Duzallo

• It is used to lower uric acid in the blood.

Duzallo®, a combination of lesinurad, a uric acid transporter 1 (URAT1) inhibitor, and allopurinol, a xanthine oxidase inhibitor, is indicated for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a medically appropriate daily dose of allopurinol alone [see Clinical Studies (14)].

Limitations of Use

Duzallo is not recommended for the treatment of asymptomatic hyperuricemia.

Duzallo (lesinurad and allopurinol) tablets contain 2 oral medications used in the treatment of hyperuricemia: lesinurad and allopurinol. Lesinurad is a URAT1 inhibitor and allopurinol is a xanthine oxidase inhibitor.

Lesinurad

Lesinurad has the following chemical name: 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid. The molecular formula is C17H14BrN3O2S and the molecular weight is 404.28. The structural formula is:

Allopurinol

Allopurinol has the following chemical name: 1,5-dihydro-4H-Pyrazolo[3,4-d]pyrimidin-4-one. The molecular formula is C5H4N4O and the molecular weight is 136.11146 Daltons. The structural formula is:

Duzallo

Duzallo is available as a light orange film-coated tablet containing 200 mg of lesinurad and 200 mg of allopurinol or a dark orange film-coated tablet containing 200 mg of lesinurad and 300 mg of allopurinol. The capsule-shaped tablets include the following inactive ingredients: crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: hypromellose, iron oxide red, iron oxide yellow, titanium dioxide, and triacetin. Duzallo 200/200 mg tablets are coated with Opadry orange and 200/300 mg tablets are coated with Opadry beige.

Mechanism of Action

Duzallo combines two medications with complementary mechanisms of action for treatment of hyperuricemia associated with gout: lesinurad, a uric acid reabsorption inhibitor, and allopurinol, a xanthine oxidase inhibitor. Duzallo lowers serum uric acid levels by increasing excretion and inhibiting production of uric acid.

Lesinurad

Lesinurad reduces serum uric acid levels by inhibiting the function of transporter proteins involved in uric acid reabsorption in the kidney. Lesinurad inhibited the function of two apical transporters responsible for uric acid reabsorption, uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4), with IC50 values of 7.3 and 3.7 µM, respectively. URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen. OAT4 is a uric acid transporter associated with diuretic-induced hyperuricemia. Lesinurad does not interact with the uric acid reabsorption transporter SLC2A9 (Glut9), located on the basolateral membrane of the proximal tubule cell.

Allopurinol

Allopurinol acts on purine catabolism, without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation. Allopurinol is a structural analogue of the natural purine base, hypoxanthine. It is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in humans. Allopurinol is metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.

Reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by allopurinol and oxypurinol. This reutilization does not disrupt normal nucleic acid anabolism because feedback inhibition is an integral part of purine biosynthesis. As a result of xanthine oxidase inhibition, the serum concentration of hypoxanthine plus xanthine in patients receiving allopurinol for treatment of hyperuricemia is usually in the range of 0.3 to 0.4 mg/dL compared to a normal level of approximately 0.15 mg/dL. A maximum of 0.9 mg/dL of these oxypurines has been reported when the serum urate was lowered to less than 2 mg/dL by high doses of allopurinol. These values are far below the saturation levels at which point their precipitation would be expected to occur (above 7 mg/dL).

Pharmacodynamics

Effects on Serum Uric Acid and Urinary Excretion of Uric Acid

Lesinurad

In gout patients, lesinurad lowered serum uric acid levels and increased renal clearance and fractional excretion of uric acid. Following single and multiple oral doses of lesinurad to gout patients, dose-dependent decreases in serum uric acid levels and increases in urinary uric acid excretion were observed.

Allopurinol

Allopurinol reduces both the serum and urinary uric acid levels by inhibiting the formation of uric acid.

Effect on Cardiac Repolarization

Lesinurad

The effect of lesinurad on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and gout patients. Lesinurad at doses up to 1600 mg did not demonstrate an effect on the QTc interval.

Allopurinol

The effect of allopurinol on cardiac repolarization has not been evaluated.

Pharmacokinetics

Duzallo

After the administration of Duzallo with a high-fat breakfast in healthy subjects, the exposure (AUC) for lesinurad and allopurinol were comparable to the fasted state. Compared to the fasted state, the fed state resulted in 46% and 18% reductions and 2.5 hours and 1.75 hours delays, in the peak (Cmax) concentrations of lesinurad and allopurinol, respectively. This effect of food is not considered to be clinically meaningful. Oxypurinol Cmax and AUC were similar in the fed and fasted states.

Absorption

Lesinurad

The absolute bioavailability of lesinurad as monotherapy is approximately 100%. Lesinurad is rapidly absorbed after oral administration. Following administration of a single dose of a lesinurad tablet in either fed or fasted state, Cmax was attained within 1 to 4 hours. Cmax and AUC exposures of lesinurad increased proportionally with single doses of lesinurad from 5 to 1200 mg. Administration with a high-fat meal (800 to 1000 calories with 50% of calories being derived from fat content) decreases Cmax by up to 18% but does not alter AUC as compared with fasted state. In clinical trials, lesinurad was administered with food.

