Adult: In combination with xanthine oxidase inhibitor, in patients who have not achieved target serum uric acid levels with xanthine oxidase inhibitor monotherapy: 200 mg once daily, given at the same time as the xanthine oxidase inhibitor.
Special Patient Group
Lesinurad is metabolised primarily by CYP2C9 enzyme. Genetic polymorphism of CYP2C9 may affect the pharmacokinetics and clinical safety of lesinurad. CYP2C9*2 and *3 are identified as the allele variants which are associated with the reduction of CYP2C9 activity. The prevalence of *2 allele is more common in Caucasian (10-20%) than in the Asian (1-3%) or African (0-6%) populations, while the *3 allele is less common in most populations (<10%) and is extremely rare in African populations.
Individuals who are deficient in CYP2C9 enzyme activity are CYP2C9 poor metabolisers (carriers of 2 decreased function alleles e.g. *2/2, *3/*3, *2/*3).
A cross-study pharmacogenomic analysis assessed the association between CYP2C9 polymorphism and lesinurad exposure in patients receiving single or multiple doses of lesinurad at 200 mg, 400 mg, or 600 mg. CYP2C9 poor metabolisers (n=1) had a 1.8-fold higher lesinurad exposure as compared to CYP2C9 extensive metabolisers (n=41) after receiving the 400 mg dose.
CYP2C9 poor metabolisers should be treated with caution as the potential risk of renal-related adverse effects may be increased.
Tab: Should be taken with food. Take in the morning.
Patients with tumour lysis syndrome or Lesch-Nyhan syndrome, end-stage renal disease; on dialysis, or kidney transplant recipients. Severe renal (CrCl <30 mL/min) impairment.
CYP2C9 poor metabolisers. Pregnancy and lactation. Not recommended for patients taking allopurinol <300 mg daily (or <200 mg with CrCl <60 mL/min).
Significant: Gout flares, increased serum creatinine, renal failure, nephrolithiasis. Gastrointestinal disorders: Gastroesophageal reflux disease. Immune system disorders: Rarely, hypersensitivity reactions (e.g. photosensitivity). Infections and infestations: Influenza. Nervous system disorders: Headache.
Monitor renal function prior to treatment initiation and periodically thereafter.
Increased serum concentrations with moderate CYP2C9 inhibitors (e.g. fluconazole, amiodarone) and epoxide hydrolase inhibitors (e.g. valproic acid). Decreased serum concentrations with moderate CYP2C9 inducers (e.g. rifampicin, carbamazepine). Reduced plasma concentrations of CYP3A4 substrates (e.g. lovastatin, simvastatin, sildenafil, felodipine, nisoldipine, amlodipine). Decreased therapeutic effect of lesinurad with high-dose aspirin (>325 mg/day). Decreased serum concentration and effect of hormonal contraceptives (e.g. oestrogen).
Description: Lesinurad inhibits uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4), increasing urinary excretion of uric acid, lowering plasma urate concentrations, and eventually reducing urate deposits in the tissues. Pharmacokinetics: Absorption: Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 100%. Time to peak plasma concentrations: Within 1-4 hours. Distribution: Volume of distribution: Approx 20 L. Plasma protein binding: >98%, mainly to albumin. Metabolism: Undergoes oxidative metabolism mainly by CYP2C9. Excretion: Via urine (63%; approx 30% as unchanged drug); faeces (32%). Elimination half-life: Approx 5 hours.
M04AB05 - lesinurad ; Belongs to the class of preparations increasing uric acid excretion. Used in the treatment of gout.
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