaxis period, a greater proportion (36%) of patients treated with febuxostat 120 mg required treatment for gout flare-up than both treatments with febuxostat 80 mg (22%) and allopurinol 300 mg (21%).

After the 8-week prophylaxis period, the incidence of acute attacks gradually increased and decreased over time (64% and 70% of subjects received treatment for acute gout attacks from week 8 to week 52). Gout attacks 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 patients.

The percentage of patients who required treatment for a gout flare (APEX and FACT Studies) was numerically lower in the groups that achieved a mean post-baseline serum urate level.

During the CONFIRMS study, the percentages of patients requiring treatment for gout attacks (Day 1 through Month 6) were 31% and 25% for the febuxostat 80 mg and allopurinol groups, respectively. There was no difference in the proportion of patients needing treatment for gout attacks between the febuxostat 80 mg and 40 mg groups.

Long-term open label extension studies

EXCEL Study (C02-021): EXCEL was a three-year Phase 3, open-label, multicentre, randomized, 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: ADENURIC 80 mg once daily (n = 649), ADENURIC 120 mg once daily (n = 292) and allopurinol 300/100 mg once daily (n = 145). Approximately 69% of patients required no treatment changes to achieve a stable final response. Patients who had three consecutive urica levels> 6.0 mg / dL were withdrawn.

Serum urate levels were maintained over time (e.g. 91% and 93% of patients on initial treatment with febuxostat 80 mg and 120 mg, respectively, had uricaemia

Three-year data demonstrated a reduction in the incidence of gout flare-ups with less than 4% of patients requiring treatment for an exacerbation (i.e. more than 96% of patients requiring no treatment for an exacerbation) after 16-24 months and 30-36 months 46% and 38% of patients on final stable treatment with febuxostat 80 mg or 120 mg once daily, respectively, had complete resolution of palpable primary tophus from baseline to final visit.

FOCUS Study (TMX-01-005): FOCUS was a 5-year Phase 2, open-label, multicenter, safety extension study for patients who had completed 4 weeks of febuxostat dosing in the double-blind TMX study -00-004. 116 patients were enrolled and initially received febuxostat 80 mg once daily. 62% of patients required no dose adjustment to maintain uricaemia

The proportion of patients with serum urate levels

During phase 3 clinical trials, mild changes in liver function test values (5.0%) were observed in patients treated with febuxostat. These values were similar to those reported for allopurinol (4.2%) (see section 4.4). Increased TSH values (> 5.5 mcIU / mL) were observed in long-term open-label extension studies in patients. long-term treated with febuxostat (5.5%) and in patients treated with allopurinol (5.8%) (see section 4.4).

05.2 Pharmacokinetic properties

In healthy subjects, the Cmax (maximum plasma concentration) and AUC (area under the curve) of febuxostat increased dose proportionally after single and repeated dose administration from 10 mg to 120 mg. For febuxostat doses ranging from 120 mg and 300 mg, a greater than dose proportional increase in AUC is observed. No appreciable accumulation is evident after the administration of doses of 10 mg to 240 mg every 24 hours. Febuxostat has an apparent terminal elimination half-life (t1 / 2) of approximately 5-8 hours.

Population pharmacokinetic / pharmacodynamic analyzes were conducted on 211 patients with hyperuricaemia and gout who were treated with ADENURIC at a dose of 40-240 mg once daily.

In general, the pharmacokinetic parameters of febuxostat, estimated by these analyzes, are consistent with those observed in healthy subjects, indicating that healthy subjects are representative for the purpose of pharmacokinetic / pharmacodynamic evaluation in the gout patient population.

Absorption

Febuxostat is absorbed rapidly (Tmax of 1.0-1.5 h) and almost completely (at least 84%). Following administration of a single oral dose or multiple oral doses of 80 and 120 mg once daily, Cmax is approximately 2.8-3.2 mcg / mL, and 5.0-5.3 mcg / mL. mL, respectively. The absolute bioavailability of the febuxostat tablet formulation has not been studied.

