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In 2005 the FDA issued a memo concluding that data from large long-term controlled clinical trials do not clearly demonstrate that COX-2 selective agents (including rofecoxib) have a greater risk of serious CV events than non-selective NSAIDs. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.
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Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, allegedly resulting in between 88,000 and 140,000 cases of serious heart disease. In September 2004, Merck voluntarily withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Worldwide, over 80 million people were prescribed rofecoxib at some time. Rofecoxib gained widespread use among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Rofecoxib was available by prescription in both tablet-form and as an oral suspension. Rofecoxib was approved in the US by the US Food and Drug Administration (FDA) in May 1999, and was marketed under the brand names Vioxx, Ceoxx, and Ceeoxx. to treat osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, acute pain conditions, migraine, and dysmenorrhea. All rights reserved.Rofecoxib is a COX-2 selective nonsteroidal anti-inflammatory drug ( NSAID).
#Example bcs class 4 drugs trial#
However, due to lack of understanding of the basic physical chemistry behind these strategies formulation development is still driven by trial and error.īioavailability Dissolution rate Enhanced permeation P-gp efflux.Ĭopyright © 2017 Elsevier B.V.
#Example bcs class 4 drugs series#
Today, the pharmaceutical industry has as its disposal a series of reliable and scalable formulation strategies for BCS Class IV drugs. It also brings to forefront the current lack of regulatory guidelines which poses difficulties during preclinical and clinical testing for submission of NDA and subsequent marketing. The review also focuses on the roadblocks in the clinical development of the aforementioned strategies such as problems in scale up, manufacturing under cGMP guidelines, appropriate quality control tests, validation of various processes and variable therein etc. Some of the techniques employed are lipid based delivery systems, polymer based nanocarriers, crystal engineering (nanocrystals and co-crystals), liquisolid technology, self-emulsifying solid dispersions and miscellaneous techniques addressing the P-gp efflux problem. This article highlights the various techniques and upcoming strategies which can be employed for the development of highly notorious BCS class IV drugs. Also, ideal systems for BCS class IV should produce a therapeutic concentration of the drug at reasonable dose volumes for intravenous administration. Ideal oral dosage forms should produce both a reasonably high bioavailability and low inter and intra subject variability in absorption. To be clinically effective these drugs require the development of a proper delivery system for both oral and per oral delivery. The importance of the formulation composition and design to successful drug development is especially illustrated by the BCS class IV case. The inherent hurdles posed by these drugs hamper their translation to actual market. Formulation and development of an efficacious delivery system for BCS class IV drugs are herculean tasks for any formulator. A decade back, extreme examples of class IV compounds were an exception rather than the rule, yet today many drug candidates under development pipeline fall into this category. Also, most of the class IV drugs are substrate for P-glycoprotein (low permeability) and substrate for CYP3A4 (extensive pre systemic metabolism) which further potentiates the problem of poor therapeutic potential of these drugs. Some of the problems associated include low aqueous solubility, poor permeability, erratic and poor absorption, inter and intra subject variability and significant positive food effect which leads to low and variable bioavailability. BCS class IV drugs (e.g., amphotericin B, furosemide, acetazolamide, ritonavir, paclitaxel) exhibit many characteristics that are problematic for effective oral and per oral delivery.