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safety profile of DUZALLO

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In gout patients when a medically appropriate daily dose of allopurinol alone was not enough to achieve goal sUA,
DUZALLO* nearly doubled the number of patients who achieved goal sUA <6 mg/dL at Month 61,4,10
CLEAR 1: Difference of proportion 0.26 (95% C.I. 0.17, 0.36)
CLEAR 2: Difference of proportion 0.32 (95% C.I. 0.23, 0.41)
Clinical trial design   

Two phase III, randomized, double-blind, multicenter, placebo-controlled trials of lesinurad in combination with allopurinol in adult patients with gout1,4,10

* Bioequivalence of DUZALLO to coadministered lesinurad and allopurinol was demonstrated. Efficacy of the combination of allopurinol and lesinurad has been demonstrated in 2 phase III studies (CLEAR 1 and CLEAR 2). There have been no phase III clinical trials with DUZALLO.

Both studies were 12-month multicenter, randomized, double-blind, placebo-controlled clinical studies. Patients were randomized to receive lesinurad or placebo once daily; all were to continue on their stable allopurinol dose. The majority of patients in these studies received daily allopurinol doses of 200 mg or 300 mg corrresponding to the allopurinol doses contained in DUZALLO.

Primary endpoint: the proportion of patients who achieved an sUA level <6.0 mg/dL by Month 6.

Study populations

  • CLEAR 1—N=402: 201 in the lesinurad 200 mg in combination with allopurinol group and 201 in the allopurinol monotherapy group
  • CLEAR 2—N=410: 204 in the lesinurad 200 mg in combination with allopurinol group and 206 in the allopurinol monotherapy group

At baseline

  • 61% of patients had mild or moderate renal impairment
  • 12% of patients had a history of kidney stones
  • 81% of patients had at least 1 comorbid condition, including hypertension (66%), hyperlipidemia (46%), and diabetes (17%)
  • ~90% of patients were taking allopurinol 300 mg
  • Mean age was 52 years (range: aged 18-82 years) and 95% were male

Inclusion criteria

  • Stable dose of allopurinol ≥300 mg (or ≥200 mg for patients with moderate renal impairment)
  • sUA ≥6.5 mg/dL at screening and ≥6 mg/dL at Day -7 visit
  • Reported at least 2 gout flares during the prior 12 months

Exclusion criteria

  • Experiencing an acute gout flare that has not resolved at least 7 days before baseline visit
  • Taking any other ULT approved for the treatment of gout besides allopurinol
  • Known hypersensitivity or allergy to allopurinol
  • eCLcr <30 mL/min
Clinical trial design   
In gout patients when a medically appropriate daily dose of allopurinol alone was not enough to achieve goal sUA,
DUZALLO* reduced mean sUA levels to <6 mg/dL at Month 1 and maintained goal sUA through Month 121
Data in the chart are pooled results from CLEAR 1 and CLEAR 2.
Clinical trial design   

Two phase III, randomized, double-blind, multicenter, placebo-controlled trials of lesinurad in combination with allopurinol in adult patients with gout1,4,10

* Bioequivalence of DUZALLO to coadministered lesinurad and allopurinol was demonstrated. Efficacy of the combination of allopurinol and lesinurad has been demonstrated in 2 phase III studies (CLEAR 1 and CLEAR 2). There have been no phase III clinical trials with DUZALLO.

Both studies were 12-month multicenter, randomized, double-blind, placebo-controlled clinical studies. Patients were randomized to receive lesinurad or placebo once daily; all were to continue on their stable allopurinol dose. The majority of patients in these studies received daily allopurinol doses of 200 mg or 300 mg corrresponding to the allopurinol doses contained in DUZALLO.

Primary endpoint: the proportion of patients who achieved an sUA level <6.0 mg/dL by Month 6.

