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Zurampic® - Lesinurad Manufacturer: AstraZeneca FDA Approval Date: December 22, 2015 Zurampic® - Lesinurad Objectives • At the end of this presentation participants will be able to: 1. Appropriately recommend Zurampic® - Lesinurad 2. Effectively educate patients on the purpose, proper use and potential adverse effects of Zurampic® Lesinurad Zurampic® - Lesinurad Clinical Application • Indications: • In combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout • Place in therapy: • Patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone Zurampic® [package insert]. Zurampic® - Lesinurad Clinical Application • Contraindications: • Severe renal impairment, end stage renal disease, and kidney transplant recipients • Tumor lysis syndrome or Lesch-Nyhan syndrome Zurampic® [package insert]. Zurampic® - Lesinurad Clinical Application • Black Box Warnings • Acute renal failure has occurred with lesinurad and was more common when lesinurad was given alone • Lesinurad should only be used in combination with a xanthine oxidase inhibitor Zurampic® [package insert]. Zurampic® - Lesinurad Clinical Application • Pregnancy: • No available human data • No teratogenicity or effects on fetal development were observed in animal studies • Lactation: • Unknown excretion in human breast milk Zurampic® [package insert]. Zurampic® - Lesinurad Drug Facts • Pharmacology: • Uric Acid Transporter 1 (URAT1) Inhibitor • URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen Zurampic® [package insert]. Zurampic® - Lesinurad Drug Facts • Pharmacokinetics: A Rapid with bioavailability ~100% D Mean ss volume of distribution ~20 L M Metabolized primarily via CYP2C9 E Estimated half-life of 5 hours Zurampic® [package insert]. Zurampic® - Lesinurad Drug Interactions • Drug Interactions – Object Drugs: • Sildenafil (30%) • Amlodipine (35%) • Colchicine (25%) • Furosemide (30%) • Indomethacin (30%) Zurampic® [package insert]. Zurampic® - Lesinurad Drug Interactions • Drug Interactions – Precipitant Drugs: • Rifampin (30%) • Naproxen (20%) • Fluconazole (60%) Zurampic® [package insert]. Zurampic® - Lesinurad Adverse Effects • Common Adverse Effects: • Headache (5.3%) [4.1%] • Influenza (5.1%) [2.7%] • Increased blood creatinine (4.3%) [2.3%] • Gastroesophageal reflux disease (2.7%) [0.8%] Zurampic® [package insert]. Zurampic® - Lesinurad Monitoring Parameters • Efficacy Monitoring: • Serum uric acid levels every 2 to 5 weeks during uric acid lowering therapy titration then every 6 months • Toxicity Monitoring: • SCr and CrCl Zurampic® [package insert]. Zurampic® - Lesinurad Prescription Information • Dosing: • 200mg by mouth daily • Administer in the morning with food and water at the same time in the morning as the dose of xanthine oxidase inhibitor • Cost: Unknown Zurampic® [package insert]. Zurampic® - Lesinurad Literature Review • RDEA594-203 Study • Purpose: To assess the efficacy and tolerability of lesinurad in combination with allopurinol vs. allopurinol alone in patients with an inadequate response to allopurinol Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7. Zurampic® - Lesinurad Literature Review • Design: randomized, double-blind, placebocontrolled trial • Conducted in: Canada, Georgia, Poland, Spain, Ukraine, the UK, and the USA • November 2009 to January 2011 Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7. Zurampic® - Lesinurad Literature Review Inclusion Criteria Exclusion Criteria • Men and postmenopausal or surgically sterile women • 18–80 years old • Gout diagnosis • Inadequate urate-lowering response (sUA ≥6 mg/dL on • ≥2 occasions ≥2 weeks apart) to allopurinol monotherapy 200–600 mg daily for ≥6 weeks and sUA ≥6 mg/dL at screening • History of kidney stones • Active liver disease • History of cardiac abnormalities • Long-term use of medications that would worsen gout • Uncontrolled hypertension • SCr >1.5 mg/dL or CrCl <60 mL/min • BMI >48 kg/m2 Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7. Zurampic® - Lesinurad Literature Review • Lesinurad 200mg with allopurinol vs. allopurinol alone • Primary Endpoint: • Percent reduction from baseline sUA levels at 4 weeks Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7. Zurampic® - Lesinurad Literature Review • Secondary Endpoint: • Proportion of patients with sUA <6, <5 and <4 mg/dL at each visit • Percent change from baseline in 24 h urine UA after 4 weeks Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7. Zurampic® - Lesinurad Literature Review • Baseline Characteristics: Placebo (N = 302) Lesinurad (N = 599) Age Male White 51.1 98.6% 93.1% 52.9 95.7% 91.3% Gout history Flares in 12 months 4.2 4.1 sUA, mg/dL 6.7 6.4 Years since gout diagnosis 7.3 10.2 Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7. Zurampic® - Lesinurad Literature Review • Results: Placebo Lesinurad Reduction from baseline sUA levels at 4 weeks P-value +2.6% -16% <0.0001 % of patient who achieved sUA <6 mg/dL 25% 63% <0.0001 Mean % change from baseline in renal UA clearance at 4 weeks 8% 43.7% <0.05 Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7. Zurampic® - Lesinurad Literature Review • Safety Endpoints: Adverse Event Placebo Lesinurad Any Discontinuation Death 45.8% 1.4% 0% 45.7% 0% 0% Common AEs Headache Nasopharyngitis Gout Flare Arthralgia 1.4% 9.6% 20.8% 5.6% 6.5% 10.5% 21.7% 6.5% Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7. Zurampic® - Lesinurad Literature Review • Trial Conclusion: • Lesinurad decreased sUA levels by 16% from baseline after 4 weeks of treatment when used in combination with allopurinol • 63% of patients on lesinurad achieved sUA <6 mg/dL Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7. Zurampic® - Lesinurad Summary • Zurampic, lesinurad, is first-in-class of Uric Acid Transporter 1 (URAT1) Inhibitor • It is indicated for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor (XOI) alone • Dosed: 200 mg by mouth once daily in the morning with food and water • Contraindicated in severe renal impairment and should be avoided in patients with CrCl < 45mL/min • Can cause serum creatinine elevations (generally reversible) – periodically monitor Zurampic® - Lesinurad References 1. www.zurampic.com 2. Zurampic package insert. AstraZeneca. Dec. 2015. 3. Roberts, S. “Zurampic Approved for Gout” https://www.nlm.nih.gov/medlineplus/news/fullstor y_156382.html. Accessed March 1, 2016. 4. Perez-Ruiz F, et al. Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol. Ann Rheum Dis 2016;0:1–7.