Duzallo - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Duzallo 200 mg/200 mg film-coated tablets

Each film-coated tablet contains 200 mg of allopurinol and 200 mg of lesinurad.

Excipient with known effect:

Each film-coated tablet contains 102.6 mg of lactose (as monohydrate)

Duzallo 300 mg/200 mg film-coated tablets

Each film-coated tablet contains 300 mg of allopurinol and

Excipient with known effect :

Each film-coated tablet contains 128.3 mg of lactose (as monohydrate).

For the full list of excipients, see secti

Duzallo 200 mg/2

Pale pink oblong film-coated tablets with 7 × 17 mmin size.

The film-coated tablets are engraved with “LES200” and “ALO200” on one side.

DuW^Oo mg/200 mg film-coated tablets

Orange and slightly brownish oblong film-coated tablets with 8 × 19 mm in size. The film-coated tablets are engraved with “LES200” and “ALO300” on one side.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Duzallo is indicated in adults for the treatment of hyperuricaemia in gout patients who have not achieved target serum uric acid levels with an adequate dose of allopurinol alone.

4.2 Posology and method of administration

Posology

Dose titration with allopurinol to an adequate dose must be done before the patient is switched to Duzallo.

The choice of the dose strength of Duzallo depends on the allopurinol dose taken as individual tablet(s).

The recommended dose is one tablet of Duzallo (200 mg/200 mg or 300 mg/200 mg) once daily. This

is also the maximum daily dose of Duzallo (see section 4.4).

Patients who are currently treated with allopurinol doses higher than 300 mg can be switched t Duzallo 200 mg/200 mg or Duzallo 300 mg/200 mg and should receive complementary allopurinol to cover the total dose of allopurinol taken before switching to Duzallo.

Patients should be instructed to stay well hydrated.

Patients should be informed that failure to follow these instructions may events (see section 4.4).

The target serum uric acid level is less than 6 mg/dL (360 pmol/L). In patients with tophi or persistent symptoms, the target is less than 5 mg/dL (300 pmol/L). Testing foyhararget serum uric acid level can be performed after 4 weeks to consider treatment adjustment to target serum uric acid level.Gout flare prophylaxis needs to be considered (see section 4.4).

Special populations

Elderly (>65 years)

No dose adjustment is necessary based on age (see section 5.2); however, elderly patients are more likely to have decreased renal function (see dosing recommendations for renal impairment).

Experience in very elderly patients (>75 years) is limited.

Renal impairment

Duzallo is contraindicated in patienh severe renal impairment (CrCL less than 30 ml/min), with end-stage renal disease, in patients on dialysis or in kidney transplant recipients (see sections 4.3 and 4.4). Based on its mechanism of action, lesinurad may not be effective in these patients (see section 5.1).

ith caution in patients with a CrCL of 30 to less than 45 mL/min (expe-tients with an estimated CrCL (eCrCL) less than 45 mL/min is limited).

ent is necessary in patients with mild or moderate hepatic impairment (Child-Pugh B) (see section 5.2). Duzallo has not been studied in patients with severe hepatic t; therefore, no dose recommendations can be given for Duzallo.

Paediatric population

The safety and efficacy of Duzallo in children and adolescents under 18 years of age have not yet been established. No data are available.

Method of administration

Oral use.

Duzallo should be taken in the morning with food and water.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Tumour lysis 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).

4.4 Special warnings and precautions for use

Pre-existing cardiovascular disease

Duzallo is not recommended in patients with unstable angina, New York Heart Association class III or IV heart failure, uncontrolled hypertension or with a recent event of myocardial stroke, or deep venous thrombosis within the last 12 months, due to insufficient data with lesinurad.

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).

Renal events

Treatment with lesinurad 200 mg in combination with allopurinol 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 Duzallo (see section 4.8)

Renal function should be evaluated prior to initiation oallo and monitored periodically thereafter (e. g. 4 times per year), based on clinical considerationh as baseline renal function, volume depletion, concurrent illness or concomitant medicinal products. Patients with serum creatinine elevations to greater than 1.5 times the pre-treatment value should be closely monitored. Duzallo should be interrupted if serum creatinine is elevated to more 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. Duzallo should not be restarted without another explanation for the serum creatinine abnormalities.

