lesinurad/allopurinol (Discontinued)

>10%

Serum creatinine elevation 1.5 x to <2.0 x baseline, lesinurad 400 mg/allopurinol (11%)

1-10%

Blood creatinine, lesinurad 400 mg/allopurinol (8%)

Serum creatinine elevation ≥2.0 x baseline, lesinurad 400 mg/allopurinol (7%)

Influenza, lesinurad 200 mg/allopurinol (4.9%)

Serum creatinine elevation 1.5 x to <2.0 x baseline, lesinurad 200 mg/allopurinol (4.4%)

Headache, lesinurad 200 mg/allopurinol (4.2%)

Blood creatinine elevation, lesinurad 200 mg/allopurinol (3.7%)

Renal failure, lesinurad 400 mg/allopurinol (3.5%)

Gastroesophageal reflux disease (3.2%)

Nephrolithiasis, lesinurad 400 mg/allopurinol (2.2%)

Major adverse cardiovascular events (eg, cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), lesinurad 400 mg/allopurinol (1.85%)

Serum creatinine elevation ≥2.0 x baseline, lesinurad 200 mg/allopurinol (1.5%)

Renal failure, lesinurad 200 mg/allopurinol (1%)

<1%

Major adverse cardiovascular events, lesinurad 200 mg/allopurinol (0.61%)

Nephrolithiasis, lesinurad 200 mg/allopurinol (0.5%)

Frequency Not Defined

ALT increased

AST increased

Blood alkaline phosphatase increased

Diarrhea

Maculopapular rash

Nausea

Rash

Postmarketing Reports

Most common

• Gastrointestinal disorders: Diarrhea, nausea
• Investigations: Blood alkaline phosphatase increased, AST increased, ALT increased
• Skin and subcutaneous tissue disorders: Rash, maculopapular rash

Less common (<1%)

• Blood and lymphatic system disorders: Ecchymosis, thrombocytopenia, eosinophilia, leukocytosis, leukopenia
• Gastrointestinal disorders: Vomiting, abdominal pain, gastritis, dyspepsia
• General disorders and administration site conditions: Pyrexia
• Hepatobiliary disorders: Hepatitis (including hepatic necrosis and granulomatous hepatitis), hepatomegaly, hyperbilirubinemia, cholestatic jaundice
• Musculoskeletal and connective-tissue disorders: Myopathy, arthralgia
• Nervous system disorders: Headache, peripheral neuropathy, neuritis, paresthesia, somnolence, ageusia
• Renal and urinary disorders: Renal failure, azotemia
• Respiratory, thoracic and mediastinal disorders: Epistaxis
• Skin and subcutaneous tissue disorders: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, leukocytoclastic vasculitis, purpura, bullous dermatitis, exfoliative dermatitis, eczema, pruritus, urticaria, alopecia, onycholysis, lichen planus
• Vascular disorders: Necrotizing vasculitis, vasculitis

Contraindications

Severe renal impairment (CrCl <30 mL/min), end-stage renal disease, kidney transplant recipients, or patient on dialysis

Tumor lysis syndrome or Lesch-Nyhan syndrome

Known hypersensitivity to allopurinol, including previous occurrence of skin rash

Cautions

Increase risk of renal events; see Black Box Warnings

Few cases reported of reversible clinical hepatoxicity with patients taking allopurinol; if anorexia, weight loss, or pruritus develops in patients on lesinurad/allopurinol, liver function should be evaluated; in patients with pre-existing liver disease, periodic liver function tests are recommended

In clinical trials with lesinurad/allopurinol, major adverse cardiovascular events (eg, cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes) were observed

Occasional occurrence of drowsiness was reported in patients taking allopurinol; caution when engaging in activities where alertness is mandatory

Bone marrow depression has been reported in patients receiving allopurinol, most of whom received concomitant drugs with the potential for causing this reaction, ranging from 6 weeks to 6 years after initiating allopurinol therapy; see Drug interactions overview

Rash and hypersensitivity

• Rash frequently reported in allopurinol patients; in some instances, a skin rash may be followed by more severe hypersensitivity reactions associated with exfoliation, fever, lymphadenopathy, arthralgia, and/or eosinophilia, including Stevens-Johnson syndrome and toxic epidermal necrolysis; treatment should be discontinued immediately at any appearance of skin rash or other allergic signs/symptoms
• Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazide diuretics and lesinurad/allopurinol concurrently; caution with coadministration of such combinations and patients should be observed closely

