Zurampic - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Zurampic 200 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 200 mg of lesinurad.

Excipient with known effect : Each tablet contains 52.92 mg of lactose (as monohydrate)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Oval, 5.7 × 12.9 mm, blue tablets.

Tablets are engraved with “LES200” on one side

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Zurampic, in combination with a xanthine oxidase inhibitor, is indicated in adults for the adjunctive treatment of hyperuricaemia in gout patients (with or without tophi) who have not achieved target serum uric acid levels with an adequate dose of a xanthine oxidase inhibitor alone.

4.2 Posology and method of administration

Posology

The recommendedSose of Zurampic is 200 mg once daily in the morning. This is also the maximum dose (see section 4.4).

Zurampic tablets must be co-administered at the same time as the morning dose ofa xanthine oxidase inhibitor, i.e. allopurinol or febuxostat. The recommended minimum dose of allopurinol is 300 mg, or 200 mg for patients with moderate renal impairment (creatinine clearance [CrCL] of 30–59 mL/min). If treatment with the xanthine oxidase inhibitor is interrupted, Zurampic dosing must also be interrupted.

Patients should be informed that failure to follow these instructions may increase the risk of renal events (see section 4.4).

Patients should be instructed to stay well hydrated (e.g. 2 litres of liquid per day).

The target serum uric acid level is less than 6 mg/dL (360 ^mol/L). In patients with tophi or persistent symptoms, the target is less than 5 mg/dL (300 ^mol/L). Testing for the target serum uric acid level may be performed as early as 4 weeks after initiating Zurampic treatment.

4.3 Contraindications

syndrome or Lesch-Nyhan syndrome.

Severe renal impairment (CrCL less than 30 mL/min), end-stage renal disease, kidney transplant recipients or patients on dialysis (see section 4.2).

ial warnings and precautions for use

Treatment with lesinurad 200 mg in combination with a xanthine oxidase inhibitor was associated with an increased incidence of serum creatinine elevations, which are related to increased renal uric acid excretion. Adverse reactions related to renal function can occur after initiating Zurampic (see section 4.8). A higher incidence of serum creatinine elevations and renal-related adverse reactions including serious adverse reactions was observed with Zurampic 400 mg when given alone or in combination with a xanthine oxidase inhibitor, with the highest incidence when Zurampic was given as monotherapy. Zurampic should not be used as monotherapy or at doses above the recommended dose.

Experience with Zurampic in patients with an estimated CrCL (eCrCL) less than 45 mL/min is limited; therefore, Zurampic should be used with caution in patients with a CrCL from 30 mL/min to less than 45 mL/min.

Renal function should be evaluated prior to initiation of Zurampic and monitored periodically thereafter, e.g. 4 times per year, based on clinical considerations, such as baseline renal function, volume depletion, concurrent illness or concomitant medications. Patients with serum creatinine elevations to greater than 1.5 times the pre-treatment value should be closely monitored. Zurampic should be interrupted if serum creatinine is elevated to greater than 2 times the pre-treatment value or in case of an absolute serum creatinine value greater than 4.0 mg/dL. Treatment should be interrupted in patients who report symptoms that may indicate acute uric acid nephropathy including flank pain, nausea or vomiting, and measure serum creatinine promptly. Zurampic should not be restarted without another explanation for the serum creatinine abnormalities.

Pre-existing cardiovascular disease

Zurampic is not recommended in patients with unstable angina, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled hypertension or with a recent event of myocardial infarction, stroke, or deep venous thrombosis within the last 12 months, due to insufficient data. For cardiovascular patients in a stable condition, the benefit/risk balance should be assessed for each individual patient on an ongoing basis, taking into account the benefits of lowering urate levels versus a potential increase in cardiac risk (see section 4.8).

Acute gouty attacks (gout flares)

Gout flares may occur after initiation of therapy with Zurampic. This is due to reduction in serum uric acid levels resulting in mobilisation of urate from tissue deposits. Gout flare prophylaxis with colchicine or an NSAID is recommended for at least 5 months when starting Zurampic therapy (see section 4.2).

