Rofecoxib Review: Drug Discovery, Manufacture, and Clinical Impact

This report provides a comprehensive review of Rofecoxib, a nonsteroidal anti-inflammatory drug (NSAID) initially marketed as Vioxx. The report details the drug's discovery, its use in treating conditions like rheumatoid arthritis and osteoarthritis, and its mechanism of action as a COX-2 inhibitor. It delv...Read More

Drug discovery and manufacture of medicine

Drug Discovery and Manufacture of Medicine 1
Contents
Introduction............................................................................................................................ 2
Literature review..................................................................................................................... 2
Conclusion............................................................................................................................. 5
References............................................................................................................................. 6

Drug Discovery and Manufacture of Medicine 2
Introduction
Drug discovery is a procedure that discovers the new candidate medications. The drugs
before seeming suitable for the patient to have to go under the rigorous testing and cost-
effective analyses. Every year couple of dozen new drugs are licensed for usage but there
will be tens of thousands of candidates that fell by the verge. Rofecoxib is a COX-2
discerning nonsteroidal anti-inflammatory drug (NSAID). Rofecoxib was promoted by Merck
and Co. for treating rheumatoid arthritis, osteoarthritis, acute pain condition, juvenile
rheumatoid arthritis, dysmenorrhea, and migraine. Rofecoxib was permitted by US food and
drug administration (FDA) in 1999 by the US. Rofecoxib is marketed by brands like Vioxx,
Ceoxx, and Ceeoxx. Rofecoxib can be obtained through prescription in both tablet form and
oral interruption. Rofecoxib attained extensive attention among physicians and patients to
treat arthritis and several other situations leading to chronic or severe pain.
Literature review
Rofecoxib was introduced in the form of1999 as an operative and safe alternative to non-
steroidal anti-inflammatory drugs. According to Alpert, 2005, Rofecoxib is utilized for the
conduct of osteoarthritis, severe discomfort adults, rheumatoid arthritis and primary
dysmenorrhea. Migraine attacks with or without auras are also cured by Rofecoxib.
Rofecoxib is solid and links to the stilbenes. These are the animate mixtures comprising a 1,
2 diphenylethylene moiety. Stilbenes are derived from the common phenylpropene skeleton
constructing block. Rofecoxib is a white to off-white to light yellow powder, essentially
unsolvable in octanol and insoluble in water. Each pill of VIOXX comprises either 25 mg,
12.5 mg or 50 mg of Rofecoxib and sedentary constituents.
As per the opinion of Dalvi, Gerange, and Ingale, 2015, Rofecoxib was consequently
discovered to be an increased risk of cardiovascular disease, therefore it has been
withdrawn from the global market. Almost 30,000 people appealed that they had
cardiovascular proceedings while consuming the medication. Vioxx even decided to fight
against each case and deprived of the liability. In the early years of the development of
rofecoxib, it was considered that the drug can badly affect the cardiovascular system by
altering the proportion of prostacyclin to thromboxane. It acts in the opposition and balances
the blood flow and clotting. Rofecoxib was consumed in the form of Vioxx. Lowest dosage
results are effective in the shortest duration in the treatment of an individual person. The
recommended dose of rofecoxib in the starting is 12.5 mg once regularly. The patients can
also attain added benefits by enhancing the dose to 25 mg daily. It is the extreme dosage to
be consumed by the persons. In the case of severe migraine attacks, a suggested dose of
Vioxx is 50 mg once every day. It is the maximum recommended dose. The maximum dose

