Vioxx

by

Breckon Pav

Dr. Bradley

December 5, 2002

History

The selective COX-2 inhibitor Vioxx (rofecoxib) has a relatively short history on the public market.  It was presented for FDA approval in 1998 by Merck Pharmaceuticals as an alternative to the traditional pain relievers, non-steroidal anti-inflammatory drugs (NSAIDs) like Tylenol, Advil, and ibuprofen.  Vioxx was reviewed and approved in 1999 as an effective treatment of osteoarthritis, menstrual pain (dysmenorrhea), and severe pain in adults (Miceli 1).  Since then, Vioxx has undergone further studies concerning its effects on the formation of gastrointestinal ulcers and its cardiovascular threats.  Package inserts have changed for better and for worse through the few years of Vioxx’s popularity.  However, the bottom line is that rofecoxib offers powerful pain relief without the typical NSAID risk of GI tract infection and ulcers.

Chemical Properties

            Rofecoxib has a molecular weight of 314.36 amu, a structure of C₁₇H₁₄O₄S, and is chemically labeled “4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.”  The pill color ranges from white to yellowish.  Inactive ingredients in Vioxx are croscarmellose sodium, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, yellow ferric oxide, and red ferric oxide (in 50 mg pills); oral suspensions include citric acid monohydrate (·H₂O), sodium citrate dihydrate (·2H₂O), sorbitol solution, strawberry flavor, xanthum gum, purified water, sodium methylparaben (0.13% as preservative), and sodium propylparaben (0.02% as preservative) (Description 1).

The Solubility of Rofecoxib

Rofecoxib falls into a category of NSAID drugs called COX-2 inhibitors.  To understand the nature and mechanisms of Vioxx, it is necessary to first examine this enzyme and its functions.

Cyclooxygenase

The enzyme cyclooxygenase (COX) was first isolated in 1979, but it was later discovered that COX existed in two forms:  COX-1 and COX-2 (Bridges 1).  COX enzymes (also called prostaglandin endoperoxide synthase enzymes) aid in the synthesis of prostaglandins (PGs), a type of fatty acids associated with smooth muscle contraction.  Prostaglandins, when existing in a certain isoform (H₂), can cause irritation to an inflammation site.  The synthesis of these undesirable prostanoids (prostaglandins, thromboxanes, and others) occurs in the cell membrane, and is catalyzed by COX-2.  COX-2 enzymes congregate at inflamed sites, intensifying the painful effect by producing PGs.  It was therefore concluded that shutting down the enzyme pathway (COX) used to create PGs could reduce and even eliminate their effect on inflamed areas.

  The two COX enzymes exist in different concentrations throughout an organism.  At inflammation sites, COX-2 is much more abundant.  Since COX-1 helps produce prostaglandins that protect the stomach lining, it is present in larger quantities in the GI tract.  Because typical NSAIDs are not selective when targeting enzymes, they end up shutting down prostaglandin synthesis everywhere in the body.  This results in a greater risk of GI tract infection and ulceration, inciting research to develop a drug that inhibits only COX-2, the more pro-inflammatory of the two enzymes.

As shown in Figure 1, both COX enzymes catalyze a critical step in similar reactions: Converting free membrane arachidonic acid to a prostaglandin.  External physiologic stimuli (e.g. tissue damage) can activate phospholipase A₂, which cuts arachidonic acid from the membrane (Selective 1).  COX enzymes can then interact with the free membrane arachidonic acid and convert it to prostaglandin form.  This is accomplished by adding O₂ to the molecules in a two-step process.  These steps are outlined in Figure 2.  This unstable prostaglandin must immediately be changed into more stable molecules (thromboxanes, stable prostaglandins, prostacyclin).  The enzyme peroxidase is conveniently coupled to cyclooxygenase in the membrane to serve this exact purpose.  When a prostaglandin H₂ is formed from the PGG₂, it is free to enter the cytoplasm, where it is permanently stabilized by another enzyme.  From there, the prostaglandin acts as a signaling molecule to the surrounding cells that have prostaglandin receptors (which are G-protein-linked receptors).  When a PG interacts with a receptor, the cell is stimulated (through the adenylyl cyclase

 pathway) to contract.

