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QuarterWatch™ (includes data through June 2018) Focus on Newly Approved Drugs

In the latest issue of ISMP’s QuarterWatch™, we examine the adverse drug events reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for 97 new drugs and biological products approved between 2015 and 2017, including:

  • evolocumab (REPATHA) and alirocumab (PRALUENT), a new generation of cholesterol-lowering biological products that reduce low-density lipoprotein (LDL)

  • secukinumab (COSENTYX) and ixekizumab (TALTZ), two of the newest treatments for plaque psoriasis and psoriatic arthritis

  • dupilumab (DUPIXENT), a new immunosuppressant to treat atopic dermatitis and asthma

The safety profiles of the most recently approved drugs (including biological products) are of importance in an era in which US policy and law emphasizes accelerated approval of some new drugs, deferring many clinical studies until after product launch.

Report Totals

For the 12 months prior to June 30, 2018, we identified 130,028 adverse event reports associated with 97 suspect drugs approved during 2015-2017, representing 10% of all reports for all drug products. Among these reports, 49,976 (38%) described events with a serious or fatal outcome. Compared to all other drugs, the newly approved drugs had a smaller share of serious events (38% vs. 56%), with greater numbers of non-serious events likely reflecting new drug educational and marketing activities that reached a large number of consumers and health professionals.

The number of adverse event reports for the 97 new drugs varied widely and is influenced by the number of patients exposed, the toxic properties of the drug, and the reporting rate, which can be influenced by marketing. Drugs with disproportionately large report totals typically combine all three factors. Just two of the drugs examined in this report, evolocumab and secukinumab, accounted for 31% of all the reports for the 97 new drugs. At the lower extreme lies a group of drugs with few or no adverse event reports. This included 8 specialty drugs without any reports and 16 drugs with 50 or fewer reports.

Signals for Key New Products

The five new drugs examined in depth in this report share common features. Unlike many therapeutic drugs, these biological products are genetically engineered monoclonal antibodies administered through periodic self-injections. Three of the five drugs (and numerous others not reviewed here) are immunosuppressants. Like many new drugs, their costs (including out-of-pocket expenses) are much higher than generic drugs, which account for 90% of all outpatient prescriptions. Also, the five drugs target diseases that are widely prevalent—serious cardiovascular disease, psoriasis, and atopic dermatitis.

Evolocumab and Alirocumab

FDA approval of evolocumab and alirocumab opened a new chapter in reducing the risk of heart attack and stroke through cholesterol-lowering medications. These new biological products inhibit a lipid regulatory enzyme PCSK9 (proprotein convertase subtilisin kexin type 9), allowing liver cells to clear much greater quantities of LDL from the blood. While evolocumab and alirocumab achieve substantially higher reductions (45-60%) in circulating levels of LDL than statins, they require monthly or twice-monthly self-injections and are much more expensive than statins. Also, recently published large trials in high-risk patients produced modest clinical benefit, reducing cardiovascular events by only 14-15% and having no effect on cardiovascular deaths. However, the results were challenging to interpret because all the patients were also taking and tolerating high-dose statins.  

Adverse event reports. We identified 27,481 adverse event reports for both drugs, including 4,192 reports of serious or fatal outcomes. As Table 1 indicates, the most frequently reported adverse event type for both drugs was musculoskeletal pain, similar to what is reported for statins. However, this group of reports did not include any cases of the most severe form of muscle harm, rhabdomyolysis (as sometimes seen with statins). The other large categories of adverse event types were injection site reactions and medication errors. There were also some reports of memory loss.

Table 1. Frequent adverse event reports for new PCSK9 inhibitors (12 months ending June 30, 2018); *One report can include several adverse event types
Adverse Event Type Evolocumab Alirocumab
Number (%) Number (%)
Total reports* 24,551 2,930
Serious/fatal outcome 3,699 (15) 493 (17)
Musculoskeletal pain 5,162 (21) 689 (24)
Injection site reactions 4,629 (19) 396 (14)
Medication errors 4,602 (19) 442 (15)
Memory loss 393 (2) 48 (2)

The most notable difference between the two new products is in the overall number of reports. Evolocumab accrued an unexpectedly large number of reports—8-fold more than alirocumab—ranking first among all newly approved drugs and more than 50 times higher than the median of 393 reports for the group of 97 new drugs. Alirocumab initially was approved with a narrow indication for use only in patients with genetic abnormalities that lead to exceptionally elevated cholesterol levels. Thus, prescription volume was nearly double for evolocumab compared to alirocumab. Since the percentage of adverse events in each category was similar for the two products, we suspect that some of the remaining differences in report volume may be explained by marketing activities for evolocumab that led to more contact with health professionals and consumers and therefore more reports.