Drug Discovery and Manufacture of Medicine 3
of 12.5 mg is recommended in the case of hepatic impairment. The usage of Vioxx is not
suggested in the patients having severe hepatic insufficiency. When it comes to oral
interruption, 12.5 mg is suggested and substituted for Vioxx medicines of 12.5 mg
correspondingly. On the other side, rofecoxib has also certain side effects. In the form of the
body as an entire, abscess, cyst, chest pain, fever, flushing, fluid retention, infection,
syncope, trauma, and the viral syndrome is realized. According to Graham, Jewell and
Chan, 2019, the cardiovascular system is affected in the form of venous insufficiency,
bradycardia, irregular heartbeat, angina pectoris, and palpitation. The side effect is realized
in other body parts like ears, eyes, throat, and nose in the form of allergic rhinitis, cerumen
impaction, blurred vision, dry throat, nasal congestion, and nasal secretion.
According to Gaukler et al. 2016, there are certain warnings that are associated with the
usage of rofecoxib. The cardiovascular thrombotic events are one of the results which can
be encountered due to the usage of rofecoxib. The clinical prosecutions of numerous
discerning and nonselective NSAIDs up to the duration of 3 years have represented an
augmented menace of severe cardiovascular thrombotic occurrences comprising stroke and
myocardial infarction. As per the obtainable data, it is not clear that the menace for
cardiovascular thrombotic occurrences is comparable to all NSAIDs. According to Waxman,
2005, patients with known cardiovascular thrombotic occurrences are likely to over baseline
conferred by the use of NSAID. Although the patients with identifiable CV ailment or risk
factors have an advanced absolute frequency of excess stern cardiovascular thrombotic
occurrences because of their augmented baseline rate. In order to minimalize the latent risk
for the contrary CV occurrence in NSAID treated patients, the deepest effective dose should
be taken for the probable direct duration. The patients and physicians are also suggested to
remain conscious of such events taking place.
According to Demirturk et al. 2017, the patients with the heredity of digestive ulcer disease
and GI bleeding who utilized NSAIDs have more than the ten-fold augmented risk of
advancing a GI bleed as associated with the patients who are not having any history. Other
aspects that upsurge the risk for GI bleeding in patients are cured with NSAIDs comprising a
lengthier duration of NSAID therapy, anticoagulants, associated usage of oral
corticosteroids, usage of alcohol, smoking, and poor overall health status. As per Starek,
Krzek, and Rotkegel, 2015, there are some strategies that can be used to lessen the GI risks
in NSAID preserved patients such as using the lowermost operative dosage for a short
period of time and avoidance of more than one NSAID at one time. The patients are also
required to remain conscious of the signs and symptoms of GI ulceration and bleeding
during NSAID therapy. Though the menace of GI toxicity is not entirely eradicated with
Vioxx.

Drug Discovery and Manufacture of Medicine 4
As per the opinion of Shim et al. 2018, precautions can be taken in general to safeguard
from the harmful effects of rofecoxib. Vioxx can be used as an additional for corticosteroids
and to treat the inadequacy of corticosteroids. The sudden cessation of corticosteroids can
lead to exacerbation of the corticosteroid-responsive disease. The patients are suggested to
go for long corticosteroid therapy in order to discontinue corticosteroids. The patients are
also suggested to go through the FDA-approved patient labeling which is accompanied by
prescription allotted. The patients, families, and caregivers should be conversant with the
information before starting therapy with Vioxx and intermittently while the process of therapy.
According to Wang and Meng, 2016, the patients are also required to be attentive for the
signs of the cardiovascular thrombotic proceedings comprising chest pain, weakness,
shortage of breath, eliding of dialogue and should be reported to the health care provider on
the immediate basis. The patients suffering from gastrointestinal bleeding, ulceration, and
perforation are suggested to be reported along with melena, dyspepsia, epigastric pain and
hematemesis. In such a case, low dose aspirin should be used for cardiac prophylaxis and
the patients should be informed of the increased risk. The patients having serious skin
infections are suggested to stop the use of Vioxx on an immediate basis if they get any kind
of rash or allergy and contact the health care provider. The females desiring NSAIDs
comprising Vioxx can be linked with the revocable postponement in ovulation. The pregnant
women should be informed of ignoring Vioxx and other NSAIDs initiating at thirty weeks'
growth due to the menace of untimely.
According to Stehlik, Rosella and Henry, 2018, recent advancement in rofecoxib has been
made by attaining guidance from US food and drug administration in 2017. Phase 3 plan
was conducted in order to discover rofecoxib in patients with hemophilia-related joint pain.
This initiative was taken during a formal meeting with the aim of getting the drug approved if
the study found positive. The initiative was aligned with program duration, size, dose and
pharmacokinetic necessities for the patients with HA (Hemophilic Arthropathy) and Tremeau.
As per the opinions of Topol, 2004, the constant bleeding in the joints results in damage and
pain in hemophilia patients. NSAIDs (Non-Steroid Anti-Inflammatory Drugs) are the
prevalent pain medications for people and patients with hemophilia can not consume such
drugs due to progressing risk by averting platelet aggregation. Though rofecoxib is an
NSAID and relates to the group of NSAIDs and targets to one or two enzymes comprised in
the pain. COX1 is one of the enzymes and comprised of platelet aggregation, rofecoxib
targets to COX2 and deliberated safer to use in hemophilia patients.
According to Thomas et al. 2017, Vioxx pulled rofecoxib in 2004 due to occurrences of
having a heart attack or stroke. Now small Tremeau pharmaceuticals are functioning to bring
it back in order to treat joint pain caused by bleeding disorder hemophilia. It is just for the few