Zurampic does not need to be discontinued because of a gout flare. The gout flare should be managed concurrently as appropriate for the individual patient. Continuous treatment with Zurampic decreases the frequency of gout flares.

Effect of CYP2C9 genotype

Patients known to be CYP2C9 poor metabolisers should be treated with caution, as the potential risk of renal-related adverse effects may be increased (see sections 4.8 and 5.2).

Clinically relevant interactions* vith other medicinal products

derate inducer of CYP3A (see section 4.5). An induction effect of lesinurad r 2 to 3 weeks of continuous co-administration of Zurampic. Additional

monitoringids and blood pressure is recommended in patients using sensitive CYP3A substrate lipid loweredicines (such as lovastatin or simvastatin) or antihypertensive medicines (such as amlodipine, felodipine or nisoldipine), since their efficacy may be reduced (see section 4.5).

Hormonal contraceptives

Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Zurampic is co-administered. Female patients of childbearing age should practice additional methods of contraception and not rely on hormonal contraception alone when taking Zurampic (see sections 4.5 and 4.6).

Very elderly (>75 years)

Therapeutic experience in patients 75 years and older is limited. Caution should be used when treating these patients with Zurampic.

Secondary hyperuricaemia

No studies have been conducted in patients with secondary hyperuricaemia (including organ transplant recipients).

Lactose intolerance

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

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Salicylates

Salicylates at doses higher than 325 mg per day may decrease the serum uric acid lowering lesinurad and should not be co-administered with Zurampic. Consistent serum uric acid low observed in patients who were receiving low dose acetylsalicylic acid in the placebo-contro studies in combination with allopurinol or febuxostat. There are no restrictions for doses of of 325 mg or less per day (i.e. for cardiovascular protection).

Thiazide diuretics

Consistent serum uric acid lowering was observed in patients who were receiving thiazide diuretics in the placebo-controlled clinical studies in combination with allopurinol or febuxostat.

Pharmacokinetic interactions

Effect of lesinurad on other medicinal products

CYP3A substrates

Mild to moderate induction of CYP3A by lesinurad may reduce plasma exposures of co-administered medicines that are sensitive substrates of CYP3A. In interaction studies conducted in healthy subjects with Zurampic and CYP3A substrates, lesinurad reduced the plasma concentrations of sildenafil and amlodipine. HMG-CoA reductase inhibithat are sensitive CYP3A substrates may interact with

ter proportion of patients using lipid lowering or antisubstrates required concomitant medicinal product change combination with a xanthine oxidase inhibitor, compared with ination with a xanthine oxidase inhibitor (35% versus 28%, reduced efficacy of concomitant medicinal products that are CYP3A and their efficacy (e.g. blood pressure and cholesterol levels) should

ion study conducted in healthy subjects with multiple doses of Zurampic 400 mg and arin (25 mg), lesinurad led to a decrease in exposure of R -warfarin (the less active d had no effect on the exposure of S -warfarin (the more active enantiomer).

y, lesinurad led to a 6–8% decrease in International Normalised Ratio (INR) and

ombin Time (PT). The standard INR monitoring schedule should be applied, and no further actions are required.

Hormonal contraceptives

Lesinurad is a mild to moderate inducer of CYP3A and therefore may lower plasma concentrations of some hormonal contraceptives, thereby decreasing contraceptive effectiveness (see sections 4.4 and 4.6).

CYP2B6 substrates

Based on in vitro data, lesinurad may be a mild inducer of CYP2B6 but this interaction has not been studied clinically. Therefore, it is recommended that patients are monitored for reduced efficacy of CYP2B6 substrates (e.g. bupropion, efavirenz) when co-administered with Zurampic.

