| Active Ingredient | VORICONAZOLE |
|---|
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| VFEND | (NDA) 021266 | PF PRISM CV | TABLET;ORAL | 50 MG, 200 MG | 200 MG | May 24, 2002 | _ | _ | 1 New molecular entity (NME) | S Standard review drug | Prescription | AB |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | (2R,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4triazol-1-yl)-2-butanol |
| CAS No | 137234-62-9 |
| Molecular Formula | C16H14F3N5O |
| Molecular Weight | 349.3 |
| Appearance | White to light-colored powder |
| Solubility | - |
| Water Solubility | Low (0.0978 mg/mL- predicted) |
| Polymorphism | Solid-state properties revealed no evidence of either polymorphism or solvates |
| pKa (Strongest Acidic) | 12.71 (Predicted) |
| pKa (Strongest Basic) | 2.27 (Predicted) |
| Log P | 1 |
| Identification | - |
| Degradation | Degradation occurs in aqueous solution, particularly under basic conditions. Oxidative degradation also takes place. The degradation products have been identified. |
| Hygroscopic | Not hygroscopic |
| Photostability study | Photodegradation takes place under severe light stress conditions. |
| Melting Point | 127-130 °C |
| BCS Class | II |
| Manufacture of API | Voriconazole is produced by organic synthesis |
| Parameters | Details |
|---|---|
| Indications and Usage | VFEND is an azole antifungal drug indicated for use in the treatment of: • Invasive aspergillosis • Candidemia (nonneutropenics) and disseminated candidiasis in skin, abdomen, kidney, bladder wall, and wounds • Esophageal candidiasis • Serious infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy |
| Dosage and Administration |
-Invasive Aspergillosis: 200 mg q12h - Candidemia in nonneutropenics and other deep tissue Candida infections: 200 mg q12h - Scedosporiosis and Fusariosis: 200 mg q12h '- Esophageal Candidiasis : 200 mg q12h • Adult patients weighing less than 40 kg: oral maintenance dose 100 or 150 mg q12 hours • See full prescribing information for instructions on reconstitution of lyophilized powder for intravenous use and reconstitution of oral suspension and important administration instructions |
| Mechanism of action | Voriconazole is an azole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of voriconazole. |
| Absorption | The pharmacokinetic properties of voriconazole are similar following administration by the intravenous and oral routes. Based on a population pharmacokinetic analysis of pooled data in healthy subjects (N=207), the oral bioavailability of voriconazole is estimated to be 96% (CV 13%). Bioequivalence was established between the 200 mg tablet and the 40 mg/mL oral suspension when administered as a 400 mg q12h loading dose followed by a 200 mg q12h maintenance dose. Maximum plasma concentrations (Cmax) are achieved 1-2 hours after dosing. when administered as the oral suspension In healthy subjects, the absorption of voriconazole is not affected by coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase gastric pH. |
| Food Effect | When multiple doses of voriconazole are administered with high-fat meals, the mean Cmax and AUCτ are reduced by 34% and 24%, respectively when administered as a tablet and by 58% and 37% respectively |
| Distribution | The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses of 200 mg or 300 mg (approximate range: 0.9-15 µg/mL). Varying degrees of hepatic and renal insufficiency do not affect the protein binding of voriconazole. |
| Metabolism | In vitro studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4. In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUCτ) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have, on average, 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts. The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. Since this metabolite has minimal antifungal activity, it does not contribute to the overall efficacy of voriconazole. |
