febuxostat

ADENURIC 80 mg tablet: Each tablet contains 80 mg of febuxostat. Excipients: Each tablet contains 76.50 mg of lactose monohydrate ADENURIC 120 mg tablet: Each tablet contains 120 mg of febuxostat. Excipients: Each tablet contains 114.75mg of lactose monohydrate

Film-coated tablet. ADENURIC 80 mg tablet: Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with “80” on one side. ADENURIC 120 mg tablet: Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with “120” on one side

Treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis).

The recommended oral dose of ADENURIC is 80 mg once daily without regard to food. If serum uric acid is> 6 mg/dl (357 µmol/l) after 2-4 weeks, ADENURIC 120 mg once daily may be considered.

ADENURIC 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 (357μmol/l).

Gout flare prophylaxis of at least 6 months is recommended.

Special populations

Renal insufficiency

No dosage adjustment is necessary in patients with mild or moderate renal impairment. The efficacy and safety have not been fully evaluated in patients with severe renal impairment.

Hepatic impairment

The recommended dosage in patients with mild hepatic impairment is 80 mg. Limited information is available in patients with moderate hepatic impairment. The efficacy and safety of febuxostat has not been studied in patients with severe hepatic impairment (Child Pugh Class C).

Elderly

No dose adjustment is required in the elderly.

Children and adolescents

As there has been no experience in children and adolescents, the use of febuxostat in such patients is not recommended.

Organ transplant recipients

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

Hypersensitivity to the active substance or to any of the excipients.

Cardio-vascular disorders

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

Acute gouty attacks (gout flare)

Febuxostat treatment should not be started until an acute attack of gout has completely subsided. As with other urate lowering medicinal products, gout flares may occur during initiation of treatment due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. At treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or colchicine is recommended.

If a gout flare occurs during febuxostat treatment, it should not be discontinued. The gout flare should be managed concurrently as appropriate for the individual patient. Continuous treatment with febuxostat decreases frequency and intensity of gout flares.

Xanthine deposition

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

Mercaptopurine/azathioprine

Febuxostat use is not recommended in patients concomitantly treated with mercaptopurine/azathioprine.

Theophylline

Febuxostat should be used with caution in patients concomitantly treated with theophylline and theophylline levels should be monitored in patients starting febuxostat therapy.

Liver disorders

During the phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (3.5%). Liver function test is recommended prior to the initiation of therapy with febuxostat and periodically thereafter based on clinical judgement.

Thyroid disorders

Increased TSH values (>5.5 µIU/ml) were observed in patients on long-term treatment with febuxostat (5.0%) in the long term open label extension studies. Caution is required when febuxostat is used in patients with alteration of thyroid function.

Lactose

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

Mercaptopurine/azathioprine

Although interaction studies with febuxostat have not been performed, inhibition of xanthine oxidase (XO) is known to result in an increase in mercaptopurine or azathioprine levels. On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended.

Drug interaction studies of febuxostat with cytotoxic chemotherapy have not been conducted. No data is available regarding the safety of febuxostat during cytotoxic therapy.

Theophylline

Although interaction studies have not been performed with febuxostat, inhibition of XO may cause an increase in the theophylline level (inhibition of the metabolism of theophylline has been reported with other XO inhibitors). Hence caution is advised if these active substances are given concomitantly, and theophylline levels should be monitored in patients starting febuxostat therapy.

Naproxen and other inhibitors of glucuronidation

Febuxostat metabolism depends on 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 250mg BID was associated with an increase in febuxostat exposure (C_max 28%, AUC 41% and t_1/2 26%). In clinical studies the use of naproxen or other NSAIDs/Cox-2 inhibitors was not related to any clinically significant increase in adverse events.

Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxen being necessary.

Inducers of glucuronidation

Potent inducers of UGT enzymes 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 ADENURIC 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, coadministration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds.

Antacids

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

A total of 4,072 subjects received at least one dose of ADENURIC (10 mg – 300 mg) in clinical studies.

Combined phase 3 randomised controlled studies

In randomised controlled phase 3 clinical studies, >2,500 patients have been treated with 40 mg to 120 mg (1513 subjects enrolled in a 26-week study (CONFIRMS), 536 subjects enrolled in a 28-week study (APEX) and 507 subjects enrolled in a 52-weeks study (FACT)). The treatment-related events (ADRs) were mostly mild or moderate in severity.

The most commonly reported ADRs (investigator assessment) are liver function abnormalities (5.0%), diarrhoea (2.7%), nausea (1.3%), headache (1.2%), rash (1.2 %).

Gout flares were also 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. As with other urate lowering medicinal products, gout flare prophylaxis is recommended.

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 PYs), but not in the CONFIRMS study. The incidence of investigator-reported cardiovascular APTC events in the combined Phase III 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.

Common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100) and rare ( 1/10,000 to < 1/1000) adverse reactions suspected (investigator assessment) to be drug related occurring in patients treated with 40 mg to 120 mg febuxostat and reported more than once in the total febuxostat treatment group are listed below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Treatment related adverse reactions in combined phase 3 randomized controlled studies

^* Treatment-emergent non-infective diarrhoea and abnormal liver function tests in the combined Phase III studies are more frequent in patients concomitantly treated with colchicine.

Long-term open label extension studies

In the long-term open label extension studies (1143 patients), the number of patients treated with febuxostat 40 mg/80 mg/120 mg up to 1 year was 909, up to 2 years was 781, up to 3 years was 348, and up to 4 and 5 years was 60. The treatment-related events reported during the long-term extension studies were similar to those reported in the Phase 3 studies (see Table 1). The most commonly reported treatment-related events (investigator assessment) are: liver function abnormalities, diarrhoea, headache, rash, hypertension, oedema.

The following treatment-related events were reported more than once in the total febuxostat treatment group and were reported as uncommon in patients taking febuxostat 40 mg/80 mg/120 mg in long-term extension studies (up to 5 years, >2,660 Patient-years of exposure). These treatment-related events were either not reported or reported at a lower frequency for these doses, in the combined Phase 3 studies: abdominal distension, cholelithiasis, bronchitis, weight increase, blood creatine increase, diabetes mellitus, hyperlipidaemia, arthritis, muscle tightness, hyposmia, hemiparesis, cough, skin discolouration, skin lesion, bursitis, proteinuria, petechiae, erectile dysfunction, blood potassium increase, blood TSH increase, lymphocyte count decreased, WBC decrease.

Adverse reactions from spontaneous reporting

There have been post-marketing reports of rare serious rashes, generalised skin rashes and severe hypersensitivity reactions. In most cases, these reactions occurred during the first month of therapy with febuxostat. Some of these patients, but not all, reported previous hypersensitivity to allopurinol.

A.Menarini Pharma U.K. S.R.L.

POM – Prescription Only Medicine

22 November 2011