This text is a companion to the article, The Impact of the FDA's Fast-track Initiatives on Drug Safety, by Jennifer I. Kuesters, Linda J. Lawrie, Rebecca S. Wells, and Alexander M. Walker, which has been submitted for publication.

Approved by the FDA in December of 1994 after approximately 33 months in priority review, lamotrigine (Lamictal), an antiepileptic drug (AED) of the phenyltriazine class, is the first AED designed specifically to inhibit glutamate and aspartate. Lamotrigine is well tolerated and does not alter concentrations of concomitant AEDs or induce hepatic enzymes, although it is a target for enzyme induction (PIA, Jan/Feb 1997).

Lamotrigine is useful for patients who cannot control their seizures adequately with current medication or who experience unreasonable side effects with such medication. In clinical studies involving more than 8000 patients internationally, physicians concluded that patients’ overall clinical status did improve in more than 65% of cases with lamotrigine treatment given as an adjunct to existing therapy (PIA, Mar. 1995).

Approximately 10% of the 3,501 patients receiving Lamictal in premarketing clinical trials discontinued use because of adverse events, such as rash, dizziness, and headache (PDR, 1998). Lamotrigine may also cause potentially fatal hypersensitivity reactions (MedWatch, Mar. 1997). After reports of adverse events post-marketing, Glaxo Wellcome, Inc. the manufacturer of lamotrigine, issued a black box warning in March 1997 noting that the drug can cause severe, and potentially life-threatening skin rashes. These rashes occur in approximately one in every thousand adults, and have included Stevens-Johnson Syndrome, and more rarely, toxic epidermal necrolysis. Rare deaths have occurred, but their numbers are too few to allow a precise estimate of the rate (MedWatch, Mar. 1997).

Nefazodone hydrochloride (Serzone), an anti-depressant for oral administration which acts as a serotonin reuptake inhibitor, was approved by the FDA in December 1994 after almost 37 months in the standard review process. In comparative studies of patients with major depression, nefazodone proved to be more effective than placebo and better tolerated than imipramine, a tricyclic antidepressant. Nefazodone has little effect on hemodynamics and is less sedating compared to other antidepressants (PIA, Nefazodone). Nefazodone does interact with certain benzo-diazepines (e.g., triazolam) (Frewer and Lader, 1993).

Coadministration of terfenadine, astemizole or cisapride with Serzone is contraindicated due to potential interactions. In addition, there is potential for interaction with Monoamine Oxidase Inhibitors (MAOI). Approximately 16% of the 3496 patients taking nefazodone in an international premarketing clinical trial discontinued use due to an adverse event. The more common (³ 1%) events associated with discontinuation and which were considered to be drug related included nausea, dizziness, insomnia, asthenia, and agitation (PDR, 1998).

Lamivudine (Epivir, formerly known as 3TC), an anti-HIV nucleoside analogue, was granted accelerated approval from the FDA’s Antiviral Drugs Advisory Committee to be used in combination with zidovudine (AZT) for HIV treatment. The combination exhibited more effect on surrogate markers of HIV than either drug by itself or the combination of zidovudine (AZT) and zalcitabine (ddC) (PIA, Dec. 1995). Lamivudine was rapidly reviewed in 4.37 months in the priority drug review process and obtained approval from the FDA in November 1995.

Accelerated release of lamivudine was based on four controlled clinical trials which showed the effectiveness of the lamivudine/zidovudine combination on the surrogate endpoints of HIV infection – CD4 cell counts and viral load. These studies documented that lamivudine plus zidovudine significantly reduced viral load and increased CD4 cell counts in patients previously treated with zidovudine (AZT) as well as in previously untreated patients. Epivir’s clinical benefit was demonstrated in post-marketing clinical studies by measuring clinical endpoints – survival and disease progression (PR Newswire, 1997).

Regulatory clearance for Epivir was additionally based on results from the CAESAR clinical trial which measured clinical endpoints of progression to a new protocol-defined AIDS event or death. The trial was terminated following the second interim analysis because results showed highly significant reductions in progression to AIDS or death in lamivudine-treated patients compared with patients receiving placebo (Randomised, 1997). Most commonly reported adverse reactions were headache, nausea, fatigue, nasal congestion and diarrhea (PR Newswire, 1997).

In response to reported post-marketing adverse events, a "Dear Health Professional" letter was issued in September 1997 (MedWatch, Sept. 1997). Subsequently, in December 1997 Glaxo Wellcome included a black box warning to the label of Epivir because "lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including lamivudine" (PDR, 1998).

Bicalutamide tablets (Casodex) are non-steroidal antiandrogens indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analogue for the treatment of Stage D₂ metastatic carcinoma of the prostate. In a phase III trial comparing Casodex plus LHRH analogue therapy to flutamide plus LHRH analogue therapy, results showed longer median survival with the Casodex-LHRH combination regimen. In addition to the advantage of having to take Casodex only once daily as opposed to taking flutamide three times a day, Casodex is also associated with less adverse effects, such as lower incidence of diarrhea (Kolvenbag et al., 1998).

Casodex was granted accelerated approval, reviewed in 12.7 months, and was approved by the FDA in October 1995. Reported adverse events include pain, pelvic pain, infection, constipation, dyspnea, and hematuria (Zeneca, 1998). Breast pain and gynecomastia also have been reported in up to 39% of individuals in clinical studies. In vitro studies have shown that Casodex can displace coumarin anticoagulants, such as warfarin, from their protein-binding sites (PDR, 1998).

Troglitazone (Rezulin) is the first oral antidiabetic agent specifically designed to target insulin resistance. Troglitazone was considered a priority drug by the FDA and was reviewed in just 6 months (PIA, Mar/Apr 1997). Official approval came in January 1997.

Results of several major clinical studies in individuals with non-insulin-dependent diabetes mellitus (NIDDM) show that after 6 months of treatment, troglitazone significantly decreases both HbA1c levels and the need for insulin injections. Most frequently reported adverse events included: headache, pain, asthenia, dizziness, and nausea (PIA, Mar/Apr 1997).

During clinical studies in North America, a total of 48 of 2510 (1.9%) patients treated with Rezulin and 3 of 475 (0.6%) patients treated with placebo had alanine aminotransferase (ALT) levels more than 3 times the upper limit of normal. Two of the 20 patients treated with Rezulin developed reversible jaundice. These individuals normalized after discontinuing use of the drug (MedWatch, Nov. 1997).

As of October 1997, 35 post-marketing reports of adverse events regarding liver injury (ranging from mildy elevated blood levels of the liver enzymes to liver failure leading to one liver transplant and one death) were received by Parke-Davis (FDA T97-55, 1997). In response, Parke-Davis incorporated liver enzyme monitoring requirements to its drug labeling and communicated these changes in "Dear Health Professional" letters (Warner-Lambert, 1999). After futher modifications in monitoring requirements, Parke Davis issued a black box warning on the label of Rezulin in December 1997 to state that rare cases of severe idiosyncratic hepatocellular injury have been reported during marketing use. The hepatic injury is commonly reversible, but very rare cases of hepatic failure leading to liver transplant or death have been reported (MedWatch, Nov. 1997). Based on clinical studies, approximately 2% of Rezulin-treated patients can be expected to discontinue use of the drug because of elevated liver enzymes (MedWatch, Nov 1997).

Fatal adverse events have occurred in connection with most, if not all, oral antidiabetic agents, some of which may also be associated with increased cardiovascular mortality, liver dysfunction, and/or other serious adverse reactions. The post-marketing data conclude that Parke-Davis has been effective in its effort to significantly reduce the frequency of adverse liver events. In addition, the FDA has determined that the benefits of Rezulin outweigh possible associated risks (Warner-Lambert, 1999). It should be noted that the drug has been voluntarily withdrawn from the market in the United Kingdom, where it is marketed by Glaxo Wellcome (PNN, Dec. 1997). However, after review of the safety data and concluding that the benefits are greater than possible associated risks, Glaxo Wellcome has petitioned to permit re-introduction of the drug in the U.K. (Warner-Lambert, 1999).

Topiramate (Topamax) is an antiepileptic agent for the adjunctive treatment of adults with partial-onset seizures (PIA, Jan/Feb 1997). Topiramate was approved within 24 months by the FDA in December 1996. Topiramate enhances gamma-aminobutyric acid (GABA) and inhibits glutamate by blocking sodium channels (PIA, Jan/Feb 1997). In premarketing clinical trials, topiramate significantly decreased the frequency of epileptic seizures, including refractory partial seizures (Privitera, 1997).

The most frequently reported adverse events in clinical trials were psychomotor slowing, speech and language problems, difficulty concentrating, somnolence, and fatigue. These adverse effects were commonly dose related. During clinical studies, 1.5% of patients treated with topiramate developed kidney stones, which represents a two- to fourfold increase over the normal rate of stone formation. This may be due to topirmate’s ability to inhibit carbonic anhydrase. Therefore, topiramate should not be used with other carbonic anhydrase inhibitors. Topiramate may also interact with phenytoin and carbamazepine and dose adjustments may be required (PIA, Jan/Feb 1997).

Stavudine is an antiretroviral nucleoside analogue for treatment of advanced HIV approved in June 1994. The drug is intended for use in patients who cannot tolerate other approved therapies or who have undergone deterioration of their condition while on those therapies (PIA, Sept. 1994). Accelerated approval was granted by the FDA in 5.9 months after clinical tests found an improvement in CD4 cell count, the surrogate endpoint, with stavudine therapy. In a large multicenter trial of 359 patients, interim results showed a 22 cells/mm³ increase in CD4 cell count in patients treated with stavudine in contrast to a decrease of 22 cells/mm³ in those on continued zidovudine (AZT) therapy. Bristol-Myers is committed to conducting post-marketing studies to further determine safety, efficacy and optimum dosing (PIA, Sept. 1994).

Laboratory tests conducted on patients receiving stavudine therapy often showed mild to moderately elevated hepatic enzyme levels (PIA, Sept. 1994). The elevated hepatic enzymes were also noted in phase I and II clinical trials (Skowron, 1995). Stavudine received a black box warning in February 1998 warning of lactic acidosis and severe hepatomegaly with steatosis (MedWatch Summary, Mar. 1998). Another adverse reaction discovered during phase I and II clinical trials and further noted in efficacy trials conducted after approval is dose related peripheral neuropathy (Skowron, 1995; Spruance et al., 1997; Petersen et al., 1995).

Imiglucerase is an analogue of beta-glucocerebrosidase, a lysosomal enzyme, that catalyzes the hydrolosis of glucocerebroside, which accumulates in tissue macrophages in patients with Gaucher’s disease. It was approved in May 1994 after 12.1 months of review by the FDA. Imiglucerase for injection is produced by recombinant-gene technology and is an alternative to alglucerase for injection (Ceredase), which is derived from placentas (PIA, Jul.1994). The advantage is that Cerezyme has the potential of being unlimited in supply and free of pathogenic entities (Grabowski, 1995). In a clinical trial comparing Cerezyme to Ceredase, Cerezyme was found to be equally efficacious and no major immunologic adverse events were noted in either group (Grabowski, 1995). In addition, there are no contraindications to the use of Cerezyme (PDR, 1998).

Mibefradil is a calcium-channel blocker approved for treatment of hypertension and chronic stable angina in June 1997 (review time 15.3 months). Mibefradil’s therapeutic mechanism of action is vasodilation of vascular and peripheral arteries. The drug was evaluated in patients with chronic stable angina already undergoing beta-blocker therapy. Statistically significant improvements in variables such as time to onset of angina were found with the combination therapy (PIA Mibefradil, 1997).

After approval, two risks were discovered with mibefradil therapy, extremely low heart rates and risk of muscle injury. The latter event can occur when mibefradil is taken in combination with certain cholesterol lowering drugs (MedWatch News, Dec. 19,1997). This finding led to the distribution of a "Dear Doctor" letter in December 1997 (MedWatch News, Dec. 18, 1997). The preliminary results of a post-marketing, three-year study of mibefradil in treatment of congestive heart failure found no significant difference between mibefradil and placebo, and provided further information on adverse events associated with treatment. These results led to the voluntary withdrawal of mibefradil from the market in June 1998 (Roche News Release, 1998).

Tamsulosin is used in the treatment of benign prostatic hypertrophy and was approved by the FDA in May 1997 after a review lasting twelve months. The drug is an alpha-1a adrenoreceptor antagonist, which causes smooth muscle relaxation. Compared to other alpha-antagonists, tamsulosin has greater specificity for alpha-1a receptors and does not affect alpha receptors on blood vessels. The result is less orthostasis than previous alpha-antagonists. Phase III placebo controlled clinical trials found statistically significant improvements in American Urological Society efficacy parameters, such as symptom scores, after treatment with tamsulosin (Lepor, 1998; Narayan, 1998). The only side effects found in trials were abnormal ejaculation and dizziness. Studies will be continued to determine long–term safety of tamsulosin (PIA, Sept. 1997).

In November 1995, a FDA Advisory Committee recommended the approval of dexfenfluramine for treatment of obesity; the committee thought the drug’s benefits outweighed its potential risks (Cruzan,1995). This led to the approval of the drug in April 1996. A previous drug, fenfluramine (Pondimin) was a mixture of the dextro- and levo- isomers of this compound. The levo- isomer was thought to potentially have some non-weight loss activities, and therefore, isolation of the dextro- isomer was achieved in dexfenfluramine (PIA, Jun.1996; MedWatch News, Redux 1997). In addition, dexfenfluramine was touted for weight loss and weight maintenance whereas fenfluramine and phenteramine (another weight loss drug) were recommended only for short term use. The International Dexflenfluramine Index Trial, which was conducted prior to the approval of the drug, found that 29% of 297 patients lost 15% of baseline body weight with Redux treatment compared with 16% of 262 patients given placebo. Serious side effects occurred with about the same frequency in the treatment and placebo groups (PIA, Jun. 1996; Dec. 1995).

Concerns raised about dexfenfluramine prior to approval included possible neurotoxic effects and primary pulmonary hypertension. What eventually led to the voluntary withdrawal of dexfenfluramine from the market by Wyeth-Ayerst in September 1997, however, was the discovery of heart valve defects associated with its use (PIA, Jun. 1996; Connolly et al., 1997; MedWatch News, Sept. 1997). Connolly et al. state "the appearance of clinically significant left-sided regurgitant valvular heart disease in a population less than 50 years old is rare" (1997). Most of the cases of heart valve disease were associated with the off label combination of either dexfenfluramine or fenfluramine with phenteramine, but there were also reported cases in patients taking dexfenfluramine alone (MedWatch News, Aug.1997). A "Dear Doctor" letter had been distributed in July 1997 warning of valvular disease with the combination therapy (MedWatch News, Jul.1997).

Nicotrol NS is one of the new nicotine replacement systems used to help people quit smoking approved in March 1996. Three clinical trials using 730 patients found that by six months 31-35% had quit smoking. No serious adverse events occurred during the trial (PDR,1998). The advantages noted for the nasal spray include the rapid absorption and action of the nicotine in the nasal spray form. The rapid action is closer in sensation to smoking a cigarette than the more slowly absorbed forms of nicotine. However, this makes the product have more addiction potential than other forms of nicotine replacement. It is recommended that the product not be used longer than 6 months because safety beyond this point is unknown (PIA, May 1996).

Bromfenac is a non-steroidal anti-inflammatory drug used in the short-term treatment of pain, without the side effects of opioids (PIA, Bromfenac 1997). The drug was approved in July 1997 after 27.7 months of review. Pre-marketing studies found Bromfenac to be efficacious with no unusual or unexpected adverse events (Mehlisch, 1997; Johnson et al., 1997; Bostrom et al., 1994).

There had been no reports of serious liver damage in clinical trials, but elevations in liver enzymes were noted in some patients treated long term with bromfenac; this information was included in the product label and only short-term use was recommended. A boxed warning was placed on the drug in February 1998 due to serious liver damage associated with use of the drug for longer than the recommended 10 days. In June 1998, Wyeth-Ayerst voluntarily withdrew bromfenac from the market. This action was prompted by the post marketing reports of severe liver damage in people for whom the drug was used for long-term pain management despite the black box warning. In addition, there are other therapies available for pain management (MedWatch News, Jun. 1998).

Cerivastatin sodium is a cholesterol lowering agent for use in patients with primary hypercholesterolemia and mixed dyslipidemia which was approved by the FDA in June 1997. The review of the drug lasted 12 months. Cerivastatin is especially useful for those patients in which simple dietary restriction or other non-drug therapies are not adequate. Another advantage is that only low doses are needed for the drug to be effective (PIA, Jun. 1997).

Phase IIa placebo-controlled dosing trials (n=385) found cerivastatin decreased LDL levels by 30.5% with the incidence of adverse events similar in the placebo and treatment groups (Hunninghake, 1998). Adverse reactions include rhinitis, pharyngitis, and headaches; care should be taken in treatment of patients with diffuse mylagias, muscle tenderness or weakness and marked increases in creatine kinase (PIA, Cervistatin 1997). Cervastatin can be used in combination with other common drugs such as warfarin, digoxin, cimetidine and antacids (PIA, Cervistatin 1997; Muck, 1998; PIA, Cervistatin 1997).

Tolcapone is the first anti-parkinsonian drug of the COMT (catechol-o-methyltransferase) inhibitor class. It was approved for marketing in January 1998. In clinical trials, the drug increased the amount of on time/good functioning daily by 1.7 to 2.9 hours (PNN, 1998; Adler et al.,1998). Tolcapone was approved as an adjunct to levodopa/carbidopa therapy. Patients given tolcapone in clinical trials were found to have reductions of levodopa dose greater than patients given placebo (Dupone et al., 1997). The most common side-effects in pre-marketing studies included dyskinesias, nausea and diarrhea (PNN, 1998; Dupont et al., 1997; Waters et al., 1998). It was noted at the time of marketing that liver transaminases should be monitored for the first six months of therapy (Tasmar package labeling).

In November 1998, a black box warning was added to the labeling of Tasmar due to cases of severe hepatocellular injury, such as fulminant hepatitis, noted with its use. In a "Dear Doctor" letter Roche urged that the drug be used as an adjunctive therapy in Parkinson's disease only in those who are not reponsive to or not appropriate candidates for other therapies, or who are experiencing symptom flucuations. The company also recommended more closely monitoring patients on tolcapone therapy for signs of liver disease. On November 17, 1998, the European Union asked that member states suspend the use of tolcapone. Roche maintains that the risks associated with tolcapone are outweighed by its benefits for a restricted group of Parkinson's patients (PIA, Nov. 1998; Medwatch, Nov. 1998; FDA, Nov. 1998).

Control 8: Prandin (repaglinide/Novo Nordisk):

Prandin was approved in December 1997 for the treatment of Type II diabetes; it is the first oral hypogycemic agent in the meglitinide class. The drug is intended for those patients who do not have satisfactory glucose control with diet and exercise alone (PNN, Dec. 1997-Jan. 1998). Prandin has the advantages of being rapid acting and having a short duration of action. However, it needs to be taken three times daily (before each meal) in comparison to other once-a-day therapies (PNN, Dec.1997-Jan.1998).

In a Phase II clinical trial comparing repaglinide to placebo, HbA1c levels were reduced in patients taking repaglinide while they were increased in placebo patients. Mean fasting blood glucose levels were also reduced in the treatment group. During the trial, repaglinide was well tolerated (Glodberg et al., 1998). The major adverse effect seen with use of repaglinide is hypoglycemia (Guay, 1998). In addition, there is a special warning of increased risk of cardiovascular mortality with use of the drug compared with diet alone or diet plus insulin.