Drug interactions overview

• Lesinurad is a substrate of CYP2C9, OAT1, and OAT3; no clinical studies have been conducted with OAT1/OAT3 inhibitors; caution with moderate CYP2C9 inhibitors or inducers
• Lesinurad is a weak inducer of CYP3A and has no relevant effect on any other CYP enzyme for induction (CYP1A2, CYP2C8, CYP2C9, CYP2B6, or CYP2C19) or inhibition (CYP1A2, CYP2B6, CYP2D6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4); monitor for potential reduction in efficacy in CYP3A substrates
• Reported that allopurinol prolongs the half-life of dicumarol, a coumarin anticoagulant; prothrombin time should be reassessed periodically in patients receiving coumarin anticoagulants (dicumarol, warfarin) concomitantly with lesinurad/allopurinol

• Allopurinol with mercaptopurine or azathioprine

  • Patients taking allopurinol and mercaptopurine or azathioprine require a reduction in dose to approximately one third to one quarter of the usual dose of mercaptopurine or azathioprine
  • Subsequent dose adjustments of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects; closely monitor therapeutic response and appearance of toxicity

Pregnancy

No available human data on use of lesinurad/allopurinol or lesinurad in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Limited published data on allopurinol use in pregnant women do not demonstrate a clear pattern or increase in frequency of adverse development outcomes

Animal Data

• Lesinurad

  • In an embryofetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-17, lesinurad was not teratogenic and had no affect fetal development or survival at exposures up to ~45 times the maximum recommended human dosage (MRHD) (on an AUC basis at maternal oral doses up to 300 mg/kg/day)
  • In an embryofetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-20, lesinurad was not teratogenic and did not affect fetal development at exposures up to ~10 times the MRHD (on an AUC basis at maternal oral doses up to 75 mg/kg/day); severe maternal toxicity, including mortality, was observed in rats and rabbits at exposures equal to or greater than ~45 and 4 times the MRHD (on an AUC basis at maternal oral doses of 300 mg/kg/day in rats and 25 mg/kg/day and higher in rabbits), respectively

• Allopurinol

  • In embryofetal development studies with pregnant rats or rabbits, allopurinol administered during the period of organogenesis (gestation days 8–16) was not teratogenic or fetotoxic in either species at doses up to ~6 times the MRHD (on a mg/m2 basis at maternal oral doses up to 200 mg/kg/day in rats and 100 mg/kg/day in rabbits)
  • However, in an embryofetal development study with pregnant mice, single intraperitoneal doses of allopurinol on gestation days 10 or 13 produced significant increases in fetal deaths and teratogenic effects, including external and skeletal malformations, at 0.8 times the MRHD and higher (on a mg/m2 basis at maternal intraperitoneal doses of 50 or 100 mg/kg); it is uncertain whether the findings in mice represented a fetal effect or an effect secondary to maternal toxicity.

Lactation

Unknown if distributed in human breast milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Lesinurad: Selective uric acid reabsorption inhibitor (SURI); it acts by inhibiting the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid; it also inhibits organic anion transporter 4 (OAT4), a uric acid transporter associated with diuretic-induced hyperuricemia

Allopurinol: Xanthine oxidase inhibitor that inhibits conversion of hypoxanthine to xanthine to uric acid; decreases production of uric acid without disrupting synthesis of vital purines

Absorption

Lesinurad

• Bioavailability: ~100% (monotherapy)
• Peak plasma time: 1-4 hr (single dose)
• Administration with a high-fat meal, decreases plasma concentration of lesinurad compared with fasted state

Allopurinol

• Peak plasma time: 1-4 hr (allopurinol and oxypurinol)
• Peak plasma concentration, single 300 mg dose: 3 mcg/mL (allopurinol); 6.5 mcg/mL (oxypurinol)

Distribution

Protein bound: 98% (lesinurad)

Vd: ~20 L (lesinurad)

Metabolism

Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome CYP2C9 enzyme; metabolites are not known to contribute to the uric-acid lowering effects of lesinurad; caution with use in CYP2C9 poor metabolizers, and in patients taking moderate CYP2C9 inhibitors; see Cautions

Allopurinol is metabolized to oxypurinol (alloxanthine), which also is a xanthine oxidase inhibitor

Elimination

Half-life: 5 hr (lesinurad); 1-2 hr (allopurinol); ~26 hr (oxypurinol)

Clearance: 6L/hr (lesinurad)

Allopurinol is cleared essentially by glomerular filtration; oxypurinol is reabsorbed in the kidney tubules similarly to the reabsorption of uric acid

Excretion: Feces (20%, allopurinol)

Pharmacogenomics

Caution with CYP2C9 poor metabolizers

Oral Administration

Take PO qDay in the morning with food and water

Instruct patient to stay well hydrated (eg, 2 liters of liquid per day)

Storage

Store at 20-25°C (68-77°F); excursions permitted from 15-30°C (59-86°F)