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

syndrome, Stevens-Johnson-Syndrome (SJS ) and toxic epidermal necrolysis (TEN)

Allopurinol hypersensitivity reactions can manifest in many different ways, including maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) and SJS/TEN. Re-challenge should not be undertaken in patients with hypersensitivity syndrome and SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions.

Duzallo and all additional doses of allopurinol should be discontinued immediately at the first appearance of allopurinol-induced skin rash or other signs which may indicate an allergic reaction and additional medical care should be provided as needed.

Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving diuretics (in particular thiazides) and Duzallo concurrently (see sections 4.5 and 4.8).

HLA-B*5801 allele

The HLA-B*5801 allele has been shown to be associated with the risk of developing allopurinol related hypersensitivity syndrome and SJS/TEN. The frequency of the HLA-B*5801 allele varies widely between ethnic populations: up to 20% in Han Chinese population, 8–15% in the Thai, about 12% in the Korean population and 1–2% in individuals of Japanese or European origin. Screening for

HLA-B*5801 should be considered before starting treatment with allopurinol in patient subgroups where the prevalence of this allele is known to be high. Chronic kidney disease may increase the risk in these patients additionally. If no HLA-B*5801 genotyping is available for patients with Han Chinese, Thai or Korean descent, the benefits should be thoroughly assessed and considered to outweigh the possible higher risks before starting therapy. The use of genotyping has not been established in other patient populations. If the patient is a known carrier of HLA-B*5801, especia those who are of Han Chinese, Thai or Korean descent, allopurinol should not be started unless th are no other reasonable therapeutic options and the benefits are thought to exceed risks. Extra vigilance for signs of hypersensitivity syndrome or SJS/TEN is required and the patient s informed of the need to stop treatment immediately at the first appearance of symptoms.

SJS/TEN can still occur in patients who are found to be negative for HLA-B*5 ethnic origin.

Acute gouty attacks (gout flares)

Gout flares may occur after initiation of therapy with Duzallo. This is due to reduction in serum uric acid levels resulting in mobilisation of urate from tissue deposits. Gout flare prophylaxis needs to be considered (see section 4.2).

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

Impaction of uric acid renal stones

Adequate therapy with allopurinol will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.

L) were observed in patients on long-term treatment with allong term open label extension study. Caution is required when allopurinol is alteration of thyroid function.

teractions with other medicinal products

tes

Lesinmild to moderate inducer of CYP3A (see section 4.5). An induction effect of lesinurad shoulnticipated after 2 to 3 weeks of continuous co-administration of Duzallo. Additional monitoring of lipids and blood pressure is recommended in patients using sensitive CYP3A substrate lipid lowering medicinal products (such as lovastatin or simvastatin) or antihypertensive medicinal products (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 Duzallo is co-administered. Female patients of childbearing age should practice additional methods of contraception and not rely on hormonal contraception alone when taking Duzallo (see sections 4.5 and 4.6).

Lactose intolerance

Duzallo contains lactose. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Not recommended concomitant use with:

Salicylates and non-selective uricosuric active substances such as probenecid

Salicylates at doses higher than 325 mg per day may decrease the serum uric acid lowering activity lesinurad and should not be co-administered with Duzallo. There are no restrictions for doses of salicylates of 325 mg or less per day (i.e. for cardiovascular protection).

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

Oxypurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted by the kidney in a similar way to urate.

Hence, medicinal products with known non-selective uricosuric activity such as probenecid or large doses of salicylates may accelerate the excretion of oxypurinol. This may decrease the therapeutic activity of Duzallo which contains the active substance allopurinol, but the significance needs to be assessed in each case.

Ampicillin/amo­xicillin

An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both medicinal products. The cause of the reported association has not been established. However, it is recommended that in patients receiving Duzallo which contains ampicillin or amoxicillin is used where available.

