QuarterWatchâ„¢ (second quarter 2011) Signals identified for fingolimod and inFLIXimab
April 5, 2012

QuarterWatch (second quarter 2011)
Signals identified for fingolimod and inFLIXimab

QuarterWatch is an ISMP surveillance program that monitors all serious, disabling, and fatal adverse drug events reported to the US Food and Drug Administration (FDA) by drug manufacturers and by the public through the agency’s 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 we judge 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.

Reporting totals and trends

In the second quarter of 2011, FDA received 40,222 reports of domestic, serious adverse events, including reports of 6,617 patient deaths. The total number of reports was similar to the previous quarter but 20% higher than the same quarter in 2010. The trend continued with increasing numbers of reports from drug manufacturers and a more rapid increase in reports from consumers than from health professionals.

ADE signals for selected medications

Fingolimod (GILENYA). Fingolimod, a drug used to treat multiple sclerosis (MS), exhibits a novel immunosuppressant effect achieved by inhibiting lymphocytes from exiting lymph nodes (sphingosine-1-phosphate receptor blocker). This effect has been shown to reduce the frequency of MS exacerbations. Fingolimod provides benefits not available from other treatments; most notably, it is administered orally and has superior results for MS relapse prevention and progression. However, the drug is also associated with substantial risks that raise the question of whether it is safe for unrestricted use. 

Clinical testing of fingolimod prior to FDA approval revealed safety issues that might have halted the development of the drug if it had been indicated for another disorder with a less serious long-term prognosis. The drug was initially tested in 2.5 mg and 5 mg doses as an immunosuppressant to prevent renal transplant rejection. Development was halted because toxicity, including eight cardiovascular deaths, exceeded the benefits observed. When Novartis sought to test the drug in lower doses for MS, FDA agreed only after insisting on additional safety precautions. During the trials, testing of a 1.25 mg dose was also halted due to serious adverse events including the death of two young patients, 23 and 29 years old, from opportunistic infections, as well as six vascular events. However, approval was “fast tracked” for the 0.5 mg dose to speed the availability of this new type of immunosuppressant for the treatment of MS, despite this safety record.

Numerous adverse effects were reported during premarket trials. As occurred with some other immunosuppressants, serious and fatal infections were reported, particularly herpes infections, lower respiratory tract infections, and unusual infections of the ear, sinus, and eye. The drug caused macular edema, including cases involving loss of visual acuity or hospitalization. Other forms of eye injury were observed, including swelling of the optic disk, retinal thrombosis, and retinal detachment. Lung function was decreased in treated patients, and 8% of patients taking the recommended dose had laboratory evidence of liver damage, although routine liver testing is not currently recommended. One prominent side effect was a sudden drop in heart rate after the first dose, sometimes so severe that intervention was required to prevent harm. To address this risk, monitoring for the first 6 hours after starting the medication is recommended. The drug also caused birth defects.

Problems of widespread toxicity already evident in clinical testing are now producing strong signals post-market. In the second quarter of 2011 we identified 286 cases of reported serious adverse effects, including six deaths, eight cases of permanent disability, indications of liver damage, disruption of normal heart rhythm, vaginal hemorrhage, cognitive disorders, and a variety of symptoms suggesting MS relapses. Notable among the 286 cases were 60 cases of injuries to the retina and other effects on vision, including macular edema or degeneration, hyperemia, hemorrhage, swelling, infection, and blindness. The adverse events also included 68 reports of infections at various sites including the eye, skin, urinary tract, and upper respiratory tract. Possible complications of its vascular adverse effects included reports of blackouts or syncope, hypotension, bradycardia, and peripheral edema. 

Assessments in prominent medical journals in the US and France have questioned whether fingolimod should be available without restriction. All doses higher than 0.5 mg proved too toxic for human use. Given that toxicity appears dose-dependent, it raises the question of whether fingolimod should have been tested at a lower dose to see if efficacy could be maintained with a reduction of adverse effects. The FDA is now requiring the study of a 0.25 mg dose to be completed by 2015, along with nine additional studies to address other unanswered safety questions. For now, at a minimum, we believe FDA and the manufacturer should consider substantial restrictions on the use of fingolimod as well as enhanced monitoring.