Study populations

  • CLEAR 1—N=402: 201 in the lesinurad 200 mg in combination with allopurinol group and 201 in the allopurinol monotherapy group
  • CLEAR 2—N=410: 204 in the lesinurad 200 mg in combination with allopurinol group and 206 in the allopurinol monotherapy group

At baseline

  • 61% of patients had mild or moderate renal impairment
  • 12% of patients had a history of kidney stones
  • 81% of patients had at least 1 comorbid condition, including hypertension (66%), hyperlipidemia (46%), and diabetes (17%)
  • ~90% of patients were taking allopurinol 300 mg
  • Mean age was 52 years (range: aged 18-82 years) and 95% were male

Inclusion criteria

  • Stable dose of allopurinol ≥300 mg (or ≥200 mg for patients with moderate renal impairment)
  • sUA ≥6.5 mg/dL at screening and ≥6 mg/dL at Day -7 visit
  • Reported at least 2 gout flares during the prior 12 months

Exclusion criteria

  • Experiencing an acute gout flare that has not resolved at least 7 days before baseline visit
  • Taking any other ULT approved for the treatment of gout besides allopurinol
  • Known hypersensitivity or allergy to allopurinol
  • eCLcr <30 mL/min
Clinical trial design   
* Bioequivalence of DUZALLO to coadministered lesinurad and allopurinol was demonstrated. Efficacy of the combination of lesinurad and allopurinol versus allopurinol alone has been demonstrated in 2 randomized, double-blind, placebo-controlled phase III studies (CLEAR 1 and CLEAR 2). There have been no phase III clinical trials with DUZALLO.1
What are your patients not telling you about their gout?
In gout patients when a medically appropriate daily dose of allopurinol alone was not enough to achieve goal sUA,
DUZALLO is the first and only therapy that addresses both mechanisms of hyperuricemia in gout with one pill1,3

The combination of a xanthine oxidase inhibitor (XOI) with a uricosuric (as found in DUZALLO) is recommended by the American College of Rheumatology for patients unable to reach goal sUA on a medically appropriate dose of an XOI alone.1,9

See the pathways in action
The allopurinol component of DUZALLO is a xanthine oxidase inhibitor that blocks the conversion of purines into uric acid, which reduces the production of uric acid.
The lesinurad component of DUZALLO is a uricosuric that selectively inhibits* the transporter proteins involved in uric acid reabsorption, URAT1 and OAT4, which increases excretion of uric acid.
*Lesinurad does not interact with Glut9.
 See the pathways in action   
Allopurinol monotherapy only addresses overproduction of uric acid.1
Incidence of renal-related adverse reactions and nephrolithiasis1
  • The incidence of blood creatinine increased was higher with DUZALLO* (3.7%) than allopurinol monotherapy (2.2%)   Learn more
  • Renal-related adverse reactions resulted in a similar discontinuation rate with DUZALLO* (1.0%) and allopurinol monotherapy (1.0%)
Incidence of renal failure and kidney stones was similar between groups. Incidence of blood creatinine increased was higher for DUZALLO1*
a Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, and acute prerenal failure.
There was a higher incidence of serum creatinine elevation in the DUZALLO* group. The majority of cases resolved by end of study without interruption in therapy1
  • DUZALLO should be interrupted if serum creatine is elevated to >2 times the pretreatment value
Renal-related adverse reactions by baseline renal function1
a Renal failure includes the following adverse reactions: renal failure, renal impairment, renal failure chronic, renal failure acute, and acute prerenal failure.
  • Across all treatment groups, patients with moderate renal impairment had a higher occurrence of renal-related adverse reactions compared with patients who had mild renal impairment or normal renal function
Incidence of the most common adverse reactions in the 12-month controlled clinical trials1
  • In clinical trials, major adverse cardiovascular events (cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes) were observed. A causal relationship has not been established
There were no clear differences in safety and effectiveness of DUZALLO* in patients with mild renal impairment compared with patients with normal renal function.1
Allopurinol monotherapy may not be enough for many patients to adequately lower their sUA levels.6-8
* Bioequivalence of DUZALLO to coadministered lesinurad and allopurinol was demonstrated. Efficacy of the combination of lesinurad and allopurinol versus allopurinol alone has been demonstrated in 2 randomized, double-blind, placebo-controlled phase III studies (CLEAR 1 and CLEAR 2). There have been no phase III clinical trials with DUZALLO.1
For patients on a medically appropriate daily dose of allopurinol 300 mg or 200 mg and not at goal sUA, switch to one pill of DUZALLO once daily1
  • There are two strengths of DUZALLO available: lesinurad 200 mg/allopurinol 300 mg and lesinurad 200 mg/allopurinol 200 mg
    • One tablet of DUZALLO contains the maximum daily lesinurad dose (200 mg)
  • DUZALLO is not recommended for patients taking daily doses of allopurinol <300 mg (or <200 mg in patients with an eCLcr <60 mL/min)
  • DUZALLO should be discontinued when eCLcr is persistently <45 mL/min
  • Assess renal function before initiating DUZALLO. Do not initiate DUZALLO if eCLcr is <45 mL/min
Not actual size.
Administration1
  • The total daily dose of allopurinol should be maintained at the time of initiating DUZALLO, taking into account the allopurinol dose contained in DUZALLO
  • Gout flares may occur after initiation of any urate-lowering therapy, including DUZALLO, because of changing serum uric acid levels resulting in mobilization of urate from tissue deposits
  • For patients not currently taking lesinurad, gout flare prophylaxis is recommended when starting DUZALLO, according to practice guidelines
How to take DUZALLO1
  • Take one tablet of DUZALLO in the morning with food and water
  • Do not take a missed dose of DUZALLO later in the day, but wait to take DUZALLO on the next day, and do not double the dose
  • Do not take DUZALLO with ZURAMPIC® (lesinurad)
  • Stay well-hydrated (eg, 2 liters of liquid per day)
Not actual size.
Identify the signs of uncontrolled gout (sUA >6 mg/dL) in your patients.

