Post Marketing Surveillance…No wonder doctors are skeptical to the point of confusion

For another class, I had to write a paper on the safety of statins (you’ll see why in the second paragraph). (But for now – a little background)…Statins are well established first-line drugs for the treatment of hypercholesterolaemia and dyslipidaemia implicated in the pathogenesis of coronary heart disease and atherosclerosis.1 Stains lower cholesterol levels by blocking the enzyme HMG CoA (don’t worry about the acronym for now) in the liver involved in the synthesis of cholesterol.2 There are five drugs (use to be 6 – again, second paragraph) in this drug class – each associated with certain toxicities (particularly myopathy) which may lead to a debilitating condition called rhabdomyolysis.3-5 One problem is, statin-induced myopathy is not well understood.1, 6-8 The other problem is, rhabdomyolysis is a rare muscle wasting disorder that results in muscle cell breakdown and release of the contents of muscle cells into the bloodstream. If unchecked, this could lead to renal (kidney) damage. Symptoms of rhabdomyolysis include muscle pain, weakness, tenderness, malaise, fever, dark urine, nausea, and vomiting. The muscle groups involved most frequently are the calves and lower back; however, some patients report no symptoms of muscle injury. The FDA states “in rare cases” (this probably came from the product information or package insert – can’t remember what they are calling it these days – you know, the PI) the muscle injury is so severe that patients develop fatal organ damage, including renal failure.9

The controversy (here we go) over statin use stems from Bayer Pharmaceutical’s voluntary withdrawal of Baycol®/Lipobay® (cerivastatin) in August 2001.10 Bayer received numerous reports of side effects involving muscular weakness, particularly in patients treated concurrently with gemfibrozil. Subsequently the FDA reported 31 deaths associated with cerivastatin use; 12 were associated with concurrent use with gemfibrozil.9 (What happened?) In 1997 the FDA approved cerivastatin labeling for 0.2 – 0.3 mg/day; in 1998 0.4 mg/day; and in 2000 0.8 mg/day was approved without recommendations for a maximum dose.5, 11 However, reports indicate that many physicians prescribed cerivastatin at 0.8 mg/day instead of starting at the lower dose then titrating up.5 Furthermore according to an FDA report, the rate of fatal rhabdomyolosis associated with cerivastatin is up to 80 times as high as the rates for any other statin.5 Also, concomitant medications are pervasive in statin-patient populations with high-risk factors for cardiovascular mortality. Therefore, the risk of drug-drug interactions (DDI) is quite high.

What caught my attention was a report by Psaty et al (2004) who stated that internal company reports from Bayer, specifically case reports, suggested cerivastatin-gemfibrozil DDI data was available within 100 days of the 1998 drug launch; yet the company did not add contraindications about concomitant use to the product information until 18 months after launch.11 (Okay – they knew there was a potential problem but they waited for…what to report it)? According to a 2003 European news report, Bayer fought back (of course they did!) against “claims that it was aware of possible dangers long before the drug was voluntarily withdrawn…”12 Yet, Bayer paid out $125 million to 450 individuals who experienced “serious side effects” and was in negotiations with another 500 cases through 2005.10

Ultimately, who is responsible for post-marketing surveillance? Drug companies! Pharmaceutical companies are responsible for conducting their own post-marketing trials but this is usually more beneficial to the company than it is for the safety of patients. Post-marketing trials are usually conducted to expand the label: new indications, new patient populations (e.g., children), and voila patent extension. Physicians are also responsible to report adverse drug events to the FDA – however, this is voluntary. In collaboration with the FDA’s, CDER, division of pharmacoepidemiology, safety data is gathered and shared with the product firm and an agreement is reached with the firm to determine the next step. In essence, the responsibility to pull a drug lies with the company in question; the FDA may “support” the decision and in some cases engage in litigation when companies do not comply with specific FDA recommendations. Confusing?

How must doctors feel? One minute a drug is on the market and being marketed aggressively then the next its being recalled. One minute a drug is deemed safe and “well tolerated” by patients and the next it could be a lethal weapon. Let’s face it, drugs (I do mean drugs, plural) are a necessary part of life (so is food and yes, cosmetics, too for many of us). But who is ultimately accountable for ensuring, beyond a shadow of doubt, that what we put in and on our bodies will not cause harm (including death)? Surely, drug companies cannot be the sole bearers of responsibility – for reasons, shall we call it, conflict of interest…! Then the government needs to do its job and be allowed to do its job by expanding resources which means more money more money more money…! Less we forever ride the roller-coaster of post-marketing surveillance.

Holly Tomlin
Blog 9

References

1. Tiwari A, Bansal V, Chugh A, Mookhtiar K. Statins and myotoxicity: a therapeutic limitation. Expert Opin Drug Saf. 2006;5(5):651-666.
2. Evans M, Rees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf. 2002;25(9):649-663.
3. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006;114(25):2788-2797. Epub 2006 Dec 2711.
4. Moride Y, Hegele RA, Langer A, McPherson R, Miller DB, Rinfret S. Clinical and public health assessment of benefits and risks of statins in primary prevention of coronary events: resolved and unresolved issues. Can J Cardiol. 2008;24(4):293-300.
5. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346(7):539-540.
6. Smogorzewski M. The myopathy of statins. J Ren Nutr. 2005;15(1):87-93.
7. Jamal SM, Eisenberg MJ, Christopoulos S. Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J. 2004;147(6):956-965.
8. Strippoli G, Navaneethan S, Johnson D, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ. 2008;336:645-651.
9. FDA. http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01095.html; 2001.
10. Bayer Withdraws Baycol/Lipobay. PR Newswire; 2001.
11. Psaty BM, Furberg CD, Ray WA, Weiss NS. Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis. Jama. 2004;292(21):2622-2631. Epub 2004 Nov 2622.
12. Milmo S. Bayer Defends Itself on Baycol. Chemical Market Reporter. 2003;263(9).