Urece

See Table 1.

Click on icon to see table/diagram/image

URECE Tablets 1 mg: Each tablet contains 1 mg dotinurad.
URECE Tablets 2 mg: Each tablet contains 2 mg dotinurad.
Excipients/Inactive Ingredients: URECE Tablets: Lactose hydrate, D-mannitol, microcrystalline cellulose, hypromellose, carmellose, magnesium stearate, red ferric oxide (for 2 mg only).

Pharmacology: Antihyperuricemic drug; Selective uric acid reabsorption inhibitor.
Pharmacodynamics: Mechanism of Action: Dotinurad selectively inhibits URAT1, which is a transporter involved in uric acid reabsorption in the kidney, and enhances urinary excretion of uric acid filtered by the glomeruli and thereby reduces blood uric acid levels.
Inhibition of URAT1: Dotinurad inhibited uric acid uptake in cells expressing human URAT1 with an IC₅₀ of 0.0372 μmol/L. In addition, inhibition of BCRP (ABCG2), OAT1, and OAT3, which are transporters involved in uric acid secretion from blood into the small intestine or renal tubules, was evaluated using cells expressing human ABCG2, OAT1, or OAT3. The IC₅₀ values were 4.16, 4.08, and 1.32 μmol/L, respectively, suggesting that dotinurad is a uric acid reabsorption inhibitor that is highly selective for URAT1 (in vitro).
Reduction in Blood Uric Acid Levels: After single oral administration to capuchin monkeys at doses of 1, 5, and 30 mg/kg, dotinurad reduced the plasma uric acid levels and increased the fractional excretion of uric acid in a dose-dependent manner (in vivo).
Clinical Studies: Clinical Studies for Efficacy and Safety: Japanese phase III study (Benzbromarone-controlled): A benzbromarone-controlled, double-blind, parallel-group comparative study was conducted in 201 patients with hyperuricemia including gout (excluding uric acid overproduction hyperuricemia). Treatment with dotinurad was started at a dose of 0.5 mg/day, followed by a gradual dose increase to 1 mg/day after 2 weeks of treatment and then to 2 mg/day after 6 weeks of treatment, which was then maintained until 14 weeks after the start of treatment. Treatment with benzbromarone was started at a dose of 25 mg/day, followed by a dose increase to 50 mg/day after 2 weeks of treatment, which was then maintained until 14 weeks after the start of treatment.
The percent reduction in serum uric acid level from baseline at the final visit (primary endpoint) is shown in the table as follows. The non-inferiority of dotinurad 2 mg/day to benzbromarone 50 mg/day was shown in terms of percent reduction in serum uric acid level at the final visit (noninferiority margin: -10%). The proportion of subjects achieving a serum uric acid level of ≤ 6.0 mg/dL at the final visit (secondary endpoint) was 86.27% (88/102 subjects) in the dotinurad group and 83.67% (82/98 subjects) in the benzbromarone group. (See Table 2.)

Click on icon to see table/diagram/image

The incidence of adverse reactions was 14.7% (15/102 subjects) in the dotinurad group and 15.2% (15/99 subjects) in the benzbromarone group. Common adverse reactions were gouty arthritis (7.8%, 8/102 subjects) and arthritis (2.9%, 3/102 subjects) in the dotinurad group, and gouty arthritis (5.1%, 5/99 subjects), AST increased (2.0%, 2/99 subjects), and ALT increased (2.0%, 2/99 subjects) in the benzbromarone group. The incidence of gouty arthritis in each treatment period is shown in the table as follows. [See Precautions.] (See Table 3.)

