Lesinurad

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 lesinurad. 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).

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

Lesinurad exposure is increased when it is co-administered with inhibitors of CYP2C9. Fluconazole, a moderate CYP2C9 inhibitor, increased lesinurad AUC (56%) and C_max (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 lesinurad 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 lesinurad is co-administered with a CYP2C9 inducer.

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 lesinurad 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 lesinurad 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.

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 lesinurad.

Based on interaction studies in healthy subjects or gout patients, lesinurad does not have clinically significant interactions with NSAIDs (naproxen and indomethacin), colchicine, repaglinide, tolbutamide, febuxostat or allopurinol. Lesinurad 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.

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

Lesinurad has not been studied in patients with severe hepatic impairment; therefore, dose recommendations cannot be given.

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

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

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.

Available pharmacodynamic/toxicological data in rats have shown excretion of lesinurad in milk. A risk to the newborns/infants cannot be excluded. Lesinurad should not be used during breast-feeding.

In an interaction study conducted in healthy subjects with multiple doses of lesinurad 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 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.

Patients known to be CYP2C9 poor metabolisers should be treated with caution, as the potential risk of renal-related adverse effects may be increased.

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.

As a precautionary measure, it is preferable to avoid the use of lesinurad during pregnancy. Female patients of childbearing potential should not rely on hormonal contraception alone when taking lesinurad.

Available pharmacodynamic/toxicological data in rats have shown excretion of lesinurad in milk. A risk to the newborns/infants cannot be excluded. Lesinurad 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.

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