Allopurinol

Allopurinol is approximately 90% absorbed from the gastrointestinal tract. Peak plasma levels generally occur at 1.5 hours and 4.5 hours for allopurinol and oxypurinol, respectively. After a single oral dose of 300 mg allopurinol, maximum plasma levels of about 3 mcg/mL of allopurinol and 6.5 mcg/mL of oxypurinol are produced.

Distribution

Lesinurad

Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin. Plasma protein binding of lesinurad is not meaningfully altered in patients with renal or hepatic impairment. The mean steady state volume of distribution of lesinurad was approximately 20 L following intravenous dosing of lesinurad.

Elimination

Lesinurad

The elimination half-life (t½) of lesinurad is approximately 5 hours. Lesinurad does not accumulate following multiple doses. The total body clearance is approximately 6 L/hr.

Allopurinol

Because of its rapid oxidation to oxypurinol and a renal clearance rate approximately that of glomerular filtration rate, allopurinol has a plasma half-life of about 1 to 2 hours. Oxypurinol, however, has a longer plasma elimination half-life (approximately 26 hours) and therefore effective xanthine oxidase inhibition is maintained over a 24-hour period with single daily doses of allopurinol. Whereas allopurinol is cleared essentially by glomerular filtration, oxypurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid.

Metabolism

Lesinurad

Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome P450 CYP2C9 enzyme. Plasma exposure of metabolites is minimal (<10% of unchanged lesinurad). Metabolites are not known to contribute to the uric acid lowering effects of lesinurad. A transient oxide metabolite is rapidly eliminated by microsomal epoxide hydrolase in the liver and not detected in plasma.

Patients who are CYP2C9 poor metabolizers are deficient in CYP2C9 enzyme activity. 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. At the 400 mg dose, lesinurad exposure was approximately 1.8-fold higher in CYP2C9 poor metabolizers (i.e., subjects with CYP2C9 *2/*2 [N=1], and *3/*3 [N=1] genotype) compared to CYP2C9 extensive metabolizers (i.e., CYP2C9 *1/*1 [N=41] genotype). Use with caution in CYP2C9 poor metabolizers, and in patients taking moderate inhibitors of CYP2C9 [see Drug Interactions (7.1)].

Allopurinol

Allopurinol is metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.

Excretion

Lesinurad

Within 7 days following single dosing of radiolabeled lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in feces. Most of the radioactivity recovered in urine (> 60% of dose) occurred in the first 24 hours. Unchanged lesinurad in urine accounted for approximately 30% of the dose.

Allopurinol

Approximately 20% of the ingested allopurinol is excreted in the feces. The remainder is primarily metabolized to oxypurinol.

SPECIFIC POPULATIONS

Renal Impairment

A dedicated renal impairment study was not conducted with Duzallo.

Lesinurad

Two dedicated studies were performed to assess pharmacokinetics (PK) of lesinurad in renal impairment (classified using the Cockcroft-Gault formula) subjects. In both studies, Cmax was comparable in renal impairment subjects compared to healthy subjects. Study 1 was a single-dose, open-label study evaluating the PK of lesinurad 200 mg in subjects with mild (eCLcr 60 to less than 90 mL/min) and moderate renal impairment (eCLcr 30 to less than 60 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6; eCLcr greater than or equal to 90 mL/min), plasma AUC of lesinurad was increased by approximately 30% and 73% in subjects with mild (N=8) and moderate (N=10) renal impairment, respectively. Study 2 was a single-dose, open-label study evaluating the PK of lesinurad 400 mg in subjects with moderate and severe renal impairment (eCLcr less than 30 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6), plasma AUC of lesinurad was increased by approximately 50% and 113% in subjects with moderate (N=6) and severe (N=6) renal impairment, respectively.

Allopurinol

Allopurinol and its metabolites are primarily eliminated by the kidney. Impairment of renal function may lead to retention of the drug and its metabolites with consequent prolongation of action. Patients with reduced renal function require lower doses of allopurinol than those with normal renal function.

Hepatic Impairment

A dedicated hepatic impairment study was not conducted with Duzallo.

Lesinurad

Following administration of a single dose of lesinurad at 400 mg in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, lesinurad Cmax was comparable and lesinurad AUC was 7% and 33% higher, respectively, compared to individuals with normal hepatic function. There is no clinical experience in patients with severe (Child-Pugh class C) hepatic impairment.

Allopurinol

No information is available in patients with hepatic impairment [see Warnings and Precautions (5.3)].

Effect of Age, Gender, Race and Ethnicity on Pharmacokinetics

Lesinurad

Based on the population PK analysis, age, gender, race and ethnicity do not have a clinically meaningful effect on the PK of lesinurad [see Use in Specific Populations (8.5)].

Allopurinol

No information is available for age, gender, race, or ethnicity effects on the PK of allopurinol.