Secukinumab and Ixekizumab

Secukinumab and ixekizumab join a group of immunosuppressants used to treat plaque psoriasis and psoriatic arthritis. Both are monoclonal antibodies that inhibit interleukin-17A (IL-17A) and are administered by injection every 4 weeks after a series of loading doses. During clinical trials, 51-68% of patients treated with secukinumab were clear or almost clear of psoriasis plaques at 12 weeks, compared to 81-83% who were clear at 12 weeks with ixekizumab.

Adverse event reports. Secukinumab was the primary suspect in 15,500 adverse event reports, second only to evolocumab among all new drug products, compared to just 2,339 reports for ixekizumab. The difference can be partially explained by a 2.4-fold greater prescription volume for secukinumab and possible marketing differences. However, we observed specific adverse reactions for which notable differences persist despite adjustments for report volume. The key findings are shown in Table 2.

Table 2. Selected adverse event reports for new IL-17A inhibitors (12 months ending June 30, 2018); *PRR = proportional reporting ratio; PRR less than 1 = fewer than expected ** One report can include several adverse event types
Adverse Event Type Secukinumab Ixekizumab
Number PRR* Number PRR*
Total reports** 15,500   2,339  
Serious/fatal reports 4,337   403  
Injection site reactions 603 1.8 630 15.6
Colitis 198 2.5 50 5.1
Drug efficacy issues 2,908 2.0 137 0.06

The most revealing columns are labeled PRR, or the proportional reporting ratio, which compares the number of specific adverse events reported for the target drug with those expected based on all other comparison drugs in the 12-month period. For example, if reports of hypotension occurred in 12% of all cases with the suspect drug but occurred in only 3% of the cases with comparison drugs, it would produce a PRR of 4. For injection site reactions (e.g., redness, pain, swelling, hypersensitivity reaction, injection site mass), ixekizumab had 15.6 times the number of expected reports. We also observed an unexpectedly large number of adverse event reports indicating colitis. The signal was stronger for ixekizumab with 5.1 times the number of reports expected, compared to 2.5 times the number of expected reports for secukinumab. The leading complaint about secukinumab was that the product either didn’t work or made the condition worse. In these early data we did not detect a signal for increased cancer risk, as we have previously reported for STELARA (ustekinumab).

Dupilumab

Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by binding to the IL-4Rα subunit. The drug is approved to treat adult atopic dermatitis, a skin disorder causing itchy, reddened skin and oozing blisters. The drug recently gained approval for use in certain forms of asthma. Clinical trial results showed that at 16 weeks, 36-39% of treated patients were clear or almost clear of atopic dermatitis; however, treatment also resulted in unexpectedly large numbers of reported eye inflammation and other ocular adverse effects. The first year of post-market surveillance confirmed and extended these safety signals for eye-related adverse effects.

Adverse event reports. We identified 3,778 adverse event reports for dupilumab, far more than the median of 393 cases for newly approved drugs. Eye problems were identified in 1,131 (30%) of the adverse event reports, or 7.2 times the number expected compared to all other drugs. Reported events included conjunctivitis (n = 383), inflammation or redness (n = 217), itchy eyes (n = 244), irritation (n = 138), dry eyes (n = 165), and excessive tearing (n = 104). Only 10% of the reports about eye problems were coded as medically serious, about the same as all adverse event reports for this drug. The Prescribing Information (PI) for dupilumab includes a warning about eye problems but does not clearly state that eye problems can occur in 1 in 3 patients over a year’s treatment. The Patient Information section of the PI also provides only a limited mention of eye problems.

Conclusions

The new biological products reviewed in this report illustrate an important truth about many new drugs: Although new drug sponsors are primarily focused on the main effect of the drug on a disease target, drugs have many other effects throughout the body. Notably, dupilumab has a positive effect on atopic dermatitis but a substantial negative effect on the eyes. Secukinumab and ixekizumab produce a substantial benefit for psoriasis but a possible harmful effect on another autoimmune disorder, colitis. A second important consideration is the absence of data on the long-term risks of these potent immunosuppressants. Several risks of potential harm from immunosuppression, such as serious infection and cancer risk, have not been adequately studied beyond 1 year. 

For dupilumab, we believe that FDA and the manufacturer should review and strengthen the warnings for eye disorders. Current warnings in the prescribing information understate not only the findings in these new adverse event data, but also the risks seen during clinical trials. Evolocumab and alirocumab have a dramatic effect in lowering LDL, but clinical trials revealed smaller than expected benefits in reducing cardiovascular risks, and no measurable benefits for cardiovascular deaths. For secukinumab and ixekizumab, better measurement of the long-term extent to which these medications increase the risks of serious infection, other autoimmune disorders, and cancer is needed, along with a comparison of their safety profiles to other drug treatments for psoriasis.

The full QuarterWatch™ report with references can be found at: www.ismp.org/node/482.