Following administration of multiple oral doses of 80 mg once daily or a single 120 mg dose together with a high-fat meal, a reduction in Cmax of 49% and 38%, respectively, and a decrease in Cmax were observed. "AUC of 18% and 16% respectively.

However, no clinically significant change was observed in the percentage reduction in serum uric acid concentration when evaluated (repeated doses of 80 mg). Therefore, ADENURIC can be taken either near or away from meals.

Distribution

The apparent volume of distribution at steady state (Vss / F) of febuxostat ranges from 29 to 75 l after oral doses of 10-300 mg. Plasma protein binding of febuxostat is approximately 99.2%, (mainly albumin), and remains constant over the concentrations achieved with doses of 80 to 120 mg. Plasma protein binding of metabolites assets is between 82% and 91% approximately.

Biotransformation

Febuxostat is extensively metabolised by conjugation via the uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and by oxidation via the cytochrome P450 (CYP) system. Four pharmacologically active hydroxyl metabolites have been identified, three of which can be observed in human plasma. Studies in vitro with human liver microsomes showed that these oxidative metabolites consisted mainly of CYP1A1, CYP1A2, CYP2C8 or CYP2C9 and febuxostat glucuronide mainly from UGT 1A1, 1A8, and 1A9.

Elimination

Febuxostat is eliminated by both hepatic and renal routes. After oral administration of an 80 mg dose of 14C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), active substance acylglucoronide (30%), its oxidative metabolites together with their conjugates (13%), and other unknown metabolites (3%). In addition to elimination via urine, approximately 45% of the dose was recovered in the faeces in the form of unchanged febuxostat (12%), acylglucuronide of the active ingredient (1%), its known oxidative metabolites together with their conjugates (25 %), and other unknown metabolites (7%).

Renal impairment

After administration of repeated doses of 80 mg of ADENURIC in patients with mild, moderate or severe renal impairment, the Cmax of febuxostat was not different from that of subjects with normal renal function.The overall mean AUC of febuxostat increased approximately 1.8-fold from 7.5 mcg.h / mL in the normal renal function group to 13.2 mcg.h / mL in the severe renal impairment group. "AUC of the active metabolites increased up to 2 and 4 fold, respectively. However, no dose adjustment is necessary in subjects with mild or moderate renal impairment.

Hepatic impairment

After repeated administration of 80 mg of ADENURIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, the Cmax and AUC of febuxostat and its metabolites did not change significantly. compared to subjects with normal hepatic function No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

Age

No significant changes in the AUC of febuxostat or its metabolites were observed after repeated administration of oral doses of ADENURIC in elderly subjects compared to younger healthy subjects.

Type

Following repeated oral doses of ADENURIC, Cmax and AUC were 24% and 12% higher in females than in males, respectively. However, weight-adjusted Cmax and AUC were similar for both genders. No dose adjustment is required based on gender.

05.3 Preclinical safety data

Effects that occurred in non-clinical studies were generally observed with drug exposures in excess of the maximum human exposure.

Carcinogenesis, mutagenesis, impairment of fertility

In male rats, a statistically significant increase in bladder tumors (transitional cell papilloma and carcinoma) was observed only in the presence of xanthine stones in the group treated with the highest dose, corresponding to doses approximately 11 times higher than the exposure. No significant increase in any of the other tumor types was observed, neither in male mice or rats, nor in female mice or rats. These observations are considered to be a consequence of species-specific metabolism of purines and urine composition and it is of no relevance to the clinical use of the medicinal product.

A standard battery of genotoxicity tests did not reveal any relevant genotoxic effects of febuxostat.

Febuxostat at oral doses up to 48 mg / kg / day had no effect on fertility and reproductive performance in both male and female rats.

There was no evidence of impaired fertility, teratogenic effects or harmful consequences for the fetus from the action of febuxostat. In rats, at high doses and with an exposure of approximately 4.3 times that of humans, it was observed a toxicity for the mother accompanied by a reduction in the weaning index and a delay in the development of the offspring. Teratological studies conducted on pregnant rats and rabbits with exposure of approximately 4.3 and 13 times that for humans, respectively did not reveal any teratogenic effects of febuxostat.