Dosing & Uses
Dosage Forms & Strengths
April 2019: Product discontinued by manufacturer
tablet
- 200 mg/200 mg
- 200 mg/300 mg
Gout
Indicated for hyperuricemia associated with gout in patients who have not achieved target serum uric acid (sUA) levels with allopurinol alone
Use 1 tablet of lesinurad/allopurinol equivalent to the total daily dose (TDD) of allopurinol; maintain TDD of allopurinol when initiating lesinurad/allopurinol
Recommended combination dose based on current allopurinol
- For patients who have not achieved target sUA on a medically appropriate dose of allopurinol >300 mg, lesinurad/allopurinol may be initiated by using 1 tablet in place of an equivalent portion of the TDD of allopurinol
- Allopurinol 300 mg: Initiate 1 tablet of lesinurad 200 mg/allopurinol 300 mg PO qDay
- Allopurinol 200 mg: Initiate 1 tablet of lesinurad 200 mg/allopurinol 200 mg PO qDay
- Lesinurad coadministered with allopurinol: Initiate 1 tablet PO qDay equivalent to the daily lesinurad and allopurinol doses
Dosage Modifications
Renal impairment
- Mild-to-moderate (CrCl ≥45 mL/min): No dosage adjustment necessary; monitor CrCl more frequently if CrCl <60 mL/min
- Moderate-to-severe (CrCl 30-45 mL/min): Do not initiate; discontinued if CrCl is persistently <45 mL/min while taking lesinurad/allopurinol
- Severe renal impairment (CrCl <30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis: Contraindicated
- See Black Box Warnings
Hepatic impairment
- Mild-to-moderate (Child-Pugh A and B): No dosage adjustment necessary
- Severe (Child-Pugh C): Safety and efficacy not established
Gout flares
- Gout flares may occur after initiation of urate-lowering therapy, including lesinurad/allopurinol, owing to changing sUA levels resulting in mobilization of urate from tissue deposits
- Patients not previously taking lesinurad: Gout flare prophylaxis is recommended when initiating treatment, according to practice guidelines
- If a gout flare occurs during treatment, lesinurad/allopurinol need not be discontinued; gout flare should be managed concurrently, as appropriate for the individual patient
Dosing Considerations
Limitation of use: Not recommended for treatment of asymptomatic hyperuricemia
1 tablet of lesinurad/allopurinol contains the maximum daily lesinurad dose (200 mg)
Do not take more than 1 tablet of lesinurad/allopurinol per day
Do not combine lesinurad/allopurinol with additional lesinurad
Safety and efficacy not established
No dosage adjustment necessary
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (23)
- aspirin
aspirin decreases effects of lesinurad by unspecified interaction mechanism. Avoid or Use Alternate Drug. Aspirin at doses >325 mg/day may decrease lesinurad efficacy. Aspirin doses 325 mg/day or less (ie, for cardiovascular event prophylaxis) does not decrease lesinurad efficacy and can be coadministered.
- azathioprine
allopurinol increases levels of azathioprine by decreasing metabolism. Avoid or Use Alternate Drug. Increased risk of bone marrow toxicity.
- benazepril
benazepril increases toxicity of allopurinol by unspecified interaction mechanism. Avoid or Use Alternate Drug. May increase risk for allergic or hypersensitivity reactions to allopurinol. Monitor for symptoms of hypersensitivity reactions if both drugs must be used together.
- captopril
captopril, allopurinol. Mechanism: unknown. Avoid or Use Alternate Drug. Risk of anaphylaxis, Stevens Johnson syndrome.
captopril increases toxicity of allopurinol by Mechanism: unspecified interaction mechanism. Avoid or Use Alternate Drug. May increase risk for allergic or hypersensitivity reactions to allopurinol Monitor for symptoms of hypersensitivty reactions if both drugs must be used together. - didanosine
allopurinol increases levels of didanosine by unknown mechanism. Contraindicated.