Based on interaction studies in healthy subjects or gout patients, Zurampic does not have clinically significant interactions with NSAIDs (naproxen and indomethacin), colchicine, repaglinide, tolbutamide, febuxostat or allopurinol. Zurampic slightly decreased exposure of oxypurinol (a URAT1 substrate), the major metabolite of allopurinol; however, the uric acid-lowering effect of the combination with allopurinol was significantly greater than for either substance alone.

Effect of other medicinal products on lesinurad

CYP2C9 inhibitors and inducers

Lesinurad exposure is increased when it is co-administered with inhibitors of CYP2C9. Fluconazole, a moderate CYP2C9 inhibitor, increased lesinurad AUC (56%) and Cmax (38%), as well as the amount of lesinurad excreted unchanged in urine. Other moderate CYP2C9 inhibitors, such as amiodarone, would also be expected to affect lesinurad pharmacokinetics to a similar degree. Therefore, it is recommended that Zurampic should be used with caution in patients taking moderate inhibitors of CYP2C9. Lesinurad exposure is expected to decrease when it is co-administered with inducers of CYP2C9 (e.g. carbamazepine, a moderate CYP2C9 inducer). Monitor for decreased efficacy when Zurampic is co-administered with a CYP2C9 inducer.

Rifampin

Rifampin, an inhibitor of OATPs and an inducer of CYP2C9, decreased lesinurad exposure and slightly reduced the amount of lesinurad excreted unchanged in urine with no clinically relevant effect.

The lack of an observed interaction could be due to the com inhibition of OATP1B1 and 1B3.

Epoxide hydrolase inhibitors

Inhibitors of microsomal Epoxide Hydrolase (mEH) (e.g. valproic acid, valpromide) may interfere with the metabolism of lesinurad. Zurampic should not be administered with inhibitors of mEH.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use o

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Zurampic during pregnancy. Female patients of childbearing potential should not rely on hormonal contraception alone when taking Zurampic (see sections 4.4 and 4.5).

acodynamic/to­xicological data in rats have shown excretion of lesinurad in milk. A rns/infants cannot be excluded. Zurampic should not be used during breast-feeding.

Fertility

The effect of lesinurad on fertility in humans has not been studied. In rats, there was no effect on mating or fertility with lesinurad (see section 5.3).

4.7 Effects on ability to drive and use machines

Lesinurad has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The safety of Zurampic 200 mg was evaluated in the Phase 3 combination therapy clinical trials (including extension studies). The most commonly reported adverse reactions during treatment with Zurampic 200 mg are influenza, gastro-oesophageal reflux disease, headache and blood creatinine increased. The serious adverse reactions renal failure, renal impairment and nephrolithiasis have occurred uncommonly (less than 1 case per 100 patients) (see Table 1). In clinical trials, most adverse reactions were mild or moderate in intensity and resolved while continuing Zurampic therapy. The most common adverse reaction leading to discontinuation of Zurampic was blood creatinine increased (0.8%).

Tabulated list of adverse reactions

Adverse reactions are classified according to frequency and System Organ Class. Freque are defined according to the following conventions: very common (>1/10), common (>1 uncommon (>1/1000 to <1/100), rare (>1/10000 to <1/1000) and very rare (<1/10,0o0)^

Table 1 lists adverse reactions identified in clinical studies with patients receivi once daily in combination with a xanthine oxidase inhibitor, allopurinol or

*Photodermatosis, photosensitivity reaction, dermatitis allergic, pruritus and urticaria.

Includes the preferred terms: renal failure, renal failure chronic and renal failure acute.

tption of selected adverse reactions

Renal events

Zurampic causes an increase in renal uric acid excretion, which may lead to transient increases in serum creatinine, renal-related adverse reactions and kidney stones. Although other doses have been studied, the recommended dose of Zurampic is 200 mg once daily in combination with a xanthine oxidase inhibitor.

