| Active Ingredient | FEBUXOSTAT |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ULORIC | (NDA) 021856 | TAKEDA PHARMS USA | TABLET;ORAL | 40MG, 80MG | 40MG, 80MG (RS) | February 13, 2009 | - | - | 1 New molecular entity (NME) | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid |
| CAS No | 144060-53-7 |
| Molecular Formula | C16H16N2O3S |
| Molecular Weight | 316.375 |
| Appearance | white crystalline powder |
| Solubility | It is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The solubility of febuxostat in a wide range of pH buffer solutions shows that its solubility is low in acid and increases with the increase in pH from neutral to high pH. |
| Water Solubility | 0.0183 mg/mL (Predicted) |
| Polymorphism | - |
| pKa (Strongest Acidic) | 3.08 (Predicted) |
| pKa (Strongest Basic) | 0.39 (Predicted) |
| Log P | 3.8 (Predicted) |
| Identification | IR and HPLC |
| Degradation | Stress testing at a temperature range between 50-70˚C in various container closure systems showed no changes in appearance assay, impurities content ordegradation product and crystalline form. |
| Hygroscopic | non-hygroscopic |
| Photostability study | - |
| Melting Point | 205˚C to 208˚C |
| BCS Class | II |
| Manufacture of API | Febuxostat is synthesised in six steps from one starting material including crystallisation and milling. |
| Parameters | Details |
|---|---|
| Indications and Usage | ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia. |
| Dosage and Administration |
For treatment of hyperuricemia in patients with gout, ULORIC is recommended at 40 mg or 80 mg once daily. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended. ULORIC can be taken without regard to food or antacid use. |
| Mechanism of action | ULORIC, a xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid. ULORIC is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic oncentrations. |
| Absorption |
In healthy subjects, maximum plasma concentrations (Cmax) and AUC of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg. There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately 5 to 8 hours. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy subjects. The absorption of radiolabeled febuxostat following oral dose administration was estimated to be at least 49% (based on total radioactivity recovered in urine). Maximum plasma concentrations of febuxostat occurred between 1 and 1.5 hours post-dose. After multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.6 ± 0.6 mcg/mL (N=30), and 2.6 ± 1.7 mcg/mL (N=227), respectively. Absolute bioavailability of the febuxostat tablet has not been studied. |
| Food Effect |
Following multiple 80 mg once daily doses with a high fat meal, there was a 49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed (58% fed vs. 51% fasting). Thus, ULORIC may be taken without regard to food. Concomitant ingestion of an antacid containing magnesium hydroxide and aluminum hydroxide with an 80 mg single dose of ULORIC has been shown to delay absorption of febuxostat (approximately one hour) and to cause a 31% decrease in Cmax and a 15% decrease in AUC∞. As AUC rather than Cmax was related to drug effect, change observed in AUC was not considered clinically significant. Therefore, ULORIC may be taken without regard to antacid use. |
| Distribution | The mean apparent steady state volume of distribution (Vss/F) of febuxostat was approximately 50 L (CV ~40%). The plasma protein binding of febuxostat is approximately 99.2%, (primarily to albumin), and is constant over the concentration range achieved with 40 mg and 80 mg doses. |
| Metabolism |
Febuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 and 2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at a much lower extent than febuxostat. In urine and feces, acyl glucuronide metabolites of febuxostat (~35% of the dose), and oxidative metabolites, 67M-1 (~10% of the dose), 67M-2 (~11% of the dose), and 67M-4, a secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of febuxostat in vivo. |
| Elimination |
Febuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the drug (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the feces as the unchanged febuxostat (12%), the acyl glucuronide of the drug (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%). |
| Peak plasma time (Tmax) | 1 and 1.5 hours |
| Half life | 5 to 8 hours |
| Bioavailability | - |
| Age, gender |
The pharmacokinetics of ULORIC in patients under the age of 18 years have not been studied. The Cmax and AUC of febuxostat and its metabolites following multiple oral doses of ULORIC in geriatric subjects (≥65 years) were similar to those in younger subjects (18 to 40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger subjects. No dose adjustment is necessary in geriatric patients. Following multiple oral doses of ULORIC, the Cmax and AUC24 of febuxostat were 30% and 14% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. In addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is necessary based on gender. No specific pharmacokinetic study was conducted to investigate the effects of race. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 24822 | A | II | March 30, 2011 | DR REDDYS LABORATORIES LTD |
| 25664 | I | II | October 12, 2010 | ALP PHARM BEIJING CO LTD |
| 25761 | A | II | February 24, 2012 | UNIMARK REMEDIES LTD |
| 26043 | A | II | January 31, 2013 | CHONGQING SHENGHUAXI PHARMACEUTICAL CO LTD |
| 26071 | A | II | May 31, 2012 | CADILA HEALTHCARE LTD |
| 26217 | I | II | December 7, 2012 | HETERO DRUGS LTD |