Drug Discovery and Manufacture of Medicine 5
patients who took Vioxx pills for arthritis and other enduring pain. But if it will be approved by
the doctors then it could be legally prescribed to anyone. Several hemophilia patients
depend on opioid painkillers as almost every other pain reliever enhances the risk of internal
bleeding. The considerable research represents Vioxx does not do that. On the other side,
Tremeau is deciding the brand name of the drug. Whereas Vioxx is no longer protected by
the trademark.
Conclusion
Rofecoxib attained widespread acceptance. But due to the progressive menace of heart
attack and stroke linked in the long term, the continuation of Rofecoxib was stopped in
September 2004. The drug was inhibited from the market after revealing the risks contained
by the physicians. The constant use of the drug resulted in 80,000 to 140,000 cases of stern
heart disease. In 2017, Massachusetts based Tremeau Pharmaceuticals has broadcasted its
plan to bring back rofecoxib in the market for the treatment of hemophilic arthropathy. The
company has even attained FDA feedback on its development plan.

Drug Discovery and Manufacture of Medicine 6
References
Alpert, J.S., 2005. The vioxx debacle. The American journal of medicine, 118(3), pp.203-
204.
Dalvi, P.B., Gerange, A.B. and Ingale, P.R., 2015. Solid dispersion: strategy to enhance
solubility. Journal of Drug Delivery and Therapeutics, 5(2), pp.20-28.
Demirturk, E., Gulsun, T., Cayli, Y.A., Izat, N., Sahin, S. and Oner, L., 2017. Preparation and
In Vitro/In Vivo Evaluation of Rofecoxib Containing Bovine Serum Albumin
Microspheres. Latin American Journal of Pharmacy, 36(6), pp.1096-1104.
Gaukler, S.M., Ruff, J.S., Morrison, L.C. and Potts, W., 2016. Rofecoxib-induced deleterious
effects escape detection by organismal performance assays. Journal of pharmaceutical
negative results, 7(1), p.4.
Graham, D.Y., Jewell, N.P. and Chan, F.K., 2019. Rofecoxib and clinically significant
gastrointestinal events: response. The American journal of the medical sciences, 358(3),
pp.e9-e10.
Shim, J., Luo, H., Zhang, P. and Li, Y., 2018. Systematic analysis of drug combinations that
mitigate adverse drug reactions. IBM Journal of Research and Development, 62(6), pp.7-1.
Starek, M., Krzek, J. and Rotkegel, P., 2015. TLC determination of piroxicam, tenoxicam,
celecoxib and rofecoxib in biological material. Journal of Analytical Chemistry, 70(3), pp.351-
359.
Stehlik, P., Rosella, L. and Henry, D., 2018. Commentary: Renewed controversy over
cardiovascular risk with non-steroidal anti-inflammatory drugs. International journal of
epidemiology, 47(2), pp.362-367.
Thomas, D., Ali, Z., Zachariah, S., Sundararaj, K.G.S., Van Cuyk, M. and Cooper, J.C.,
2017. Coxibs refocus attention on the cardiovascular risks of non-aspirin NSAIDs. American
Journal of Cardiovascular Drugs, 17(5), pp.343-346.
Topol, E.J., 2004. Failing the public health—rofecoxib, Merck, and the FDA. New England
Journal of Medicine, 351(17), pp.1707-1709.
Wang, H. and Meng, F., 2016. Molecular simulation study on concentration effects of
rofecoxib with POPC bilayer. Journal of Molecular Graphics and Modelling, 70, pp.94-99.

Drug Discovery and Manufacture of Medicine 7
Waxman, H.A., 2005. The lessons of Vioxx—drug safety and sales. New England Journal of
Medicine, 352(25), pp.2576-2578.