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Important Safety Information

WARNING: RISK OF ACUTE RENAL FAILURE

  • Acute renal failure has occurred with lesinurad, one of the components of DUZALLO

Contraindications:

  • Severe renal impairment (estimated creatinine clearance [eCLcr] <30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis
  • Tumor lysis syndrome or Lesch-Nyhan syndrome
  • Known hypersensitivity to allopurinol, including previous occurrence of skin rash

Warnings and Precautions:

  • Renal events: Adverse reactions related to renal function, including acute renal failure, can occur after initiating DUZALLO. Renal function should be evaluated prior to initiation of DUZALLO and periodically thereafter, as clinically indicated. More frequent renal function monitoring is recommended in patients with eCLcr <60 mL/min or with serum creatinine elevations 1.5 to 2 times the value when lesinurad treatment was initiated. DUZALLO should not be initiated in patients with an eCLcr <45 mL/min. Interrupt treatment with DUZALLO if serum creatinine is elevated to >2 times the pretreatment value or if there are symptoms that may indicate acute uric acid nephropathy, including flank pain, nausea, or vomiting. DUZALLO should not be restarted without another explanation for the serum creatinine abnormalities
  • Skin rash and hypersensitivity: Skin rash is a frequently reported adverse event in patients taking allopurinol. 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. Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment, seizures, and on rare occasions, death. Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function who are receiving thiazide diuretics and DUZALLO concurrently. DUZALLO should be discontinued immediately at the first appearance of skin rash or other signs that may indicate an allergic reaction, and additional medical care should be provided as needed
  • Hepatotoxicity: A few cases of reversible clinical hepatotoxicity have been reported in patients taking allopurinol and, in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develops in patients taking DUZALLO, evaluation of liver function should be performed. In patients with preexisting liver disease, periodic liver function tests are recommended
  • Cardiovascular events: In clinical trials, major adverse cardiovascular events (defined as cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes) were observed with DUZALLO. A causal relationship has not been established
  • Bone marrow depression: Bone marrow depression has been reported in patients receiving allopurinol, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as 6 weeks to as long as 6 years after the initiation of allopurinol therapy. Rarely, a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol alone. Patients taking allopurinol and mercaptopurine or azathioprine require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine
  • Increase in prothrombin time: It has been reported that allopurinol prolongs the half-life of dicumarol, a coumarin anticoagulant. The prothrombin time should be reassessed periodically in patients receiving coumarin anticoagulants (dicumarol, warfarin) concomitantly with DUZALLO
  • Drowsiness: Occasional occurrence of drowsiness was reported in patients taking allopurinol. Patients should be alerted to the need for caution when engaging in activities where alertness is mandatory

Adverse Reactions:

  • The most common adverse reactions in controlled studies (occurring in 2% or more of patients on lesinurad in combination with allopurinol and at least 1% greater than observed in patients on allopurinol alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease
  • The most common adverse reactions identified during post-approval use of allopurinol are skin rash, nausea, and diarrhea

Indication and Limitations of Use:

DUZALLO, a combination of lesinurad, a 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.

  • DUZALLO is not recommended for the treatment of asymptomatic hyperuricemia

Please see full Prescribing Information, including Boxed Warning, and Medication Guide.