| 26289 | A | II | July 9, 2012 | MSN ORGANICS PRIVATE LTD |
| 26417 | A | II | January 10, 2012 | ALEMBIC PHARMACEUTICALS LTD |
| 26549 | A | II | August 25, 2012 | WATERSTONE PHARMACEUTICALS HUBEI CO LTD |
| 26582 | A | II | November 2, 2013 | LUPIN LTD |
| 26607 | A | II | August 2, 2013 | SUN PHARMACEUTICAL INDUSTRIES LTD |
| 26657 | A | II | January 15, 2013 | MYLAN LABORATORIES LTD |
| 26722 | A | II | December 29, 2012 | SUN PHARMACEUTICAL INDUSTRIES LTD |
| 26741 | A | II | December 31, 2012 | APOTEX PHARMACHEM INDIA PVT LTD |
| 26815 | A | II | January 2, 2013 | EMCURE PHARMACEUTICALS LTD |
| 26848 | A | II | February 13, 2013 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD |
| 28149 | A | II | April 23, 2014 | MACLEODS PHARMACEUTICALS LTD |
| 28834 | A | II | November 2, 2015 | INDOCO REMEDIES LTD |
| 28897 | A | II | February 4, 2015 | TEVA PHARMACEUTICAL INDUSTRIES LTD |
| 29716 | A | II | September 22, 2015 | ZHEJIANG AUSUN PHARMACEUTICAL CO LTD |
| 30353 | A | II | March 30, 2016 | JUBILANT GENERICS LTD |
| 31340 | A | II | February 1, 2017 | MSN ORGANICS PRIVATE LTD |
| 31397 | A | II | February 9, 2017 | AUROBINDO PHARMA LTD |
| Parameters | Details | ||||
|---|---|---|---|---|---|
| Strength | 40MG (US) | 80MG (US) | 80MG (EU) | 120MG (EU) | |
| Excipients used | lactose monohydrate (149.812MG), microcrystalline cellulose (49.938MG), hydroxypropyl cellulose (6.243MG), sodium croscarmellose (20MG), silicon dioxide (1.25MG) and magnesium stearate (4MG) |
lactose monohydrate (299.625MG), microcrystalline cellulose (99.875MG), hydroxypropyl cellulose, sodium croscarmellose (40MG), silicon dioxide (2.5MG) and magnesium stearate (8MG) |
lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate |
||
| Composition of coating material | Opadry II, green |
Opadry II yellow, 85F42129 containing: polyvinyl alcohol, titanium dioxide (E171), macrogols 3350, talc, iron oxide yellow (E172) |
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| Composition of caspule shell | - | ||||
| Pharmaceutical Development |
Based on the solubility, stability and permeability characteristics of febuxostat an immediate release oral dosage form was developed. Well known excipients were used in the preparation of the formulation. Hydroxypropylcellulose is used as a binder, lactose monohydrate and microcrystalline cellulose are used as fillers, croscarmellose sodium is used as disintegrant, magnesium stearate as a lubricant and silica as ant-adherent. Changes were made to the formulation during the development and therefore bioequivalence studies were performed to confirm that the formulations used in the clinical trials are equivalent to the proposed formulation for commercialisation. In addition, discriminatory in vitro studies (dissolution studies) also showed that the release profile of the proposed formulation is comparable to that used in the pivotal clinical trials. |
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| Manufacture of the product |
The manufacturing process for febuxostat tablets uses standard pharmaceutical equipment and unit operations. The manufacture of the finished product comprises (1) blending of the active substance with the excipients (2) wet granulation of the blend (3) dryingof the granulation (4) sizing (5) addition of final excipients and blend (6) lubrication (7) tabletting (8) coating (9) packaging. |
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| Tablet / Capsule Image |
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| Appearance | light green to green, round, debossed with “TAP” on one side and "40" on the other side | light green to green, teardrop shaped, debossed with “TAP” on one side and "80" on the other side | pale yellow to yellow in colour and capsule shaped marked on one side with ‘80’ | pale yellow to yellow in colour and capsule shaped marked on one side with ‘120’ | |
| Imprint code / Engraving / Debossment | debossed with “TAP” on one side and "40" on the other side | debossed with “TAP” on one side and "80" on the other side | marked on one side with ‘80’ | marked on one side with ‘120’ | |
| Score | no score | no score | no score | no score | |
| Color | light green to green | light green to green | Pale yellow | Pale yellow | |
| Shape | ROUND | TEARDROP | CAPSULE | CAPSULE | |
| Dimension | 9mm | 14mm | - | - | |
| Mfg by | - | Patheon (EU) | |||
| Mfg for | - | ||||
| Marketed by | Takeda Pharmaceuticals (US) | Menarini (EU) | |||
| Distributed by | Takeda Pharmaceuticals (US) | - | |||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N021856 | 1 | 5614520 | March 25, 2019 | Y | Y | U - 954 | - | Download |
| N021856 | 1 | 6225474 | June 18, 2019 | Y | - | - | - | Download |
| N021856 | 1 | 7361676 | March 8, 2024 | - | Y | - | - | Download |
| N021856 | 1 | 8372872 | September 8, 2031 | - | - | U - 1346 | - | Download |
| N021856 | 1 | 9107912 | September 8, 2031 | - | - | U - 1346 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 75 | 0.05 M Phosphate Buffer, pH 6.0 | 900 | 5, 10, 15, 20 and 30 | August 15, 2013 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | Download |
| European Public Assessment Report | Download |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | ADENURIC | Download |
| UK | ADENURIC | Download |
| US | ALEMBIC PHARMS LTD (ANDA #205421)* | Download |
| US | LUPIN LTD (ANDA #205406)* | |
| US | MYLAN PHARMS INC ( (ANDA # 205385)* | Download |
| US | ROXANE (ANDA #205414)* | Download |
| US | ULORIC | Download |
| - |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