- dienogest/estradiol valerate
lesinurad decreases effects of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.
- enalapril
enalapril, allopurinol. Mechanism: unknown. Avoid or Use Alternate Drug. Risk of anaphylaxis, Stevens Johnson syndrome.
- ethinylestradiol
lesinurad decreases effects of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.
- etonogestrel
lesinurad decreases effects of etonogestrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.
- ivosidenib
ivosidenib will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP2C9 substrates with ivosidenib or replace with alternate therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
- levonorgestrel intrauterine
lesinurad decreases effects of levonorgestrel intrauterine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.
- levonorgestrel oral
lesinurad decreases effects of levonorgestrel oral by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.
- medroxyprogesterone
lesinurad decreases effects of medroxyprogesterone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.
- norethindrone
lesinurad decreases effects of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.
- pacritinib
lesinurad will decrease the level or effect of pacritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- perindopril
perindopril, allopurinol. Mechanism: unknown. Avoid or Use Alternate Drug. Risk of anaphylaxis, Stevens Johnson syndrome.
- pexidartinib
allopurinol and pexidartinib both increase Other (see comment). Avoid or Use Alternate Drug. Pexidartinib can cause hepatotoxicity. Avoid coadministration of pexidartinib with other products know to cause hepatoxicity.
- pretomanid
allopurinol, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- protamine
allopurinol increases effects of protamine by decreasing metabolism. Avoid or Use Alternate Drug.
- ropeginterferon alfa 2b
ropeginterferon alfa 2b, allopurinol. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression.
- theophylline
allopurinol increases levels of theophylline by decreasing metabolism. Avoid or Use Alternate Drug.
- valproic acid
valproic acid, lesinurad. Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid coadministration with inhibitors of epoxide hydrolase (valproic acid) which may interfere with metabolism of lesinurad.
- warfarin
allopurinol increases effects of warfarin by anticoagulation. Avoid or Use Alternate Drug.
Monitor Closely (51)
- acalabrutinib
acalabrutinib, allopurinol. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration may increase risk of myelosuppressive effects.
- alpelisib
alpelisib will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- aluminum hydroxide
aluminum hydroxide decreases levels of allopurinol by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Separate by 2 hours.
- amiodarone
amiodarone will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- amlodipine
lesinurad decreases levels of amlodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- amoxicillin
allopurinol decreases toxicity of amoxicillin by Other (see comment). Use Caution/Monitor. Comment: Allopurinol may increase potential for allergic or hypersensitivity reactions to amoxicillin.
- apalutamide
apalutamide will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Coadministration of apalutamide, a weak CYP2C9 inducer, with drugs that are CYP2C9 substrates can result in lower exposure to these medications. Evaluate for loss of therapeutic effect if medication must be coadministered.
- atogepant
lesinurad will decrease the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- bosentan
bosentan will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- calcium carbonate
calcium carbonate decreases levels of allopurinol by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Separate by 2 hours.
- cannabidiol
cannabidiol will increase the level or effect of lesinurad by decreasing metabolism. Modify Therapy/Monitor Closely. Cannabidiol may potentially inhibit CYP2C9 activity. Consider reducing the dose when concomitantly using CYP2C9 substrates.
- capecitabine
capecitabine will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- carbamazepine
carbamazepine will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- cyclophosphamide
allopurinol increases toxicity of cyclophosphamide by decreasing metabolism. Use Caution/Monitor.
- dichlorphenamide
dichlorphenamide and allopurinol both decrease serum potassium. Use Caution/Monitor.
dichlorphenamide, allopurinol. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Both drugs can cause metabolic acidosis. - ethambutol
ethambutol decreases effects of allopurinol by Other (see comment). Use Caution/Monitor. Comment: Hyperuricemia reported with ethambutol and precipitation of gout reported; uric acid lowering agents may be require dosage adjustment.