Until quite recently, COX enzymes were inhibited by non-steroidal anti-inflammatory drugs (or NSAIDs).  These drugs, such as ibuprofen or Tylenol, boasted pain relief to inflamed or injured areas.  However, since NSAIDs inhibited all COX enzymes without selectivity, the COX-1 enzyme could not perform its proper function of catalyzing the synthesis of protective PGs for the stomach and kidneys.  Thus, when taken in high doses, NSAIDs generated unwanted side effects of GI tract infection and even stomach and intestinal ulcers.  To get enough pain relief for rheumatoid arthritis, achy joints, or post-surgical pain, NSAIDs would have to be taken in amounts high enough to invoke gastric ulcers.  Therefore, NSAIDs did not adequately solve the COX problem.

The need for an effective and selective COX-2 inhibitor resulted in the research production of two similar drugs:  celecoxib (Celebrex) and rofecoxib (Vioxx).  Although pharmacies began distributing celecoxib first, with an impressive 375-fold selectivity rate for COX-2, rofecoxib bragged a much higher rate of selectivity (Kaplan-Malchis 27).  Yet both attempt to accomplish the same goal of inhibiting COX-2 only.

Rofecoxib (and similar COX-2 inhibitors) is extremely selective in its enzyme inhibitions, with an incredible selectivity ratio of COX-2 to COX-1 greater than 800:1 (27).  Since COX-2 exists in high concentrations at the site of inflammation, the drug’s effects are detected mostly in this area.  Pro-inflammatory prostaglandins are prevented from developing, significantly reducing swelling and acute pain at potential inflammatory sites.

  Rofecoxib is able to accomplish its task by taking advantage of a key difference in amino acid sequences on COX-1 and COX-2.  At a specific spot where COX-1 has isoleucine, COX-2 carries a valine.  The presence of the valine allows the selective COX-2 inhibitor to bind only to that site on COX-2.  Rofecoxib searches for this valine in a COX enzyme and binds to the site only when it is present.  In this way, the drug can selectively inhibit COX-2 from producing PGs.

Administration of Rofecoxib

            Vioxx is taken orally in doses of 12.5 mg, 25 mg, or 50 mg, with or without food.  The 50 mg tablet is seldom used, as doctors only recommend a maximum of 25 mg per day.  Since rofecoxib interacts with certain other drugs, it should not be taken with methotrexate, warfarin, rifampin, ACE inhibitors, or lithium (Jillard 1).  Vioxx is 93% absorbed by the body, and excreted over 99% of the time by urine (Clinical 1).  It can also be given in oral suspensions of 12.5 mg/mL or 25 mg/mL (Jillard 1).

Side Effects

            Initially, Vioxx inserts contained warnings identical to traditional NSAIDs regarding GI tract infection and ulceration until a survey showed some impressive results.  Both U.S. and international studies of the connection between Vioxx and endoscopic gastroduodenal ulcers, a 25 mg dose exhibited about the same effect on stomach lining as a placebo (sugar pill).  Ibuprofen understandably had nearly three times as many ulcer cases as the placebo.  It can be concluded, therefore, that due to the selective nature of rofecoxib, Vioxx does not interact with COX-1 nearly as much as Ibuprofen.  Tables 2 and 3 show the results of these studies.

 

Endoscopic Gastroduodenal Ulcers at 12 weeks Multinational Study
Treatment Group	Number of Patients with Ulcer/ Total Number of Patients	Cumulative Incidence Rate	Ratio of Rates vs. Placebo	95% Cl on Ratio of Rates
Placebo	5/182	5.1%	--	--
VIOXX 25 mg	9/187	5.3%	1.04	(0.36, 3.01)
VIOXX 50 mg	15/182	8.8%	1.73	(0.65, 4.61)
Ibuprofen	49/187	29.2%	5.72	(2.36, 13.89)
*by life table analysis

            These studies show the frequency in occurrence of intestinal ulcers over a twelve-week period for individuals who took these drugs.  For the few cases that resulted in ulcers, these side effects can be traced back to the fact that rofecoxib is not exclusively selective of COX-2, and in fact, some COX-1 enzymes are inhibited in the process.  This causes a rare incident of gastroduodenal ulceration.