Didanosine

In healthy volunteers and HIV patients receiving didanosine, plasma didanosine maximum plasma concentration (Cmax ) and area under the curve (AUC) values were approximately doubled with concomitant allopurinol treatment (300 mg daily) without affecting terminal half-life. Coadministration of these 2 active substances is generally not recommended. If concomitant use is

idanosine may be required, and patients should be closely

Epoxide hydrolase inhibitors (e.g. valproic acid, valpromide)

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

Concomanruse which needs to be taken into consideration:

An increased risk of hypersensitivity has been reported when allopurinol is given with diuretics, in particular thiazides, especially in renal impairment (see section 4.4 and section 5.1).

Angiotensin-converting-enzyme (ACE) inhibitors

Concurrent use of allopurinol and ACE inhibitors may lead to an increased risk of hypersensitivity, especially if there is pre-existing renal impairment.

6-mercaptopurine and azathioprine

Serum concentrations of 6-mercaptopurine and azathioprine can reach toxic levels unless dose reduction is undertaken. Patients taking Duzallo which contains the active substance allopurinol and 6-mercaptopurine or azathioprine must reduce their dose to 25 % of the intended dose of 6-mercaptopurine or azathioprine. Patients should be closely monitored for therapeutic response and the appearance of toxicity.

Cytostatics

With administration of allopurinol and cytostatics (e.g. cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkylating agents), blood dyscrasias occur more frequently than when these active substances are administered alone.

Blood count monitoring should therefore be performed at regular intervals.

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 Duzallo 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 Duzallo is co-administered with a CYP2C9 inducer.

Coumarin anticoagulants

An interaction between allopurinol and coumarins has been seen under experimental conditions. The clinical relevance is not clear. A possible interaction should be taken into account when a patient on oral anticoagulants is given Duzallo. All patients receiving coumarin anticoagulants must be carefull monitored.

Aluminium hydroxide

If aluminium hydroxide is taken concomitantly, allopurinol-containing medicinal products may have an attenuated effect. There should be an interval of at least 3 hours between the concomitant use of those medicinal products.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of lesinurad and limited amo pregnant women.

Studies in animals with lesinurad do not indicate direct or indirect harmful effects.

Studies with allopurinol are insufficient with respect to reproductive toxicity (see section 5.3).

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

Breast-feeding

Allopurinol and its metabolite o recommended during breastfeeding.

Fertility

The effect of lesinurad and allopurinol on fertility in humans has not been studied.

In male and female rats, there was no effect on mating or fertility with lesinurad.

Reproductive studies with allopurinol have been performed in rats and rabbits at doses up to twenty times the usual human dose and it was concluded that there was no impaired fertility.

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

However, since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients receiving allopurinol (see section 4.8), patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that Duzallo does not adversely affect their ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The safety of lesinurad 200 mg was evaluated in the Phase 3 combination therapy clinical trials (including extension studies). The most commonly reported adverse reactions during treatment with lesinurad 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 lesinurad therapy. The most common adverse reaction leading to discontinuation of lesinurad was blood creatinine increased (frequency 0.8%).

For allopurinol, undesirable effects may vary in their incidence depending on the dose received also when given in combination with other medicinal products.

Tabulated list of adverse reactions

Adverse reactions are classified according to frequency and System Organ categories are defined according to the following conventions: very comm (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10000 to <1/ (<1/10,000).

Table 1 lists adverse reactions identified in clinical studies with patients receiving lesinurad 200 mg once daily in combination with allopurinol and those adverse reaction that are established for allopurinol alone.

Table 1 Adverse reactions by System Organ Class and frequency

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

Lesinurad

There is no specific treatment in the event of an overdose, and symptoms of overdose are not established.

Allopurinol

Based on literature and following ingestion of one single dose of 20 g allopurinol symptoms such as nausea, vomiting, diarrhoea and dizziness occurred in one patient. In another patient     take of

• 22.5 g allopurinol caused no adverse reactions. A specific antidote is unknown.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antigout preparatio

ATC code: M04AA51

Mechanism of action

Duzallo contains lesinurad and allo complimentary mechanisms of acti

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)also inhibits OAT4, a uric acid transporter involved in diuretic-induced hyperurica

Lesinurad, when combined with a xanthine oxidase inhibitor, increases uric acid excretion and decreases uric acid production resulting in greater sUA lowering.