In three 12-month placebo-controlled trials of Zurampic in combination with a xanthine oxidase inhibitor versus a xanthine oxidase inhibitor alone (placebo), serum creatinine elevations between 1.5-fold and 2-fold over baseline occurred in 3.9% of patients on Zurampic 200 mg, 10.0% of patients on Zurampic 400 mg and 2.3% on placebo; serum creatinine elevations 2-fold or greater over baseline occurred in 1.8% of patients on Zurampic 200 mg, 6.7% of patients on Zurampic 400 mg and 0% on placebo. These serum creatinine elevations generally resolved, most without treatment interruption. Renal-related adverse reactions were reported in patients treated with Zurampic 200 mg (5.7%) and Zurampic 400 mg (11.8%) compared to placebo (4.5%), resulting in discontinuation of treatment in 1.2%, 3.3% and 1%, respectively (see section 4.4). The most frequent renal-related adverse reaction was blood creatinine increased (4.3% with Zurampic 200 mg and 7.8% with Zurampic 400 mg compared to 2.3% with placebo). In patients with moderate renal impairment, the incidence of renal-related adverse reactions was similar across all treatment groups: Zurampic 200 mg (12.7%), Zurampic 400 mg (16.3%) and placebo (13.3%). Serious renal-related adverse reactions, e.g. acute renal failure and renal impairment, were reported in patients treated with lesinurad 400 mg (1%) and placebo (0.4%) and in no patients on lesinurad 200 mg. Including the combination long-term extension studies, the incidences of serious renal-related adverse reactions (including acute renal failure) per 100 patientyears of exposure were 0.4 and 1.4 for Zurampic 200 mg and Zurampic 400 mg in combination with a xanthine oxidase inhibitor, respectively (see sections 4.2 and 4.4). Data from the long-term extension studies until 24 months revealed a renal safety profile consistent with that observed in the placebo-controlled studies.

In a 6-month double-blind, placebo-controlled monotherapy study of Zurampic, renal-related adverse reactions and serious renal-related adverse reactions (including acute renal failure) were reported in 17.8% and 4.7% of patients respectively, receiving Zurampic 400 mg alone and in no patients receiving placebo (see sections 4.2 and 4.4). Among serious renal-related adverse reactions: renal failure, renal failure acute and renal impairment were reported in 1.9%, 1.9% and 0.9% respectively, of patients receiving lesinurad 400 mg monotherapy and in no patients receiving placebo. Since the incidence of severe renal-related adverse events was increased with the monotherapy as compared to the combination therapy with a xanthine oxidase inhibitor, Zurampic should not be used as monotherapy (see sections 4.2 and 5.1).

Patients with a history of kidney stones were permitted entry into the 12-month studies of Zurampic in combination with a xanthine oxidase inhibitor. In these studies, kidney stone adverse reactions (nephrolithiasis being the most frequent) were reported in patients treated with Zurampic 200 mg (0.6%), Zurampic 400 mg (2.5%) and placebo (1.7%).

Cardiovascular safety

In the randomised, double-blind, placebo-controlled combination therapy clinical studies, the incidences of patients with adjudicated Major Adverse Cardiovascular Events (CV death, non-fatal myocardial infarction or non-fatal stroke) per 100 patient-years of exposure were: 0.71 (95% CI 0.23, 2.21) for placebo, 0.96 (95% CI 0.36, 2.57) for Zurampic 200 mg, and 1.94 (95% CI 0.97, 3.87) for Zurampic 400 mg, when used in combination with a xanthine oxidase inhibitor. A causal relationship with Zurampic has not been established. All patients with a Major Adverse Cardiovascular Event treated with Zurampic 200 mg had a history of heart failure, stroke or myocardial infarction. Post-hoc analyses in a subgroup of patients with high cardiovascular risk at baseline (as defined by transient ischemic attack, angina pectoris, heart failure, myocardial infarction, peripheral vascular disease and/or stroke), showed that the incidence of Major Adverse Cardiovascular Events was 1/52 for placebo and 4/53 for Zurampic 200 mg, when used in combination with a xanthine oxidase inhibitor.

Hypersensitivity

Rare cases of hypersensitivity (photodermatosis, photosensitivity reaction, dermatitis allergic, pruritus and urticaria) have been reported with lesinurad during the clinical programme. None of these were serious or required hospitalisation.

