The usefulness of new drugs is evaluated by its benefit-risk assessment at the time of approval. To ensure the drug safety, the risk management plan should be consistently monitored from drug development to postmarketing stage. Many drugs have been withdrawn from the market or distribution restricted as a result of spontaneous reports of serious adverse reactions andor drug interactions. In recent years, several drugs have been withdrawn from the market or distribution restricted due to safety reasons based on postmarketing clinical trials. The implementation of a pharmacovigilance plan and risk minimization activities corresponding to the drug's characteristics is significant for the life cycle management of new drugs, as well as other old drugs.
The burden of adverse drug reaction (ADR) is not limited to morbidity and mortality. It also causes healthcare burden as measured by direct cost of hospitalization, etc. as well as economic burden including indirect cost of labor loss and the withdrawal of drugs from the market. It inflicts additional burden on healthcare resources because of litigations that often ensue in cases of serious ADR. Drug withdrawal can be very costly for the companies involved. Since the 2000s, pharmacogenetics has attracted attention as a means of preventing ADRs. The Council for International Organizations of Medical Sciences (CIOMS) published a report on pharmacogenetics in 2005. The Committee to review cases of “Yakugai” hepatitis in Japan and the regulation aimed at preventing its recurrence was established in association with Ministry of Health, Labor and Welfare (MHLW) in May 2008. This paper reviewed the various research on drug withdrawal conducted in the UK and the rest of the world, the US, and Japan. Several litigation cases were introduced. Four preventive measures were discussed, i.e. 1)use of pharmacogenetics in preventing ADRs, 2)use of economic Darwinism by providing longer exclusivity periods to those drugs proven to be safe through long-term clinical trials, etc., 3)use of private or foreign drug review agency as well as margin and insurance systems, and 4)voluntary marketing suspension of drugs with questionable safety profile initiated by pharmaceutical companies.
Phenylpropanolamine (PPA) is a sympathomimetic used as a cold remedy for the relief of nasal congestion. PPA was also used as an appetite suppressant in several countries (e.g., US and Australia). Since 1969, there have been case reports and spontaneous reports on the association between PPA and hemorrhagic stroke among young people. The US Food and Drug Administration (FDA) and manufacturers of products containing PPA agreed to collaborate to resolve the issue by implementing a case-control study. As a result, PPA was shown to increase the risk of hemorrhagic stroke in women particularly when used as an appetite suppressant. The US FDA asked the firms to commit voluntary withdrawal of all products containing PPA in November 2000. In Japan and Korea, following the label change of the drug containing PPA, PPA was eventually withdrawn during the period 2001-2003. As the incidence of hemorrhagic stroke is high in eastern Asia, the association between hemorrhagic stroke and PPA may differ from that in the US. The Korean FDA then implemented a case-control study similar to that conducted in the US. The results suggested that PPA contained in cold remedies increases the risk of hemorrhagic stroke regardless of age and dose of PPA. Unfortunately, such a study was not implemented in Japan. In general, it is difficult for the government to take appropriate action regarding the safety concerns of a drug using only limited information. It is therefore highly desirable to attempt to verify the action by implementing scientific studies.
Statins are well established as first-line agents for LDL-cholesterol lowering therapy to prevent cardiovascular diseases. However, statin therapy may cause myopathy, including rhabdomyolysis, the risk of which is increased by certain interactions. Cerivastatin has caused hundreds of cases of rhabdomyolysis, especially when administered concomitantly with gemfibrozil; and it was eventually withdrawn from the market. In general, significant myopathy is rare with an incidence of less than 0.5% of patients, and statins are safety drugs and well tolerable. Statin side effects may be dose related; due in part to the drug-drug interactions. Cerivastatin drug interactions are involved in CYP3A4, CYP2C8, and organic anion transporting polypeptide (OATP). Recently, common variants in SLCO1B1, encoding OATP1B1, have been reported to be closely related to the increased risk of statin-induced myopathy. The development of pharmacogenetics (PGx) can help to promote drug usefulness and reduce side effects including the drug-drug interactions. Alternatively, careful medical care by physicians, employing precise, rapid information provision for serious adverse effects, including black box warning, and the establishment of a proper post-marketing surveillance system are important for preventing serious adverse drug effects and should also be performed proactively.
Two isozymes of cyclooxygenase (COX), COX-1 and COX-2 were discovered in 1991. Based upon the molecular composition of COX-1 and COX-2, selective COX-2 inhibitors such as celecoxib and rofecoxib were synthesized. The incidence of severe gastrointestinal events in patients treated with selective COX-2 inhibitors has been proven to be lower than in patients treated with conventional nonsteroidal anti-inflammatory drugs (NSAIDs). However, there were small differences in renal complications between the two groups. In contrast, an increased incidence of cardiovascular diseases, such as myocardial infarction and cardiac failure after administration of selective COX-2 inhibitors may occur in patients with risk factors for atherosclerotic or thrombotic complications. Rofecoxib was withdrawn from the world market due to collected reports of the cardiovascular complications, while celecoxib remained because of lower concern. In addition, the population-based nested case-control analysis for the risk of myocardial infarction suggested increased cardiovascular diseases by use of all NSAIDs. Further basic and clinical studies need to be investigated in the future.
A thiazolidinedione derivative, troglitazone, which binds peroxysome proliferator-activated receptor γ (PPARγ) to improve insulin resistance, was introduced into the market in 1997 as the first agent to improve insulin resistance in type2 diabetes mellitus. However, this agent caused severe hepatic dysfunction and was withdrawn from the market in 2003. Causes for severe hepatic dysfunction by troglitazone have not yet been fully understood. Based on the clinical course, the lack of eruption, fever and eosinophia hepatic dysfunction is thought to be caused not by allergic reactions but by drug idiosyncracy. It has been reported that the combined null genotype of glutathione-S-transferase (GST) theta 1 and GST mu 1 are more prevalent among patients of hepatic dysfunction caused by troglitazone than among those who showed no hepatic abnormality. Pioglitazone, another thiazolidinedione derivative on the market, has been shown not to cause hepatic failure in a large-scale postmarketing surveillance study of more than 20,000 patients. Rosiglitazone, a thiazolidinedione derivative, has been reported to increase myocardial infarction compared with other hypoglycaemic agents or placebo by meta-analyses. Both rosiglitazone and pioglitazone increase the incidence of congestive heart failure presumably by increasing sodium and water retention.
Obesity precipitates diabetes and hypertension and other known risk factors of cardiovascular diseases and stroke. Calorie control, exercise and lifestyle changes are recommended to achieve and maintain an appropriate BMI but drug therapy may also be one of the options for refractory cases. Fenfluramine marketed in 1973 and dexfenfluramine approved in 1996 were appetite-suppressant drugs widely used with phentermine (“fen-phen” or “dexfen-phen”) in the U.S.A. and other countries. They were withdrawn in September 1997 after case reports of cardiac valve abnormalities likely induced by these drugs. In many of these cases, the valvulopathies followed the long-term use, often for cosmetic purposes, even though the long-term safety was not established for these drugs. After the withdrawal, some observational studies, including an ad-hoc study of a clinical trial disrupted by safety concern, were conducted and many of them concluded that fenfluramine or dexfenfluramine increased the risk of cardiac valve abnormalities. In the study by Khan et al., the prevalence of valvulopathies was as high as 22.7% in the users of appetite suppressants compared with 1.3% in the control group, indicating that the withdrawal of fenfluramine and dexfenfluramine was the right decision. It is important to note that a serious non-rare adverse drug reaction like appetite suppressant-related valvulopathies may go unrecognized for more than 20 years. Post-marketing observational studies are valuable especially to evaluate administrative decisions, such as withdrawal, made sometimes without sufficient information.
In 1993, the United States Food and Drug Administration (US FDA) approved cisapride, for symptomatic relief of nocturnal heartburn due to gastroesophageal reflux disease in adults. While more than 30 million prescriptions were issued in the US between 1993 and 1999, 341 (with 80 fatal) cases of cardiac arrhythmias such as QT prolongation and torsade de pointes were reported. Of those 341, 126 (37%) had a concomitant drug known to inhibit cytochrome P450 (CYP) 3A4 enzyme system serving as a major metabolic pathway of cisapride. Following label changes and a“Dear Doctor”letter (1995) or“Dear Health Care Professional”letter (1998) alerting the drug interaction, the proportion of contraindicated dispensing decreased (Guo et al., 2003). Nevertheless, reports on cardiac arrhythmias did not substantially diminish. The manufacturer (Janssen Pharmaceutica) voluntarily stopped marketing cisapride in 2000 in the US and Japan. In Europe, the regulatory decision allowed the company to maintain marketing cisapride but its indication was strictly restricted. Similarly in the US, an investigational limited access program has been successfully developed for the exceptional use of cisapride after 2000. Though there was an agreement that the proportion of adherence to the label indication was unacceptably low among prescribers, the possibility of avoiding the contraindicated use of cisapride (with an inhibitor of CYP3A4 or in patients with ischemic heart disease etc.) to provide the perfect elimination of new case development had not been tested. Strict restriction of the indication might be required in addition to avoiding contraindicated use to achieve satisfactory results.