Allopurinol is a xanthine-oxidase inhibitor. Allopurinol and its main metabolite oxypurinol lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the enzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In addition to the inhibition of purine catabolism in some but not all hyperuricaemic patients, de novo purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine phosphoribosyl­transferase. Other metabolites of allopurinol include allopurinol-riboside and oxypurinol-7-riboside.

Clinical efficacy and safety

The efficacy of lesinurad 200 mg once daily was studied in 2 multicentre, randomised, double-blind, placebo-controlled clinical studies in 812 adult patients (11% of these patients were elderly, >65 years old) with hyperuricaemia and gout in combination with allopurinol (CLEAR1 and CLEAR2). All

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

7.5 H

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

Primary end-point in patients with renal impairment

Consistent with the overall population, the proportion of patients with mild to moderate renal impairment (eCrCL 30–89 mL/min) who achieved target serum uric acid levels at Month 6 was 56% for lesinurad 200 mg versus 29% for placebo when added to allopurinol at doses ranging from 200 mg to 900 mg.

Clinical outcomes – gout flares requiring treatment

The rates of gout flare requiring treatment were low and comparable to placebo in the last 6 months of the randomised trials (after gout flare prophylaxis was discontinued) with median scores of zero. In the long-term uncontrolled extension trials, the rates of gout flares requiring treatment further decreased in the 60% of subjects who entered the extension studies and continued treatment with lesinurad 200 mg in combination with allopurinol or febuxostat for up to an additional year of treatment.

Clinical outcomes – concomitant use of thiazides

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

Clinical outcomes – renal events

In two 12-month placebo-controlled trials of lesinurad in combination with allopurinol versus allopurinol alone (placebo), serum creatinine elevations between 1.5-fold and 2-fold over baseline occurred in 4.4% of patients on lesinurad 200 mg and 2.2% on placebo; serum creatinine elevations 2fold or greater over baseline occurred in 1.5% of patients on lesinurad 200 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 lesinurad 200 mg (4.9%) compared to placebo (4.2%), resulting in discontinuation of treatment in 1.0% for both treatment setups (see section 4.4).

The most frequent renal-related adverse reaction was blood creatinine increased (3.7% with lesinurad 200 mg compared to 2.2% with placebo). In patients with moderate renal impairment, the incidence of renal-related adverse reactions was similar across all treatment groups: Lesinurad 200 mg (13.4%) and placebo (12.5%). Serious renal-related adverse reactions, e.g. acute renal failure and renal impairment, were reported in patients treated with placebo (0.2%) and in no patients on lesinurad 200 mg.

Data from long-term extension studies until 52 months revealed a renal safety profile consistent with that observed in the placebo-controlled studies.

Patients with a history of kidney stones were permitted entry into the 12-month studies of lesinurad i combination with allopurinol. In these studies, kidney stone adverse reactions (nephrolithiasis being the most frequent) were reported in patients treated with lesinurad 200 mg (0.5%) and placebo (1.2%

Clinical outcomes – cardiovascular safety

In the randomised, double-blind, placebo-controlled combination therapy clinical studies, the incidences of patients with adjudicated Major Adverse Cardiovascular Events (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) per 100 patient-years of exposure were 0.60 (95% confidence interval (C.I.) 0.15, 2.41) for placebo and 0.61 (95% C.I. 0.15, 2.43) for lesinurad 200 mg, when used in combination with allopurinol (CLEAR1 and CLEAR2). A causal relationship

with lesinurad has not been established.

In the same trials, all patients with a MACE treated with lesinurad failure, stroke or myocardial infarction. Post-hoc analyses in a s cardiovascular risk at baseline (as defined by transient ischem myocardial infarction, peripheral vascular disease and/or was 0/39 for placebo and 2/43 for lesinurad 200 mg.

Paediatric population

The European Medicines Agency has waive obligation to submit the results of studies with Duzallo in all subsets of the paediatric plation for the treatment and prevention of hyperuricaemia (see section 4.2 for information on paeiatric use).