| Elimination | Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. After administration of a single radiolabelled dose of either oral or IV voriconazole, preceded by multiple oral or IV dosing, approximately 80% to 83% of the radioactivity is recovered in the urine. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing. As a result of non-linear pharmacokinetics, the terminal half-life of voriconazole is dose dependent and therefore not useful in predicting the accumulation or elimination of voriconazole. |
| Peak plasma time (Tmax) | 1-2 hours |
| Half life | The terminal half-life of voriconazole is dose dependent and therefore not useful in predicting the accumulation or elimination of voriconazole. |
| Bioavailability | 96% (CV 13%) |
| Age, gender | - |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 19996 | A | II | November 27, 2006 | DR REDDYS LABORATORIES LTD |
| 21523 | A | II | April 8, 2008 | MSN LABORATORIES PRIVATE LTD |
| 23697 | A | II | April 7, 2010 | NEULAND LABORATORIES LTD |
| 24717 | A | II | March 31, 2011 | GLENMARK PHARMACEUTICALS LTD |
| 25100 | A | II | July 4, 2011 | APOTEX PHARMACHEM INDIA PVT LTD |
| 25343 | A | II | September 23, 2011 | MYLAN LABORATORIES LTD |
| 25707 | A | II | December 20, 2011 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD |
| 27256 | A | II | September 20, 2013 | JUBILANT GENERICS LTD |
| 27842 | A | II | January 7, 2014 | AUROBINDO PHARMA LTD |
| 27947 | A | II | February 26, 2014 | DR REDDYS LABORATORIES LTD |
| Parameters | Details | ||
|---|---|---|---|
| Strength | 200 MG | 50 MG | |
| Excipients used | Lactose monohydrate ( 253.675 mg), pregelatinized starch, croscarmellose sodium, povidone, magnesium stearate | Lactose monohydrate (63.42 mg), pregelatinized starch, croscarmellose sodium, povidone, magnesium stearate | |
| Composition of coating material | Hypromellose, titanium dioxide, lactose monohydrate and triacetin | ||
| Composition of caspule shell | - | ||
| Pharmaceutical Development | Several formulations were produced during the development, which led to the tablet composition. The manufacturing process has been well described and the critical process parameters identified. In-process controls are described and justified. The manufacturing process is typical for a wet granulated film-coated formulation. Both tablet strengths are manufactured from the same granulate (common blend). A typical batch size is 150 kg. Validation data from the first three production batches will be provided. | ||
| Manufacture of the product | The manufacturing process is typical for a wet granulated film-coated formulation. | ||
| Tablet / Capsule Image |
|
|
|
| Appearance | White, film-coated, capsule shaped, debossed with “Pfizer” on one side and “VOR200” on the reverse | White, film-coated, round, debossed with “Pfizer” on one side and “VOR50” on the reverse | |
| Imprint code / Engraving / Debossment | Debossed with “Pfizer” on one side and “VOR200” on the reverse | Debossed with “Pfizer” on one side and “VOR50” on the reverse | |
| Score | No score | No score | |
| Color | White | White | |
| Shape | Capsule | Round | |
| Dimension | - | - | |
| Mfg by | R-Pharm Germany GmbH (EU) | ||
| Mfg for | - | ||
| Marketed by | Pfizer Limited (EU) | ||
| Distributed by | Roerig Division of pfizer (US) | ||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N021266 | 1 | 5567817 | May 24, 2016 | Y | Y | U - 540 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 50 | 0.1 N HCl | 500 | 10, 20, 30 and 45 | November 25, 2008 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | Download |
| European Public Assessment Report | Download |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | VFEND | Download |
| UK | VFEND | Download |
| US | AJANTA PHARMA LTD (ANDA # 206181)* | |
| US | APPCO PHARMA LLC (ANDA # 206762)* | |
| US | AUROBINDO PHARMA LTD (ANDA # 206837)* | |
| US | GLENMARK PHARMS LTD (ANDA # 203503)* | |
| US | MYLAN PHARMS INC (ANDA # 090547)* | Download |
| US | NOVEL LABS INC (ANDA # 207371)* | |
| US | PRINSTON INC (ANDA # 206654)* | |
| US | SANDOZ INC (ANDA # 200265)* | |
| US | TEVA PHARMS (ANDA # 091658)* | |
| US | VERSAPHARM INC (ANDA # 207049)* | |
| US | VFEND | Download |
| US | ZYDUS PHARMS USA INC (ANDA # 206747)* |
| Date of first authorisation in EU: 19 March 2002 |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