Pediatric Use

Lesinurad

Studies characterizing the PK of lesinurad in pediatric patients have not been conducted.

Allopurinol

No data on the PK of allopurinol in pediatric patients are available.

Drug-Drug Interactions

Pharmacokinetic drug interaction studies with Duzallo have not been performed; however, such studies have been conducted with the individual components lesinurad and allopurinol.

Lesinurad

Based on in vitro data, lesinurad is a substrate for CYP2C9, OAT1 and OAT3; however, no clinical studies have been conducted with OAT1 and OAT3 inhibitors (eg, probenecid).

Effects of Other Drugs on Lesinurad

Figure 1 shows the effect of co-administered drugs on the PK of lesinurad.

Figure 1: Effect of Co-Administered Drugs on the Pharmacokinetics of Lesinurad

Effects of Lesinurad on Other Drugs

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).

Based on in vitro studies, lesinurad is an inhibitor of OATP1B1, OCT1, OAT1, and OAT3; however, lesinurad is not an in vivo inhibitor of these transporters. In vivo drug interaction studies indicate that lesinurad does not decrease the renal clearance of furosemide (substrate of OAT1/3), or affect the exposure of atorvastatin (substrate of OATP1B1) or metformin (substrate of OCT1). Based on in vitro studies, lesinurad has no relevant effect on P-glycoprotein.

Figure 2 shows the effect of lesinurad on co-administered drugs.

Figure 2: Effect of Lesinurad on the Pharmacokinetics of Coadministered Drugs

Effect of Allopurinol on Mercaptopurine

Allopurinol inhibits the enzymatic oxidation of mercaptopurine, the sulfur-containing analogue of hypoxanthine, to 6-thiouric acid. This oxidation, which is catalyzed by xanthine oxidase, inactivates mercaptopurine. Hence, the inhibition of such oxidation by allopurinol may result in as much as a 75% reduction in the therapeutic dose requirement of mercaptopurine when the two compounds are given together.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Administration

Advise patients:

• To take one tablet of Duzallo in the morning with food and water.
• Not to take a missed dose of Duzallo later in the day, but to wait to take Duzallo on the next day, and not to double the dose.
• Not to take Duzallo with ZURAMPIC (lesinurad).
• To stay well hydrated (eg, 2 liters of liquid per day).

Renal Events

Inform patients that renal events including transient increases in blood creatinine level and acute renal failure have occurred in some patients who take Duzallo. Advise patients that periodic monitoring of blood creatinine levels is recommended [see Warnings and Precautions (5.1)].

Serious Skin Reactions

Inform patients that Duzallo may increase the risk of serious skin side effects such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching and should ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop the drug immediately if they develop any type of rash and seek medical attention [see Warnings and Precautions (5.2)].

Gout Flares

Inform patients that gout flares may occur after initiation of Duzallo and of the importance of taking gout flare prophylaxis medication to help prevent gout flares. Advise patients not to discontinue Duzallo if a gout flare occurs during treatment [see Dosage and Administration (2.3)].

Concomitant Use with Other Medications

Inform patients that use of Duzallo may increase the risks associated with taking other medications (i.e., coumarin anticoagulants, mercaptopurine, azathioprine and thiazide diuretics, and they should follow the instructions of their health care provider [see Warnings and Precautions (5.5, 5.6), Drug Interactions (7)].

Ability to Perform Complex Tasks

Patients should be informed that drowsiness has been reported in patients taking allopurinol. Patients should be alerted to the need for due caution when engaging in activities where alertness is mandatory [see Warnings and Precautions (5.7)].

Manufactured for: Ironwood Pharmaceuticals, Inc., Cambridge, MA 02142

By: AstraZeneca AB, SE-151 85 Sodertalje, Sweden

Product of Sweden

Duzallo and ZURAMPIC are registered trademarks of the AstraZeneca group of companies.

© AstraZeneca 2017

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Upset stomach or throwing up.
• Lower back or side pain.
• Pain when passing urine.
• Swollen gland.
• Joint pain.
• Seizures.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Check with your doctor right away if you have a bloody urine, a decrease in frequency or amount of urine, an increase in blood pressure, increased thirst, loss of appetite, lower back or side pain, nausea, swelling of the face, fingers, or lower legs, troubled breathing, unusual tiredness or weakness, vomiting, or weight gain. These could be symptoms of a serious kidney problem.

Serious skin reactions can occur with this medicine. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or a skin rash, sores or ulcers on the skin, or fever or chills with this medicine.

Heart and blood vessel problems may occur with this medicine. Tell your doctor if you have chest pain or discomfort, confusion, nausea or vomiting, pain or discomfort in the arms, jaw, back, or neck, sweating, trouble speaking, or slow speech, or are unable to move your arms, legs, or facial muscles.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

This medicine may make you drowsy. Do not drive or do anything else that could be dangerous until you know how this medicine affects you.

Birth control pills, patches, implants, and injections may not work as well while you are using lesinurad and allopurinol combination. Use another form of birth control to keep from getting pregnant. Check with your doctor if you have any questions.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.