FEBUXOSTAT KRKA 120 MG FILM-COATED TABLETS - summary of medicine characteristics

Febuxostat Krka 120 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 120 mg febuxostat.

Excipient(s) with known effect

– lactose: 109 mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Brownish yellow, slightly biconvex, capsule shaped film-coated tablets scored on both sides. Tablet dimension: approximately 19 mm x 8 mm. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4.1 Therapeutic indications

Febuxostat Krka 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 Krka is indicated for the prevention and treatment of hyperuricaemia in adult patients undergoing chemotherapy for haematologic malignancies at intermediate to high risk of Tumor Lysis Syndrome (TLS).

Febuxostat Krka is indicated in adults.

4.2 Posology and method of administration

Posology

Gout: The recommended oral dose of Febuxostat Krka is 80 mg once daily without regard to food. If serum uric acid is > 6 mg/dL (357 gmol/L) after 2–4 weeks, Febuxostat Krka 120 mg once daily may be considered.

Febuxostat Krka 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 gmol/L).

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

Tumor Lysis Syndrome:

The reccomended oral dose of Febuxostat Krka is 120 mg once daily without regard to food.

Febuxostat Krka should be started two days before the beginning of cytotoxic therapy and continued for a minimum of 7 days; however treatment may be prolonged up to 9 days according to chemotherapy duration as per clinical judgment.

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.

Tumour Lysis Syndrome: in the pivotal Phase III trial (FLORENCE) only subjects with severe hepatic insufficiency were excluded from trial participation. No dose adjustment was required for enrolled patients on the basis of hepatic function.

Paediatric population

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

Method of administration

Oral use

Febuxostat Krka 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

Cardiovascular 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, nonfatal stroke) was observed in the febuxostat total group compared to the allopurinol group in the APEX and FACT studies (1.3 vs. 0.3 events per 100 Patient Years (PYs)), but not in the CONFIRMS study (see section 5.1 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).

Prevention and treatment of hyperuricaemia in patients at risk of TLS Patients undergoing chemotherapy for haematologic malignancies at intermediate to high risk of Tumor Lysis Syndrome treated with febuxostat should be under cardiac monitoring as clinically appropriate.

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. This has not been observed in the pivotal clinical study with febuxostat in the Tumor Lysis Syndrome. As there has been no experience with febuxostat, its use in patients with Lesch-Nyhan Syndrome is not recommended.

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 the 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 400 mg 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 ulU/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).

Excipients

Febuxostat Krka contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine 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 interaction

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 drugs leading to toxicity. Drug interaction studies of febuxostat with drugs (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. In the Tumor Lysis Syndrome pivotal trial febuxostat 120 mg daily was administered to patients undergoing several chemotherapy regimens, including monoclonal antibodies. However, drug-drug and drugdisease interactions were not explored during this study. Therefore, possible interactions with any concomitantly administered cytotoxic drug cannot be ruled out.

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.

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 advised when febuxostat 80 mg and theophylline are given concomitantly. No data is available for febuxostat 120 mg.

Naproxen and other inhibitors of glucuronidation

Febuxostat metabolism depends on Uridine Glucuronosyl Transferase (UGT) enzymes. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. In healthy subjects concomitant use of febuxostat and naproxen 250 mg twice daily was associated with an increase in febuxostat exposure (Cmax 28%, AUC 41% and t1/2 26%). In clinical studies the use of naproxen or other NSAIDs/Cox-2 inhibitors was not related to any clinically significant increase in adverse events.

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

Inducers of glucuronidation

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

Antacids

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Data on a very limited number of exposed pregnancies have not indicated any adverse effects of febuxostat on pregnancy or on the health of the foetus/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.

Breast-feeding

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 effects on fertility (see section 5.3). The effect of Febuxostat Krka on human fertility is unknown.

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 Krka 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.

The frequencies are based on studies and post-marketing experience in gout patients.

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.

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 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).

Tumor Lysis Syndrome

Summary of the safety profile

In the randomized, double-blind, Phase 3 pivotal FLORENCE (FLO-01) study comparing febuxostat with allopurinol (346 patients undergoing chemotherapy for haematologic malignancies and at intermediate-to-high risk of TLS), only 22 (6.4%) patients overall experienced adverse reactions, namely 11 (6.4%) patients in each treatment group. The majority of adverse reactions were either mild or moderate.