- fluconazole
fluconazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- fluorouracil
fluorouracil will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- flurbiprofen
flurbiprofen will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- fosphenytoin
fosphenytoin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- gemfibrozil
gemfibrozil will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- hydroxyurea
allopurinol, hydroxyurea. Other (see comment). Use Caution/Monitor. Comment: Combination may increase risk of myelosuppression.
- ibuprofen
ibuprofen will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- ibuprofen IV
ibuprofen IV will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- indomethacin
indomethacin will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- isavuconazonium sulfate
lesinurad will decrease the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- ketoconazole
ketoconazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- levoketoconazole
levoketoconazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- levonorgestrel oral/ethinylestradiol/ferrous bisglycinate
lesinurad will decrease the level or effect of levonorgestrel oral/ethinylestradiol/ferrous bisglycinate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. The efficacy of hormonal contraceptives may be reduced. Use an alternative method of contraception or a backup method when enzyme inducers are used with combined hormonal contraceptives (CHCs), and continue backup contraception for 28 days after discontinuing enzyme inducer to ensure contraceptive reliability.
- mefenamic acid
mefenamic acid will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- mercaptopurine
allopurinol increases levels of mercaptopurine by decreasing metabolism. Use Caution/Monitor. Potential for increased myelosuppression.
- methotrexate
allopurinol decreases effects of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Combination may increase risk of myelosuppression.
- mipomersen
mipomersen, allopurinol. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Both drugs have potential to increase hepatic enzymes; monitor LFTs.
- nicardipine
nicardipine will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- nitisinone
nitisinone will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Nitisinone inhibits CYP2C9. Caution if CYP2C9 substrate coadministered, particularly those with a narrow therapeutic index.
- phenobarbital
phenobarbital will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- phenytoin
phenytoin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- piroxicam
piroxicam will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- primidone
primidone will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- rifampin
rifampin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- rifapentine
rifapentine will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- rucaparib
rucaparib will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP2C9 substrates, if clinically indicated.
- secobarbital
secobarbital will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- sildenafil
lesinurad decreases levels of sildenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- sodium bicarbonate
sodium bicarbonate decreases levels of allopurinol by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Separate by 2 hours.
- sodium citrate/citric acid
sodium citrate/citric acid decreases levels of allopurinol by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Separate by 2 hours.
- sulfadiazine
sulfadiazine will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- sulfamethoxazole
sulfamethoxazole will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
- tazemetostat
lesinurad will decrease the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- thioguanine
allopurinol, thioguanine. unknown mechanism. Use Caution/Monitor. Potential for increased myelosuppression.
- tolbutamide
tolbutamide will increase the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
Minor (3)
- ampicillin
ampicillin, allopurinol. Mechanism: unknown. Minor/Significance Unknown. Increased incidence of rash.
- cyclosporine
allopurinol increases levels of cyclosporine by unknown mechanism. Minor/Significance Unknown.
- tacrolimus
allopurinol increases levels of tacrolimus by unknown mechanism. Minor/Significance Unknown.
Adverse Effects
>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
Warnings
Black Box Warnings
Acute renal failure reported with lesinurad and more commonly occurs when administered as monotherapy; lesinurad should be used in combination with a xanthine oxidase inhibitor; adverse reactions related to renal function, including acute renal failure, reported after initiating
Lesinurad 200 mg in combination with allopurinol associated with increased incidence of serum creatinine (Scr) elevations, mostly reversible Interrupt treatment if Scr increases to >2 times baseline; discontinue treatment if CrCl <45 mL/min
Interrupt treatment and measure Scr promptly if symptoms of acute uric acid nephropathy (eg, flank pain, nausea or vomiting) occur
Do not restart lesinurad/allopurinol unless an alternative cause of serum creatinine abnormalities is found
Evaluate renal function before treatment and periodically thereafter as clinically indicated; more frequent renal function monitoring recommended with CrCL < 60 mL/min or with Scr increases 1.5-2x baseline
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
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.Pharmacology
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
Administration
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)