Important Safety Information

WARNING: RISK OF ACUTE RENAL FAILURE

  • Acute renal failure has occurred with lesinurad, one of the components of DUZALLO

Contraindications:

  • Severe renal impairment (estimated creatinine clearance [eCLcr] <30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis
  • Tumor lysis syndrome or Lesch-Nyhan syndrome
  • Known hypersensitivity to allopurinol, including previous occurrence of skin rash

Warnings and Precautions:

  • Renal events: Adverse reactions related to renal function, including acute renal failure, can occur after initiating DUZALLO. Renal function should be evaluated prior to initiation of DUZALLO and periodically thereafter, as clinically indicated. More frequent renal function monitoring is recommended in patients with eCLcr <60 mL/min or with serum creatinine elevations 1.5 to 2 times the value when lesinurad treatment was initiated. DUZALLO should not be initiated in patients with an eCLcr <45 mL/min. Interrupt treatment with DUZALLO if serum creatinine is elevated to >2 times the pretreatment value or if there are symptoms that may indicate acute uric acid nephropathy, including flank pain, nausea, or vomiting. DUZALLO should not be restarted without another explanation for the serum creatinine abnormalities
  • Skin rash and hypersensitivity: Skin rash is a frequently reported adverse event in patients taking allopurinol. 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. Associated vasculitis and tissue response may be manifested in various ways including hepatitis, renal impairment, seizures, and on rare occasions, death. Hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function who are receiving thiazide diuretics and DUZALLO concurrently. DUZALLO should be discontinued immediately at the first appearance of skin rash or other signs that may indicate an allergic reaction, and additional medical care should be provided as needed
  • Hepatotoxicity: A few cases of reversible clinical hepatotoxicity have been reported in patients taking allopurinol and, in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develops in patients taking DUZALLO, evaluation of liver function should be performed. In patients with preexisting liver disease, periodic liver function tests are recommended
  • Cardiovascular events: In clinical trials, major adverse cardiovascular events (defined as cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes) were observed with DUZALLO. A causal relationship has not been established
  • Bone marrow depression: Bone marrow depression has been reported in patients receiving allopurinol, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as 6 weeks to as long as 6 years after the initiation of allopurinol therapy. Rarely, a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol alone. Patients taking allopurinol and mercaptopurine or azathioprine require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine
  • Increase in prothrombin time: It has been reported that allopurinol prolongs the half-life of dicumarol, a coumarin anticoagulant. The prothrombin time should be reassessed periodically in patients receiving coumarin anticoagulants (dicumarol, warfarin) concomitantly with DUZALLO
  • Drowsiness: Occasional occurrence of drowsiness was reported in patients taking allopurinol. Patients should be alerted to the need for caution when engaging in activities where alertness is mandatory

Adverse Reactions:

  • The most common adverse reactions in controlled studies (occurring in 2% or more of patients on lesinurad in combination with allopurinol and at least 1% greater than observed in patients on allopurinol alone) were headache, influenza, blood creatinine increased, and gastroesophageal reflux disease
  • The most common adverse reactions identified during post-approval use of allopurinol are skin rash, nausea, and diarrhea

Indication and Limitations of Use:

DUZALLO, a combination of lesinurad, a 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.

  • DUZALLO is not recommended for the treatment of asymptomatic hyperuricemia

Please see full Prescribing Information, including Boxed Warning, and Medication Guide.

References: 1. DUZALLO [package insert]. 2017. 2. Data on file. 2017 Gout Patient/Caregiver Survey with Creaky Joints. 2017. 3. American College of Rheumatology. Gout. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Gout. Accessed August 2, 2017. 4. Bardin T, Keenan RT, Khanna PP, et al. Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study). Ann Rheum Dis. 2017;76(5):811-820. 5. Boss GR, Seegmiller JE. Hyperuricemia and gout: classification, complications and management. N Engl J Med. 1979;300(26):1459-1468. 6. Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450-2461. 7. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59(11):1540-1548. 8. Becker MA, Schumacher HR Jr, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63. 9. Khanna D, Fitzgerald JD, Khanna PP, et al; for the American College of Rheumatology. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431-1446. 10. Saag KG, Fitz-Patrick D, Kopicko J, et al. Lesinurad combined with allopurinol: a randomized, double-blind, placebo-controlled study in gout patients with an inadequate response to standard-of-care allopurinol (a US-based study). Arthritis Rheumatol. 2017;69:203-212.