Click on icon to see table/diagram/image

Japanese phase III study (febuxostat-controlled): A febuxostat-controlled, double-blind, parallel-group comparative study was conducted in 201 patients with hyperuricemia including gout (excluding uric acid overproduction hyperuricemia). Treatment with dotinurad was started at a dose of 0.5 mg/day, followed by a gradual dose increase to 1 mg/day after 2 weeks of treatment and then to 2 mg/day after 6 weeks of treatment, which was then maintained until 14 weeks after the start of treatment. Treatment with febuxostat was started at a dose of 10 mg/day, followed by dose increase to 20 mg/day after 2 weeks of treatment and then to 40 mg/day after 6 weeks of treatment, which was then maintained until 14 weeks after the start of treatment. The percent reduction in serum uric acid level from baseline at the final visit (primary endpoint) is shown in the table as follows. The non-inferiority of dotinurad 2 mg/day to febuxostat 40 mg/day was shown in terms of percent reduction in serum uric acid level at the final visit (noninferiority margin: -10%). The proportion of subjects achieving a serum uric acid level of ≤ 6.0 mg/dL at the final visit (secondary endpoint) was 84.8% (84/99 subjects) in the dotinurad group and 88.0% (88/100 subjects) in the febuxostat group. (See Table 4.)

Click on icon to see table/diagram/image

The incidence of adverse reactions was 17.2% (17/99 subjects) in the dotinurad group and 19.8% (20/101 subjects) in the febuxostat group. Common adverse reactions were gouty arthritis (5.0%, 5/101 subjects) and β₂-microglobulin urine increased (4.0%, 4/101 subjects) in the febuxostat group. In the dotinurad group, the incidence rate of all adverse reactions was 1% or less (1/99 subjects). The incidence of gouty arthritis in each treatment period is shown in the table as follows. [See Precautions.] (See Table 5.)

Click on icon to see table/diagram/image

Japanese phase III long-term treatment study: A long-term treatment study was conducted in 330 patients with hyperuricemia including gout (excluding uric acid overproduction hyperuricemia). Treatment with dotinurad was started at a dose of 0.5 mg/day, followed by a gradual dose increase to 1 mg/day after 2 weeks of treatment and then to 2 mg/day after 6 weeks of treatment. If the serum uric acid level was more than 6.0 mg/dL after 14 weeks of treatment, the dose was further increased to 4 mg/day after 18 weeks of treatment, which was then maintained until 34 or 58 weeks after the start of treatment.
The percent reduction in serum uric acid level from baseline was 46.73% at 2 mg/day and 54.92% at 4 mg/day after 34 weeks of treatment, and 47.17% at 2 mg/day and 57.35% at 4 mg/day after 58 weeks of treatment. The proportion of subjects achieving a serum uric acid level of ≤ 6.0 mg/dL was 89.11% (229/257 subjects) at 2 mg/day and 97.50% (39/40 subjects) at 4 mg/day after 34 weeks of treatment, and 91.30% (84/92 subjects) at 2 mg/day and 100.00%(13/13 subjects) at 4 mg/day after 58 weeks of treatment.
The incidence of adverse reactions was 21.8% (72/330 subjects). Common adverse reactions were gouty arthritis (12.7%, 42/330 subjects), arthritis (2.1%, 7/330 subjects), and limb discomfort (2.1%, 7/330 subjects). [See Precautions.]
Pharmacokinetics: Blood Level: Single administration: The time course of the plasma unchanged drug concentration and the pharmacokinetic parameters after single oral administration of dotinurad to healthy adult males (36 subjects) in the fasted state at doses of 0.5, 1, 2, 5, 10, or 20 mg are shown as follows. C_max and AUC_0-inf increased in a dose-dependent manner and linearity was observed. The approved maximum dose of this product is 4 mg of dotinurad once daily. (See figure and Table 6.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Repeated administration: Pharmacokinetic parameters following repeated oral administration of dotinurad to healthy adult males (6 subjects) in the fed state at a dose of 4 mg once daily for 7 days are shown as follows. Plasma unchanged drug concentrations reached the steady state on Day 4 without accumulation. (See Table 7.)

Click on icon to see table/diagram/image

Absorption: Food effect: After single oral administration of dotinurad to healthy adult males (12 subjects) in the fed state at a dose of 4 mg, the C_max was slightly decreased and the T_max was prolonged compared to those in the fasted state, but AUC_0-t was not affected by food. (See Table 8.)