Overall, the FLORENCE trial did not highlight any particular safety concern in addition to the previous experience with febuxostat in gout, with the exception of the following three adverse reactions (listed above in table 1).

Cardiac disorders:

Uncommon: Left bundle branch block, sinus tachycardia

Vascular disorders:

Uncommon: haemorrhage

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 Yellow Card Scheme, Website:

www.mhra.gov.uk/y­ellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

In healthy subjects, maximum plasma concentrations (Cmax) 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 mean terminal elimination half-life (t1/2) 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.

Absorption

Febuxostat is rapidly (tmax of 1.0–1.5 h) and well absorbed (at least 84%). After single or multiple oral 80 and 120 mg once daily doses, Cmax is approximately 2.8–3.2 pg/mL, and 5.0–5.3 pg/mL, respectively. Absolute bioavailability of the febuxostat tablet formulation has not been studied.

Following multiple oral 80 mg once daily doses or a single 120 mg dose with a high fat meal, there was a 49% and 38% decrease in Cmax and a 18% and 16% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed where tested (80 mg multiple dose). Thus, febuxostat may be taken without regard to food.

Distribution

The apparent steady state volume of distribution (Vss/F) of febuxostat ranges from 29 to 75 L after oral doses of 10–300 mg. The plasma protein binding of febuxostat is approximately 99.2%, (primarily to albumin), and is constant over the concentration range achieved with 80 and 120 mg doses. Plasma protein binding of the active metabolites ranges from about 82% to 91%.

Biotransformation

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

Elimination

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

Renal impairment

Following multiple doses of 80 mg of febuxostat in patients with mild, moderate or severe renal impairment, the Cmax of febuxostat did not change, relative to subjects with normal renal function. The mean total AUC of febuxostat increased by approximately 1.8-fold from 7.5 pg h/mL in the normal renal function group to 13.2 Lig.li/iml. in the severe renal dysfunction group. The Cmax and AUC of active metabolites increased up to 2– and 4-fold, respectively. However, no dose adjustment is necessary in patients with mild or moderate renal impairment.

Hepatic impairment

Following multiple doses of 80 mg of febuxostat 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

There were no significant changes observed in AUC of febuxostat or its metabolites following multiple oral doses of febuxostat in elderly as compared to younger healthy subjects.

Gender

Following multiple oral doses of febuxostat, the Cmax and AUC were 24% and 12% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. No dose adjustment is needed based on gender.

5.3 Preclinical safety data

Effects in non-clinical studies were generally observed at exposures in excess of the maximum human exposure.

Pharmacokinetic modelling and simulation of rat data suggests that, when coadministered with febuxostat, the clinical 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 4.4 and 4.5).

Carcinogenesis, mutagenesis, impairment of fertility

In male rats, a statistically significant increase in urinary bladder tumours (transitional cell papilloma and carcinoma) was found only in association with xanthine calculi in the high dose group, at approximately 11 times human exposure. There was no significant increase in any other tumour type in either male or female mice or rats. These findings are considered a consequence of species specific purine metabolism and urine composition and of no relevance to clinical use.

A standard battery of test for genotoxicity did not reveal any biologically relevant genotoxic effects for febuxostat.

Febuxostat at oral doses up to 48 mg/kg/day was found to have no effect on fertility and reproductive performance of male and female rats.

There was no evidence of impaired fertility, teratogenic effects, or harm to the foetus due to febuxostat. There was high dose maternal toxicity accompanied by a reduction in weaning index and reduced development of offspring in rats at approximately 4.3 times human exposure. Teratology studies, performed in pregnant rats at approximately 4.3 times and pregnant rabbits at approximately 13 times human exposure did not reveal any teratogenic effects.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Lactose monohydrate

Cellulose, microcrystalline Hydroxypropyl­cellulose Croscarmellose sodium Silica, colloidal hydrated Magnesium stearate

Film coating

Poly(vinyl alcohol) Macrogol 3350

Titanium dioxide (E171) Talc

Iron oxide, yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister (PVC/PVDC/PVC­//Alu): 14, 28, 56 or 84 film-coated tablets, in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto, Slovenia

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 01656/0308