Other special populations

Patients with renal impairment

No overall differences in safety of Zurampic were observed in patients with mild or moderate renal impairment (eCrCL of 30–89 mL/min) compared to patients with normal renal function (see sections 4.2 and 5.2).

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 the national reporting system listed in Appendix V.

4.9 Overdose

There is no specific treatment in the event of an overdose, and symptoms of overdose are not established. In case of overdose, patients should be managed by symptomatic and supportive care including adequate hydration.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antigout preparations, preparations increasing uric acid excretion ATC code: M04AB05

Mechanism of action

Lesinurad is a selective uric acid reabsorption inhibitor that inhibits uric acid transporter URAT1. URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen. By inhibiting URAT1, lesinurad increases uric acid excretion and thereby lowers serum uric acid (sUA). Lesinurad also inhibits OAT4, a uric acid transporter involved in diuretic-induced hyperuricaemia.

Lesinurad, when combined with a xanthine oxidase inhibitor, increases uric acid excretion and decreases uric acid production resulting in greater sUA lowering. Lesinurad should only be used in combination with a xanthine oxidase inhibitor because combination use reduces the amount of uric acid available for excretion and decreases the risk of renal-related events.

Pharmacodynamic effects

Effects on serum uric acid and urinary excretion of uric acid

In healthy subjects, lesinurad 200 mg lowered sUA levels and increased renal clearance and fractional excretion of uric acid. Mean sUA reductions following Zurampic 200 mg administration alone were approximately 46% and 26% at 6 hours and 24 hours post-dose, respectively. When Zurampic 200 mg was added to a xanthine oxidase inhibitor (i.e. febuxostat), additional 25% and 19% of sUA reductions were observed at 6 hours and 24 hours post-dose, respectively.

Effect on cardiac repolarisation

Lesinurad at doses up to 1,600 mg did not demonstrate an effect on ECG parameters (including QTc interval) in healthy subjects.

Clinicafcfticacy and safety

The efficacy of Zurampic 200 mg and 400 mg once daily was studied in 3 multicentre, randomised, double-blind, placebo-controlled clinical studies in 1,537 adult patients (13% of these patients were elderly, >65 years old) with hyperuricaemia and gout in combination with a xanthine oxidase inhibitor, allopurinol (CLEAR1 and CLEAR2) or febuxostat (CRYSTAL). All studies were of 12 months duration and patients received prophylaxis for gout flares with colchicine or NSAIDs during the first 5 months of lesinurad treatment.

Based on these studies, Zurampic is only recommended at a dose of 200 mg once daily in combination with a xanthine oxidase inhibitor (see sections 4.2 and 4.4).

Zurampic as add-on to allopurinol in inadequate responders

CLEAR1 and CLEAR2 enrolled patients with gout who were on a stable dose of allopurinol of at least 300 mg (or 200 mg for moderate renal impairment), had serum uric acid levels greater than 6.5 mg/dL and reported at least 2 gout flares in the previous 12 months. Across both studies, 61% of patients had mild or moderate renal impairment and 19% had tophi at baseline. Patients continued their allopurinol dose and were randomised 1:1:1 to receive Zurampic 200 mg, Zurampic 400 mg, or placebo once daily.

The primary efficacy endpoint in both CLEAR1 and CLEAR2 was the proportion of patients achieving a serum uric acid target level of less than 6 mg/dL by Month 6. In both studies, significantly more patients treated with Zurampic 200 mg in combination with allopurinol achieved the target serum uric acid level of less than 6 mg/dL by Month 6 and by Month 12 compared with patients receiving placebo in combination with allopurinol (see Table 2).

The stability of the sustained response was demonstrated with a greater proportion of patients treated with Zurampic 200 mg in combination with allopurinol achieving the target serum uric acid level at each visit for 3 consecutive months (Months 4, 5 and 6) compared to patients treated with placebo in combination with allopurinol (see Table 2).