InFLIXimab (REMICADE). InFLIXimab is a genetically engineered biological product that inhibits tumor necrosis factor (TNF), a signaling protein in the immune system. It is approved as a first- or second-line treatment for several autoimmune disorders, notably rheumatoid arthritis, Crohn’s disease, and plaque psoriasis.

In the second quarter of 2011, inFLIXimab generated a signal for five severe side effects: life-threatening brain infections, cancers, severe liver toxicity, a lupus-like autoimmune syndrome, and nerve cell damage similar to multiple sclerosis. We identified 843 cases of serious injury, including 33 patient deaths, six cases of permanent disability, two birth defects, and 10 cases identified as life threatening. Of particular concern were 13 possible cases of lymphoma and a series of infections including histoplasmosis (5), tuberculosis (5), herpes (10), and progressive multifocal leukoencephalopathy (8).

Although four other anti-TNF products are now available, inFLIXimab has accounted for a disproportionate number of serious adverse event reports overall since its approval 14 years ago. In a review of FDA’s 1998-2005 Adverse Event Reporting System (AERS) data, inFLIXimab ranked third among all monitored drugs for the number of reported serious non-fatal adverse events, and first among biological products. In the 2010 annual QuarterWatchreport, it ranked third among all monitored drugs, and in 2011 (quarter 2), it ranked second with 843 cases.

For information and context, we provide the second quarter data for inFLIXimab and three of the four other biological products in Table 1 (see PDF version of newsletter). The newest anti-TNF product golimumab (SIMPONI) did not have enough reports for a useful comparison. On one hand, these data demonstrate that severe side effects are being reported for nearly all the anti-TNF products. On the other hand, while three months of data are not sufficient to support a full analysis of comparative safety, there could be important implications if one or more of the products in this class were measurably safer, or if they varied in the type of side effects with which they were associated.

The FDA’s regulatory response over the years has been an increasing number of prominent warnings added to the prescribing information for all the anti-TNF products—so called class warnings. These warnings included opportunistic bacterial infections including tuberculosis, invasive fungal infections, reactivation of hepatitis B infection, as well as an increased risk of heart failure, various cancers including lymphomas, and severe liver damage including acute liver failure requiring transplantation for survival. However, the class warning strategy does not provide useful information to permit clinicians to select the safest drug within the class for each patient.

While inFLIXimab and four other anti-TNF biological products have beneficial effects in a range of autoimmune disorders, they are also associated with the risk of severe adverse effects. We believe new research is needed to evaluate the comparative safety profiles of the five agents to identify the safest drug for various immune disorders. In the meantime, doctors and patients should be aware that these products have mostly second-line indications, meaning they should be used only when safer alternatives are ineffective or inappropriate.


Dabigatran (PRADAXA). Dabigatran, an anticoagulant intended to reduce the risk of stroke, was a suspect drug in 856 reported cases, more than any other regularly monitored drug, although less than the first 2011 quarter total of 931 reports. The new quarterly total included 117 reported patient deaths and 511 reported cases of hemorrhage. Hemorrhage cases were reported once again in the oldest patients, with a median age of 80 years. One-quarter of these patients were 85 years or older. Current dabigatran prescribing recommendations appear to be leading to hemorrhagic events in the oldest patients.

Metoclopramide. A total of 4,237 reports from lawsuits targeted metoclopramide, dwarfing new legal claims against all other drugs. (YAZ [drospirenone and ethinyl estradiol] was second, with 2,032 new legal cases reported.) Metoclopramide, which is used to treat reflux and other gastrointestinal disorders, can cause potentially irreversible neurological brain damage in the form of tardive dyskinesia that results in uncontrolled, involuntary movements of the lips, tongue, eye, and limbs. There are no known treatments, although some patients improve after drug discontinuation. While FDA has required this drug to carry some of the strongest boxed warnings that we have seen, these actions have been insufficient to reduce the toll of injury apparent in these reports. With safer alternatives available, we continue to believe that further regulatory action is still needed to restrict this drug or withdraw it from the market. 

Additional details, including concerns regarding a low reporting rate (1%) of some serious adverse events to FDA and difficulties with distinguishing between serious and non-serious events, can be found in the full QuarterWatch report at:

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