Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: Grünenthal GmbH, Zieglerstr. 6, 52078, Aachen, Germany, Tel.: +49-241-569-0
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with 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).
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.
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).
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.
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).
Lesinurad is a mild to moderate inducer of CYP3A (see section 4.5). An induction effect of lesinurad should be anticipated after 2 to 3 weeks of continuous co-administration of Zurampic. Additional monitoring of lipids and blood pressure is recommended in patients using sensitive CYP3A substrate lipid lowering medicines (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, 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).
Therapeutic experience in patients 75 years and older is limited. Caution should be used when treating these patients with Zurampic.
No studies have been conducted in patients with secondary hyperuricaemia (including organ transplant recipients).
Zurampic contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Salicylates at doses higher than 325 mg per day may decrease the serum uric acid lowering activity of lesinurad and should not be co-administered with Zurampic. 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. 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 thiazide diuretics in the placebo-controlled clinical studies in combination with allopurinol or febuxostat.
Effect of lesinurad on other medicinal products:
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 inhibitors that are sensitive CYP3A substrates may interact with lesinurad. In the pivotal clinical trials, a greater proportion of patients using lipid lowering or antihypertensive medicines that were CYP3A substrates required concomitant medicinal product change when treated with Zurampic 200 mg in combination with a xanthine oxidase inhibitor, compared with patients treated with placebo in combination with a xanthine oxidase inhibitor (35% versus 28%, respectively). The possibility of reduced efficacy of concomitant medicinal products that are CYP3A substrates should be considered and their efficacy (e.g. blood pressure and cholesterol levels) should be monitored (see section 4.4).
In an interaction study conducted in healthy subjects with multiple doses of Zurampic 400 mg and single dose warfarin (25 mg), lesinurad led to a decrease in exposure of R-warfarin (the less active enantiomer) and had no effect on the exposure of S-warfarin (the more active enantiomer). Additionally, lesinurad led to a 6-8% decrease in International Normalised Ratio (INR) and Prothrombin Time (PT). The standard INR monitoring schedule should be applied, and no further actions are required.
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).
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:
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, 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 combination of the induction of CYP2C9 and inhibition of OATP1B1 and 1B3.
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.
There are no data from the use of lesinurad in pregnant women.
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).
Available pharmacodynamic/toxicological data in rats have shown excretion of lesinurad in milk. A risk to the newborns/infants cannot be excluded. Zurampic should not be used during breast-feeding.
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).
Lesinurad has no or negligible influence on the ability to drive and use machines.
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%).
Adverse reactions are classified according to frequency and System Organ Class. Frequency categories are defined according to the following conventions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000) and very rare (<1/10,000).
Table 1 lists adverse reactions identified in clinical studies with patients receiving Zurampic 200 mg once daily in combination with a xanthine oxidase inhibitor, allopurinol or febuxostat.
Table 1. Adverse reactions by System Organ Class and frequency:
Common: Influenza
Rare: Hypersensitivity*
Uncommon: Dehydration
Common: Headache
Common: Gastro-oesophageal reflux disease
Uncommon: Renal failure**, Renal impairment, Nephrolithiasis
Common: Blood creatinine increased
* Photodermatosis, photosensitivity reaction, dermatitis allergic, pruritus and urticaria.
** Includes the preferred terms: renal failure, renal failure chronic and renal failure acute.
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 renalrelated 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 placebocontrolled 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%).
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.
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 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.
Not applicable.
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