Click on icon to see table/diagram/image

Distribution: Volume of distribution: After single oral administration of ¹⁴C-dotinurad to healthy adult males (6 subjects) in the fasted state at a dose of 1 mg, the volume of distribution was 14.75 L.
Protein binding rate: The human plasma protein binding rate of dotinurad was 99.2 to 99.4%, with no distribution to human blood cells (in vitro).
Metabolism: Dotinurad was mainly metabolized by UGT and SULT to glucuronic acid conjugates and sulfate conjugates.
After single oral administration of ¹⁴C-dotinurad to healthy adult males (6 subjects) in the fasted state at a dose of 1 mg, the major metabolites were glucuronic acid conjugates and sulfate conjugates.
Multiple isoforms including UGT1A1, 1A3, 1A9, and 2B7 were involved in the formation of glucuronic acid conjugates and SULT1B1 and 1A3 were involved in the formation of sulfate conjugates (in vitro).
Dotinurad inhibited CYP2C9 (Ki value: 10.4 μmol/L), but no other isoforms (CYP1A2, 2A6, 2B6, 2C19, 2D6, 2E1, and 3A4) (IC₅₀ > 100 μmol/L). Dotinurad also inhibited UGT1A1 and 2B15 (Ki value: 10.0 and 16.6 μmol/L), but no other isoforms (UGT1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, and 2B17) (IC₅₀ > 50 μmol/L) (in vitro). Dotinurad induced the mRNA expression of CYP2B6, but not for CYP1A2 or 3A4 in human hepatocytes (in vitro). None of these effects are likely to cause interactions at clinical doses.
Excretion: After single oral administration of ¹⁴C-dotinurad to healthy adult males (6 subjects) in the fasted state at a dose of 1 mg, 86.38% and 7.93% of the administered radioactivity was excreted in the urine and feces within 168 hours, respectively, and 5.02% was excreted in exhaled air within 72 hours.
Dotinurad inhibited BCRP (ABCG2), OAT1, OAT3, and OATP1B1 with IC₅₀ values of 74.7, 1.87, 2.61, and 11.5 μmol/L, respectively, but did not inhibit MDR1, OCT2, OATP1B3, MATE1, or MATE2-K. Dotinurad is unlikely to affect any drug transporters at the clinical dose (in vitro).
Patients with Specific Backgrounds: Patients with renal impairment: Pharmacokinetic parameters following single oral administration of dotinurad to subjects with mild renal impairment (6 subjects), moderate renal impairment (6 subjects), and normal renal function (6 subjects) in the fasted state at a dose of 1 mg are shown as follows. (See Table 9.)

Click on icon to see table/diagram/image

Patients with hepatic impairment: Pharmacokinetic parameters following single oral administration of dotinurad to subjects with mild hepatic impairment (6 subjects), moderate hepatic impairment (9 subjects), severe hepatic impairment (3 subjects), and normal hepatic function (6 subjects) in the fasted state at a dose of 4 mg are shown as follows. (See Table 10.)

Click on icon to see table/diagram/image

Geriatric use: Pharmacokinetic parameters following single oral administration of dotinurad to non-elderly males (6 subjects aged between 20 and 35 years), elderly males (6 subjects aged 65 years or older), non-elderly females (6 subjects aged between 20 and 35 years), and elderly females (6 subjects aged 65 years or older) in the fasted state at a dose of 1 mg are shown as follows. (See Table 11.)

Click on icon to see table/diagram/image

Toxicology: Preclinical safety data: Not applicable.

Gout, hyperuricemia.

Posology: The usual initial adult dosage for oral use is 0.5 mg of dotinurad once daily. Thereafter, the dose should be gradually increased as needed while monitoring the blood uric acid levels. The usual maintenance dosage is 2 mg once daily and may be adjusted according to the patient's condition up to a maximum dosage of 4 mg once daily.
Method of administration: For oral use.

Not applicable.

Patients with a history of hypersensitivity to any of the ingredients of URECE.