5.2 Pharmacokinetic properties

Absorption

Lesinurad

The absolute bioavailability of lesinurad is approximately 100%. Lesinurad is rapidly absorbed after oral administration. Administration of Duzallo with a high-fat/high-calorie meal did not affect lesinurad AUC while Cmax was reduced by 46% and Tmax increased from 2 to 4.5 h compared to administration under fasting conditions.

rials, lesinurad was administered with food, because the serum uric acid lowering was nder fed conditions (see section 4.2).

inurad 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.

Allopurinol

Allopurinol is rapidly absorbed from the gastrointestinal tract and is reported to have a plasma half-life of about one hour.

Administration of Duzallo with a high-fat/high-calorie meal did not affect allopurinol AUC while Cmax was reduced by 18% and Tmax increased from 1.25 to 3 h compared to administration under fasting conditions. Oxypurinol AUC and Cmax was not affected by food.

Distribution

Lesinurad

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 it did not penetrate or partition extensively into red blood cells.

Allopurinol

Allopurinol is negligibly bound by plasma proteins and therefore variations in protein binding are not thought to significantly alter clearance. The apparent volume of distribution of allopurinol is approximately 1.6 litre/kg which, suggests relatively extensive uptake by tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is likely that allopurinol and oxypurinol will be present in the highest concentrations in the liver and intestinal mucosa where xanthine oxidase activity is high.

Biotransformation                          Cj

Lesinurad

Lesinurad undergoes oxidative metabolism mainly via cytochrome P450 ( metabolite M3c (not detected in vivo ) and is subsequently metabolised by microsomal epoxide hydrolase (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. Metabolites are not known to contribute to the uric acid lowering effects of lesinurad.

Allopurinol

The main metabolite of allopurinol is oxypurinol. Other metabolites of allopurinol include allopurinolriboside and oxypurinol-7-riboside.

Elimination

Lesinurad

Renal clearance is 25.6 mL/min (coefficient of variation CV=56%). Lesinurad is highly protein bound

d to typical human glomerular filtration rate), indicating that active secretion plays an important role in the renal excretion of lesinurad. Within 7 days following single dosing of radiolabelled lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in faeces. Most of the radioactivity recovered in urine (>60% of dose) occurred in the first 24 hours. Unchanged lesinurad in urine accounted for approximately 30‘%ofme dose. The elimination half-life (f/2) of lesinurad was approximately 5 hours following a single dose. Lesinurad does not accumulate following multiple doses.

Allopurinol

Approximately 20% of the ingested allopurinol is excreted in the faeces. Elimination of allopurinol is mainly by metabolic conversion to oxypurinol by xanthine oxidase and aldehyde oxidase, with less than 10% of the unchanged active substance excreted in the urine. Allopurinol has a plasma half-life of about 0.5 to 1.5 hours.

Oxypurinol is a less potent inhibitor of xanthine oxidase than allopurinol, but the plasma half-life of oxypurinol is far more prolonged. Estimates range from 13 to 30 hours in man. Therefore effective inhibition of xanthine oxidase is maintained over a 24 hour period with a single daily dose of allopurinol. Patients with normal renal function will gradually accumulate oxypurinol until a steadystate plasma oxypurinol concentration is reached. Such patients, taking 300 mg of allopurinol per day will generally have plasma oxypurinol concentrations of 5–10 mg/litre.

Oxypurinol is eliminated unchanged in the urine but has a long elimination half-life because it undergoes tubular reabsorption. Reported values for the elimination half-life range from 13.6 hours to 29 hours. The large discrepancies in these values may be accounted for by variations in study design and/or creatinine clearance in the patients.

Linearity/non-linearity

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

In vitro assessment of interactions

Lesinurad is mainly metabolised by CYP2C9 and mEH, and to a lesser extent by CYP1A1, CYP2C19 and CYP3A. In vitro , lesinurad is an inhibitor of CYP2C8, but not of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and mEH. In addition, lesinurad is an in vitro inducer of CYP2B6 and CYP3A via constitutive androstane receptor (CAR)/pregnane X receptor (PXR). In vivo , lesinurad is neither an inhibitor nor an inducer of CYP2C9 and 2C8, but a mild to moderate inducer of CYP3A. CYP2B6 has not been studied in vivo.