Based on a clinical study of the negative effects of Vioxx compared with Ibuprofen,

Diclofenac, and a placebo, rofecoxib was proven a relatively safe and effective drug for use in pain management.  As shown in Table 4, Vioxx behaved more like a placebo in most cases than a drug.  About 25% of Vioxx recipients reported some type of side effect, with only about 5% of the total patients contracting serious health problems from the drug (Selective 1).  One of the most common side effects among patients was diarrhea (6.5%).  Several isolated cases of GI tract infection, ulceration, kidney failure, or cardiovascular complications.  All of these side effects occur due to minute COX-1 inhibition.  Along with the severe side effects, Vioxx also causes some typical medicinal side effects:  allergic reactions, skin reactions, liver problems (nausea, tiredness, itching, tenderness in the right upper abdomen, and flu-like symptoms), and other minor and rare incidents of anxiety, confusion, depression, hair loss, hallucinations, increased levels of potassium in the blood, low blood cell counts, palpitations, pancreatitis, tingling sensation, unusual headache with stiff neck (aseptic meningitis), vertigo.  Table 4 shows an exhaustive list of possible side effects for rofecoxib compared with Ibuprofen, Diclofenac, and a placebo.

Conclusion

            Vioxx has a promising future as a valid treatment for arthritic symptoms, joint pain, and post surgical recovery.  Its arrival in pharmacies is definitely a welcome relief and alternative for traditional non-selective NSAIDs.  When taken in small enough doses, rofecoxib can effectively inhibit COX-2 enzymes, eliminating the synthesis of adverse prostaglandins, without seriously affecting the recipient’s health.

 Works Cited

“Adverse Reactions:  Vioxx Prescribing Information.”  Merck & Co., Inc.  26 Nov 2002.  <http://www.vioxx.com/vioxx/product_info/pi/reactions.html>

Bridges, Alan J.  “COX-2 Inhibitors.”  Spine-Health, 1999.  26 Nov 2002.  <http://www.spine-health.com/topics/conserv/cox/cox03.html>

 “Clinical Pharmacology:  Vioxx Prescribing Information.”  Merck & Co., Inc.  26 Nov 2002.  <http://www.vioxx.com/vioxx/product_info/pi/clin_pharm.html>

“Description:  Vioxx Prescribing Information.”  Merck & Co., Inc.  26 Nov 2002. <http://www.vioxx.com/vioxx/product_info/pi/description.html>

Kaplan-Malchis, Barbara.  “A Quest for Safer NSAIDs:  Focus on the Selective COX-2 Inhibitors.”  Home Health Care Consultant.  June 2000:  25-30.  26 Nov 2002. <http://www.mmhc.com/hhcc/articles/HHCC0006/kaplanmachlis.html>

Jillard, Nancy.  “Pain and Rheumatoid Arthritis:  An Update.”  Drug Topics.  Medical Economics:  Montvale, 2000.  26 Nov 2002.  <http://www.drugtopics.com/be_core/search/show_article_search.jsp?searchurl=/be_core/content/journals/d/data/2000/0403/dce04a.html&navtype=d&heading=d&title=Pain+%26amp%3B+Rheumatoid+Arthritis%3A+An+Update>

McGriff, Nayahmka.  “Management of pain in rheumatoid arthritis.”  Drug Topics.  Medical Economics:  Montvale, 2001.  26 Nov 2002. <http://www.drugtopics.com/be_core/search/show_article_search.jsp?searchurl=/be_core/content/journals/d/data/2000/0403/dce04a.html&navtype=d&heading=d&title=Pain+%26amp%3B+Rheumatoid+Arthritis%3A+An+Update>

Miceli, David.  Physician’s Desk Reference.  53^rd-55^th editions: 1999-2002.  26 Nov 2002.  <http://www.stevensjohnsonsyndrome.com/vioxx.htm>

“Selective COX-2 Inhibitors.”  The Drug Monitor.  26 Nov 2002.  <http://www.home.eznet.net/~webtent/coxi.html>