Precautions Concerning Indications: Patients should be selected for application of URECE in reference to the disease type and the latest treatment guidelines. [See Pharmacology: Pharmacodynamics: Clinical Studies under Actions.]
Precautions Concerning Dosage and Administration: Since gouty arthritis (gout attack) may be induced by a rapid decrease in blood uric acid level in the early stage of treatment with urate-lowering drugs, the dosage of URECE should be started at 0.5 mg once daily, followed by a gradual dose increase, for instance, to 1 mg once daily after the first 2 weeks of treatment and then to 2 mg once daily after 6 weeks of treatment. Patients should be carefully monitored after a dose increase. [See as follows and Pharmacology: Pharmacodynamics: Clinical Studies under Actions.]
Important Precautions: URECE, a urate-lowering drug, may exacerbate gouty arthritis (gout attack) due to a decrease in blood uric acid level when used during gouty arthritis (gout attack). Treatment with URECE should not be started in patients with gouty arthritis (gout attack) until the symptoms have disappeared.
If gouty arthritis (gout attack) occurs during treatment with URECE, treatment should be continued without changing the dose level, and colchicine, non-steroidal anti-inflammatory drugs, and/or corticosteroids should be added according to the patient's condition. [See as follows.]
The pharmacological action of URECE causes an increase in uric acid excretion, especially in the early stages of administration, and if the urine is acidic, the patient may develop urinary calculus and resultant symptoms such as hematuria and renal colic. Urinary calculus should be prevented by increasing the water intake and thus increasing urine output, and by trying to alkalinize the urine. In this case, attention should be paid to the patient's acid-base balance.
Since serious liver disorder has been reported with other uricosurics, patients should be carefully monitored through periodic liver function testing, etc., during administration of URECE. [See as follows.]
Precautions Concerning Patients With Specific Backgrounds: Patients with Complication or History of Diseases, etc.: Patients with urinary calculus: Do not administer unless deemed unavoidable for the sake of treatment. URECE may exacerbate symptoms of urinary calculus by increasing the urinary excretion of uric acid due to its pharmacological effects. URECE has not been administered to patients with urinary calculus in clinical studies.
Patients with Renal Impairment: Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²): Alternative treatment should be considered. Since URECE acts in the renal proximal tubules, its efficacy may be reduced depending on the severity of the renal impairment. In particular, URECE should not be administered in patients with oliguria or anuria, since it is not expected to be effective.
Patients with an eGFR < 30 mL/min/1.73 m² were excluded from clinical studies.
Patients with Hepatic Impairment: Patients should be closely monitored. Serious liver disorder has been observed with other uricosurics.
Patients with serious liver disease or an AST or ALT ≧100 IU/L were excluded from clinical studies. [See as previously mentioned.]
Precautions For Co-Administration (URECE should be administered with care when co-administered with the following drugs.) (See Table 12.)

Click on icon to see table/diagram/image

Precautions Concerning Use: Precautions when Dispensing the Drug: For drugs that are dispensed in a press-through package (PTP), patients should be instructed to remove the drug from the package prior to use. If part of the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, resulting in severe complications such as mediastinitis.
Effects on ability to drive and use machines: Not applicable.

Pregnant Women: URECE should be administered to women who are or may be pregnant only if the expected therapeutic benefits outweigh the possible risks associated with treatment. Skeletal variations were observed at doses equivalent to approximately 1053 and 174 times the clinical exposure in animal studies (rats and rabbits).
Breast-feeding Women: Continuation or discontinuation of breast-feeding should be considered in view of the therapeutic benefits and the benefits of breast-feeding. It has been reported in animal studies (rats) that dotinurad was excreted in breast milk.

Since the following adverse reactions may occur, patients should be carefully monitored, and if any abnormalities are observed, appropriate measures such as discontinuation of administration should be taken.
Other Adverse Reactions: See Table 13.

Click on icon to see table/diagram/image

The pharmacokinetic parameters of dotinurad following single oral administration of dotinurad to healthy male adults (12 subjects) in the fed state at a dose of 4 mg or following oral co-administration of oxaprozin (600 mg) and dotinurad (4 mg) in the fed state on Day 6 preceded by repeated oral administration of oxaprozin in the fed state at a dose of 600 mg once daily for 5 days are shown as follows. (See Table 14.)

Click on icon to see table/diagram/image

Incompatibilities: Not applicable.
Special precautions for disposal: No special requirements.

Shelf life: 3 years.
Special precautions for storage: Storage: Do not store above 30°C.

Hyperuricemia & Gout Preparations

M04AB - Preparations increasing uric acid excretion ; Used in the treatment of gout.

S