Lesinurad is a substrate of OATP1B1, OAT1, OAT3 and OCT1. In vitro , lesinurad is OATP1B1, OAT1, OAT3, OAT4 and OCT1 at clinically relevant plasma concentrati the in vivo activity of OATP1B1, OAT1, OAT3 and OCT1 was not affected by not an in vitro inhibitor of P-glycoprotein, BCRP, OATP1B3, MRP2, MRP4, MATE2-K and BSEP.

Special populations

Renal impairment

Lesinurad

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 lesin    Cmax and AUC, respectively, were 36% and 30% higher

ent (eCrCL 60 to 89 mL/min), 20% and 73% higher g) in patients with moderate renal impairment (eCrCL 30 to higher (400 mg) in patients with severe renal impairment

Allopurinol

Allopurinol and oxypuclearance is greatly reduced in patients with poor renal function resulting in higher plasma levels in chronic therapy. Patients with renal impairment, where creatinine clearance values were between 10 and 20 ml/min, showed plasma oxypurinol concentrations of approximately 30 mg/litre after prolonged treatment with 300 mg allopurinol per day. This is approximately the concentration which would be achieved by doses of 600 mg/day in those with normal renal function. A redtion in the dose of allopurinol is therefore required in patients with renal impairment (see sec

Hepatic impairment

Following administration of a single dose of lesinurad at 400 mg in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, lesinurad Cmax was comparable and lesinurad AUC was 7% and 33% higher, respectively, compared to individuals with normal hepatic function. There is no clinical experience in patients with severe (Child-Pugh class C) hepatic impairment.

CYP2C9 poor metabolisers

Approximately half of an oral dose of lesinurad is cleared via CYP2C9 metabolism. The effect of CYP2C9 genotype on the pharmacokinetics of lesinurad was studied in 8 healthy subjects and 59 patients with gout following daily dosing of lesinurad ranging from 200 mg to 600 mg in the absence or presence of a xanthine oxidase inhibitor. At the 400 mg dose, when compared with extensive CYP2C9 metabolisers (CYP2C9 1/1 [N=41]), increased lesinurad exposures were observed in intermediate CYP2C9 metabolisers (CYP2C9 1/3 [N=4], approximately 22% increase in AUC) and in poor CYP2C9 metabolisers (CYP2C9 3/3 [N=1], approximately 111% increase in AUC) accompanied with higher lesinurad renal excretion. However, individual values were well within the range observed in the extensive metaboliser subjects.

Patients who are known or suspected to be CYP2C9 poor metabolisers based on previous history or experience with other CYP2C9 substrates should use Duzallo with caution (see section 4.4).

Other special populations

Based on population pharmacokinetic analysis, age, gender, race and ethnicity do not have a clini meaningful effect on the pharmacokinetics of lesinurad. Based on pharmacokinetic modelling simulations, patients with moderate renal impairment and reduced CYP2C9 activity (co-a of a CYP2C9 inhibitor or a CYP2C9 poor metabolizer) are predicted to have an increase i approximately 200% in comparison to normal renal function and unimpaired CYP2C9 act

Pharmacokinetics in elderly patients The kinetics of allopurinol are not lik (see section 5.2 renal impairment).

5.3 Preclinical safety data

Lesinurad

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

Allopurinol

In animal studies, long-term use of high allopurinol doses resulted in formation of xanthine precipitates, which led to changes in the urinary tract.

In vitro and in vivo studies conducted to date showed no evidence of mutagenic or carcinogenic potential.

One study in mice rece     intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of gestation

resulted in foetal abnormalities, however in a similar study in rats at 120 mg/kg on day 12 of gestation no abnormalities were observed.

Extensive studies of high oral doses of allopurinol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150 mg/kg/day during days 8 to 16 of gestation produced no teratogenic effects

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Hydroxypropyl­cellulose Microcrystalline cellulose Lactose monohydrate Crospovidone Magnesium stearate

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.5  Nature and contents of container

6.6 Special precautions for disposal

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION