QuarterWatch™ (2012—Quarter 2) Signals for finasteride, methylphenidate patches, and anticoagulants
January 10, 2013
QuarterWatch™ is an ISMP surveillance program that monitors serious, disabling, and fatal adverse drug events (ADEs) reported to the US Food and Drug Administration (FDA) by drug manufacturers, and by health professionals and the public through its MedWatch reporting program. The goal of QuarterWatch™ is to improve patient safety through the identification of signals that may represent important drug safety issues. The term signal means evidence judged to be substantial enough to warrant publication but which usually requires further investigation to determine its frequency of occurrence and establish a causal relationship to the suspect drug. The latest QuarterWatch™ examines April to June 2012 report totals and ADE signals.
During the second quarter in 2012, the FDA received 221,954 reports that were entered into the FDA Adverse Event Reporting System (FAERS). Of these, we examined 50,289 reports that met the QuarterWatch™ criteria of being serious, disabling, or fatal ADEs.
Persistent Sexual Side Effects With Finasteride
Finasteride inhibits the formation of dihydrotestosterone, a potent form of testosterone that is linked to male pattern baldness and enlargement of the prostate gland. At a 1 mg daily dose, finasteride is approved for male pattern baldness under the brand name PROPECIA. A 5 mg dose is used to treat symptoms of benign prostatic hyperplasia (BPH) under the brand name PROSCAR. Reduced sexual drive and dysfunction were the most common side effects reported in preapproval clinical trials in the 1990s. Nearly 20 years after approval, evidence is now emerging that the sexual side effects of finasteride may sometimes be persistent despite discontinuation of the drug.
Persistent side effects that do not resolve upon drug discontinuation are among the most elusive, difficult to detect and measure, and often overlooked. If the adverse effect does not resolve after discontinuing the drug, one hypothesis may be that some other factor caused the problem and that its onset soon after a drug was initiated may be coincidental. For that reason, identification of persistent drug side effects is rare with a few notable exceptions, including antipsychotic medications and tardive dyskinesia, and benzodiazepines and long-term withdrawal symptoms. Also, reports of sexual dysfunction are relatively uncommon in adverse event data, although it seems plausible that a drug that causes lasting changes in the anatomy of the prostate and the pattern of hair growth might also cause long-lasting changes in sexual desire and function.
When we examined the FDA reports for the second quarter of 2012, we found 46 adverse events for finasteride associated with a sexual problem among a total of 61 (75%) adverse events for the drug. In 28 of the 61 (46%) reports, the side effects had not resolved when the report was prepared. Of this total, 20 reports (71%) specifically indicated a significant or long-term disability. Specific side effects included penile curvature, testicular pain, scrotal pain, gynecomastia, testicular atrophy, reduced penile size, and anorgasmia. Overall, 72% of the reports were associated with the 1 mg male pattern baldness product, and the remainder of the reports were associated with either the 5 mg product for BPH or not stated.
Concern that sexual side effects might be persistent was supported by an FDA analysis(1) that led to including information about reported persistent sexual side effects in the prescribing information. A published scientific paper(2) also described a range of sexual dysfunction that persisted for a mean of 40 months after ceasing treatment in 71 otherwise healthy men between the ages of 21 and 46 years. The men had experienced a slow and gradual onset over a mean of 28 months after being treated for male pattern baldness; this occurred in young men with higher levels of sexual activity. In older or less sexually active men, a gradual change might not have been noticed or attributed to the drug. Such gaps leave us blind to whether the effects of finasteride are rare or rather occur commonly but are rarely perceived and, even more rarely, reported.
When provided with the QuarterWatch™ analysis, Merck & Co., the manufacturer of Propecia and Proscar, noted that a causal relationship had not been established, and that in clinical testing, most cases of reported sexual adverse effects had resolved. However, the clinical trials were not designed to identify slowly emerging side effects persisting after extended treatment.
Product Problems With Daytrana Patches
Methylphenidate is the second most widely used drug for Attention Deficit Hyper-activity Disorder (ADHD), accounting for 3.9 million outpatient prescriptions in the second quarter of 2012. While the market is dominated by extended-release tablets for once-a-day administration, the drug is also available as a transdermal patch under the brand name DAYTRANA. Trying to keep a patch on a hyperactive child might be challenging, but the manufacturer’s website (www.daytrana.com) highlights what the company promotes as an advantage of the patch: “On when they need it, off when they don’t.” The point this statement omits is that it takes about 8 hours after applying the patch before blood concentrations reach a maximum level. Furthermore, substantial amounts of drug remain in the body about 6 hours after patch removal. In addition, because of the slow onset of action, the manufacturer suggests applying the patch while the child is still sleeping if the drug effects are needed during the early morning routines.
For the previous 4 calendar quarters ending in the second quarter of 2012 (reports can be submitted annually), we identified 1,193 cases of reported product problems with Daytrana in young children (median age 9 years). (Unlike other events we monitor, product problem complaints usually do not have a serious outcome.) Over a year’s time, Daytrana product problems outnumbered those for all other monitored drugs. The primary problem was difficulty removing the protective liner to expose the adhesive surface. In some cases, the adhesive stuck to the protective liner, preventing the patch from adhering to the patient. Manufacturing problems began soon after approval, and the patches have been recalled 12 times since 2006, all for the protective liner problem. After repeated recalls, the product was abandoned by Shire. Noven Therapeutics took over marketing in 2010 but conducted two more recalls.
Frequent manufacturing defects were only one of the problems associated with the drug. The FDA had declined to approve the patch twice, in 2003 and 2005, before finally approving it in 2006. Safety issues identified prior to approval included weight loss, insomnia, a slow onset of action making clinical efficacy in the morning lacking, frequent skin irritation, sensitization that could render a child allergic to any form of the drug, and tics.
Another observation with the adverse event cases we reviewed was that 85% of the reports also noted that a medication error had occurred. Half the cases identified a non-specific drug administration error. More clearly described errors included 229 cases of leaving the patch on too long (or possibly not long enough), 86 cases of affixing the patch to an inappropriate site, and 89 cases of drug prescribing errors. Noven Therapeutics has responded by launching an educational program to address some of the problems, including difficulty with removing the protective lining and identifying skin irritation and rashes that could signal a serious allergic reaction (www.daytrana.com/savings-and-support/skin-care-tips.aspx). Unfortunately, education alone will not solve the product quality issues.
Given these problems, we do not see a beneficial role in clinical practice for a patch product that: 1) has been plagued by manufacturing problems for the entire 6 years since approval, 2) has no proven clinical advantage over the oral tablets, 3) causes skin irritation and rashes, 4) has a slow onset of action, and 5) is susceptible to a host of practical problems such as needing to apply it before the child awakens, risking that the patch will fall off or be accidentally removed, or forgetting to remove the patch within the 9-hour maximum wearing time.
Update on Anticoagulants
Strong signals continued for the three anticoagulant drugs, warfarin, dabigatran, and rivaroxaban. These drugs accounted for 1,734 reports to the FDA in the second quarter of 2012, including 233 patient deaths (see Table 1), reinforcing the conclusion that anticoagulants rank among the highest risks associated with drug therapy.
Three different safety signals were seen in the FDA’s adverse event data. First, the total number of case reports for these drugs remained high in the second quarter of 2012. These volumes far exceeded the average of 42 reports for all the drugs we monitor. Simple, direct comparisons that suggest warfarin is safer than the other two anticoagulants are inappropriate, given that treatment discontinuations for adverse events were roughly comparable during clinical trials. However, the reports do provide insights into the type and severity of events and do signal an important safety issue given the overall high total for the three drugs combined.
Second, for reported hemorrhage cases, the risk of a death outcome was markedly higher for dabigatran compared to the other two drugs. After adjusting for differences in age, gender, report type, and report source, dabigatran bleeding episodes resulted in death about 5 times higher than with warfarin (19% vs. 4%, adjusted odds ratio [OR] 5.2; 95% confidence interval [CI] 3.4-8.0). The adjusted odds for a rivaroxaban death were increased twofold compared to warfarin (19% vs. 8%, adjusted OR 1.93; 95% CI 1.0-3.7). Both the FDA and Boehringer Ingelheim, the manufacturer of dabigatran, cited recent, unpublished studies suggesting that major bleeding outcomes appear to be similar to or better than with warfarin. However, these studies also have limitations.
Third, for rivaroxaban, an additional quarter of data confirmed our earlier finding that blood clot-related events were reported more frequently in patients receiving the 10 mg daily dose after hip or knee replacement surgery, compared to the 20 mg regimen indicated for patients with non-valvular atrial fibrillation. After adjusting for differences in age, gender, report source, and report type, the odds of an embolic-thrombotic event were 7 times higher in the lower-dose population (56% vs. 17%, adjusted OR 7.0; 95% CI 3.9-12.6). Of the three anticoagulants, only rivaroxaban has a 50% lower recommended dose for the hip/knee surgery population compared to its other indications. Janssen Pharmaceuticals, the US licensee for rivaroxaban, objected to our comparing the two dosages, citing major differences in the patient populations, exposure, and duration of treatment that may bias the results. While there could be other explanations for our findings, these data still provide a marked signal that the lower dose of rivaroxaban after surgery is producing disproportionate numbers of reports of embolic-thrombotic events, implying a suboptimal dose of the drug.
The full QuarterWatch™ report can be found at: www.ismp.org/QuarterWatch/ default.aspx.
1) US Food and Drug Administration. Questions and answers: finasteride label changes. April 11, 2012. Accessed on January 7 at: www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm299754.htm.
2) Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med. 2011;8:1747–53.