Table 2 Proportion of patients who achieved target serum uric acid Zurampic in combination with allopurinol – Pooled data fr studies

Figure 1 Mean serum uric acid levels in pooled clinical studies with Zurampic in combination with allopurinol in patients with inadequate response (sUA >6 mg/dL) to allopurinol alone

Treatment Group :    –o– Placebo + AllopUrinol,      A Zurampic 200 mg + Allopurinol

In each of the studies, a greater proportion of patients treated with Zurampic 200 mg in combination with allopurinol compared with placebo in combination with allopurinol achieved a serum uric acid less than 5 mg/dL by Month 6 (CLEAR1: 29% versus 10%; CLEAR2: 35% versus 5%).

Zurampic in combination with febuxostat in tophaceous gout

CRYSTAL enrolled gout patients with measurable tophi. Patients received febuxostat 80 mg once daily for 3 weeks and then were randomised 1:1:1 to once daily doses of Zurampic 200 mg, Zurampic 400 mg, or placebo in combination with febuxostat. Sixty-six percent of patients had mild or moderate renal impairment^Fifty percent of patients had a baseline sUA >5.0 mg/dL, which was after 3 weeks of treatment with febuxostat alone.

Zurampic when added to febuxostat caused an immediate reduction of the mean serum uric acid levels, as compared to placebo, which was sustained in the long term in those patients who continued treatment.

In the subgroup of patients with a baseline sUA >5.0 mg/dL, after 3 weeks of febuxostat therapy, a significant difference was achieved at all study visits for Zurampic 200 mg in combination with febuxostat compared with placebo in combination with febuxostat (see Table 3).

Table 3 Proportion of patients with baseline sUA >5.0 mg/dLwho achieve target serum uric acid levels (<5 mg/dL) with Zurampic in combination with febuxostat

	Proportion of patients who met serum uric acid Target (<5.0 mg/dL) N(%)		Difference in proportion (95% C.I.)
Timepoint	Placebo + febuxostat 80 mg N=51	Zurampic 200 mg + febuxostat 80 mg N=59	Zurampic 200 mg vs. placebo
Months 4, 5, 6	6 (12%)	23 (39%)	0.27 (0.12, 0.42)
Month 6	12 (24%)	26 (44%)	0.21 X (0.03, 0.380*
Month 12	12 (24%)	27 (46%)	0.22,0 (0.05%039)

Primary end-point in patients with renal impairment

Consistent with the overall population, the proportion of patients with mild to impairment (eCrCL 30–89 mL/min) who achieved target serum uric acid level for Zurampic 200 mg versus 29% for placebo when added to allopurinol, 200 mg versus 26% for placebo when added to febuxostat in patients with

Clinical outcomes – gout flares requiring treatment

The rates of gout flare requiring treatment were low and compar      placebo in the last 6 months of

the randomised trials (after gout flare prophylaxis was disconti        ith median scores of zero. In

the long-term uncontrolled extension trials, the rates of goes requiring treatment further decreased in the 60% of subjects who entered the extensiodies and continued treatment with Zurampic 200 mg in combination with allopurinol or febuxostat for up to an additional year of treatment.

Clinical outcomes – tophus resolution and reduction

In CRYSTAL, the proportion of subjects who experienced a complete resolution (defined as 100% resolution of at least one target tophusandWosmgle tophus showing progression) of >1 target tophus was higher in the group treated with Zurampic 200 mg in combination with febuxostat compared with placebo in combination with febuxostat, although the difference was not statistically different (26% compared with 21%). After ced treatment of up to 24 months on Zurampic 200 mg in combination with febuxost       roportion of subjects who experienced complete resolution of at

least one target tophus i

ines Agency has waived the obligation to submit the results of studies with sets of the paediatric population for the treatment and prevention of hyperuricaemia or information on paediatric use).

Absorption

The absolute bioavailability of lesinurad is approximately 100%. Lesinurad is rapidly absorbed after oral administration. Following administration of a single oral dose of lesinurad in either the fed or fasted state, maximum plasma concentrations (Cmax) were attained within 1 to 4 hours. Cmax and AUC exposures of lesinurad increased proportionally with single doses of lesinurad from 5 to 1,200 mg. In the fed state, after a single dose of lesinurad 200 mg, geometric mean lesinurad Cmax and AUC were 6 pg/mL and 29 pg/hr/mL, respectively. There was no apparent influence of the fat content in the meal on the pharmacokinetics of lesinurad. In clinical trials, Zurampic was administered with food, because the serum uric acid lowering was improved under fed conditions.

Zurampic is administered as a 50:50 mixture of lesinurad atropisomers. The ratio of atropisomer 1 to atropisomer 2 AUC(0–24) was 44:56 because atropisomer 1 undergoes more extensive metabolism than atropisomer 2, causing atropisomer 1 to have lower plasma exposure than atropisomer 2.

Distribution

Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The mean steady state volume of distribution of lesinurad was approximately 20 L following intravenous dosing. Mean plasma-to-blood ratios of lesinurad AUC and Cmax were approximately 1.8, indicating that radioactivity was largely contained in the plasma space and did not penetrate or partition extensively into red blood cells.

Biotransformation

Lesinurad undergoes oxidative metabolism mainly via cytochrome P450 (CYP) 2C9 to inte metabolite M3c (not detected in vivo ) and is subsequently metabolised by mEH to metabolite M4; there is minimal contribution from CYP1A1, CYP2C19, and CYP3A to the metabolism of lesinurad.

Atropisomer 1 is extensively metabolised by CYP2C9 whereas atropisomer 2 is minimally metabolised by both CYP2C9 and CYP3A4. It is unclear if metabolite plasma exposures are minimal.

Metabolites are not known to contribute to the uric acid lowering effects of lesinurad.

Linearity/non-linearity

Following multiple once daily dosing of Zurampic, there was no evidence of time dependent changes in pharmacokinetic properties and droportionality was preserved.

YP2C9 and mEH, and to a lesser extent by CYP1A1, CYP2C19 nhibitor of CYP2C8, but not of CYP1A2, CYP2B6, CYP2C9, EH. In addition, lesinurad is an in vitro inducer of CYP2B6 and n vivo , lesinurad is neither an inhibitor nor an inducer of CYP2C9 and 2C8, ducer of CYP3A. CYP2B6 has not been studied in vivo.

Lesinurad is a substrate of OATP1B1, OAT1, OAT3 and OCT1. In vitro , lesinurad is an inhibitor of OATP1B1, OAT1, OAT3, OAT4 and OCT1 at clinically relevant plasma concentrations. However, the in    activity of OATP1B1, OAT1, OAT3 and OCT1 was not affected by lesinurad. Lesinurad is

itro inhibitor of P-glycoprotein, BCRP, OATP1B3, MRP2, MRP4, OCT2, MATE1 and

Special populations

Renal impairment

The population pharmacokinetic analysis of clinical data in gout patients treated for up to 12 months estimated increases in lesinurad exposure of approximately 12%, 31% and 65% in patients with mild, moderate, and severe renal impairment, respectively, compared with patients with normal renal function.

Following administration of a single dose of lesinurad to individuals with renal impairment compared to those with normal renal function lesinurad Cmax and AUC, respectively, were 36% and 30% higher

5.3 Preclinical safety data

Tableteare

hypromellose

micracrystalline cellulase lactase manahydrate craspavidane type A magnesium stearate

Tablet coat hypramellase titanium dioxide triacetin

Indigo Carmine Brilliant Blue FCF

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Clear (PVC/PVDC/Alu­minium) blister of 10 or 14 (calendar blister) tablets.

Pack sizes of 10, 28, 30, 98 in non-perforated blisters.

Pack size of 100 × 1 film-coated tablet in perforated unit dose blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal. Any unused medicinal pro disposed of in accordance with local requirements.

• 7. MARKETING AUTHORISATION HOLD