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QuarterWatchTM (2017 Annual Report): Four Severe Adverse Events and the Leading Suspect Drugs

In the latest issue of ISMP’s QuarterWatch, we examine a full year of adverse drug event reports received by the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) during 2017, to identify the most frequently named suspect drugs in four distinctive and severe adverse drug events:

  • Rhabdomyolysis, the destruction of skeletal muscle cells accompanied by the release of cellular proteins into the blood, with a substantial risk of causing acute renal failure
  • Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS), neurologic disorders caused by drugs that trigger abnormal serotonin levels (with SS) or block dopamine (with NMS), which results in aberrant behavior and thought, muscle spasms, and compromises to the autonomic nervous system
  • Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), a disorder in which the body’s immune system attacks and destroys the skin, producing a condition similar to severe burns
  • Progressive multifocal leukoencephalopathy (PML), an often fatal viral infection of the brain that occurs when immunosuppressive drugs or human immunodeficiency virus (HIV) compromise the body’s ability to hold a prevalent virus in check

While these disorders are thought to be relatively uncommon, at least in severe forms, their true incidence is unknown. The 4,631 cases of these adverse drug events reported to FDA in 2017 (Table 1), some of which were fatal, do not provide reliable insights into how frequently they may occur in exposed patients. All four adverse events are distinctive medical emergencies, and most are rarely confounded by signs and symptoms of the underlying medical problem being treated. Thus, the proportion of cases occurring that are subsequently reported for these disorders could be higher than for more typical and potentially elusive adverse drug events. While common adverse drug events like nausea often have many causes, with these four disorders, drugs are by far the most prominent cause. Thus, the key components of treatment are to manage the symptoms and identify and discontinue the causal drug.

Table 1. Cases reported to FDA for four severe adverse drug events, 2017
Adverse Drug Events Number of Cases Mortality Rate (%)
Rhabdomyolysis 1,549 12%
Serotonin and neuroleptic malignant syndromes 1,485 11%
Stevens-Johnson syndrome/toxic epidermal necrolysis  1,178 18%
Progressive multifocal leukoencephalopathy 419 29%

Rhabdomyolysis

Causes and symptoms. Many drugs have the unwanted ability to damage and destroy skeletal muscle cells. When this happens, the cells disintegrate and release their contents, including creatine kinase and myoglobin, into the bloodstream. If cell destruction is extensive, renal failure is possible if the kidneys cannot filter out the large quantities of cellular proteins that have been released. Notably, this is the most extreme subset of the spectrum of muscle damage induced by therapeutic drugs. Signs and symptoms of rhabdomyolysis include elevated creatine kinase, muscle pain, dark urine (from myoglobin), fever, vomiting, and muscle cramping. The release of calcium, potassium, and sodium from disintegrating cells can also trigger potentially life-threatening arrhythmias.

Suspect drugs. Rhabdomyolysis was notable for a substantial number of drugs implicated and the large population of patients exposed to this adverse drug event. The 25 drugs identified as having the strongest signals for rhabdomyolysis in 2017 are listed in Table 2. Overall, 179 different drugs were linked to 2 or more reports of rhabdomyolysis. Statins accounted for the largest proportion of cases. All the major statins were implicated, although not all met our criteria as a strong signal (10 or more cases). Also prominent were 7 of the most widely prescribed antipsychotic drugs. Most of these cases were secondary to another life-threatening adverse drug reaction, NMS (see details in the next section).

While many of the drugs in Table 2 were already known suspects, we also identified two novel and more recently approved suspect drugs, nivolumab (OPDIVO) and sacubitril/ valsartan (ENTRESTO). Nivolumab is among a group of new immune checkpoint inhibitors that block a key signaling protein (PD-1), opening tumor cells up to attack by T-cells. Growing evidence shows treatment can also result in additional T-cell attack on muscles and organs. Sacubitril/valsartan, a new combination product for heart failure, showed evidence of possible muscle harm during clinical trials.  

Table 2. Strong signals for rhabdomyolysis, 2017
Suspect Drugs Cases Suspect Drugs Cases
Statins 264 Anticonvulsants 77
atorvastatin 114 levETIRAcetam 64
simvastatin 97 lamoTRIgine 13
rosuvastatin 53 Antineoplastics 40
Antipsychotics* 184 nivolumab 25
ARIPiprazole 83 trabectedin 15
QUEtiapine 23 Antidepressants 25
risperiDONE 19 sertraline 13
OLANZapine 19 venlafaxine 12
paliperidone 18 Other 68
cloZAPine 12
haloperidol 10 metFORMIN 20
Analgesics 86 DAPTOmycin 15
methadone 30 furosemide 12
acetaminophen 24 amLODIPine 11
pregabalin 17 sacubitril/valsartan 10
gabapentin 15

*Most of these cases were secondary to NMS

Serotonin Syndrome (SS) and Neuroleptic Malignant Syndrome (NMS)

Causes and symptoms. SS and NMS share many similarities. The onset of both syndromes can be rapid—within hours of drug consumption for SS, and within days for NMS. Both involve neurotransmitters that help mediate many bodily functions, and both may lead to life-threatening disruptions of the central nervous system (CNS), including erratic or irregular heartbeats, irregular breathing, altered mental status, and loss of control over body temperature, mostly fever. The most common symptom is clonus, which can be so severe that muscle cells are damaged, resulting in rhabdomyolysis.

Suspect drugs. One way that the syndromes differ is that SS is caused by drugs that can affect serotonin reuptake, and NMS is caused by drugs that block dopamine. The 19 drugs identified as having the strongest signals for SS in 2017 are listed in Table 3. Antidepressants, mostly selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs), accounted for the largest proportion of cases. But other drugs, including certain opioids, antipsychotics, and antiemetics that block serotonin receptors were also suspects. SS was infrequently caused by a single serotonergic drug at therapeutic doses. The most commonly reported causes were interactions between multiple serotonergic drugs, or accidental or intentional drug overdoses. The syndrome varies widely in severity and can range from mild symptoms such as hypertension to severe symptoms such as agitation, hallucinations, fever, vomiting, and spastic muscle contractions. The psychiatric symptoms can sometimes be mistaken for a worsening of the mental disorder being treated.

Table 3. Strong signals for serotonin syndrome, 2017
Suspect Drugs Cases Suspect Drugs Cases
Antidepressants 284 Antipsychotics 82
sertraline 63
venlafaxine 50 ARIPiprazole 37
FLUoxetine 35 QUEtiapine 31
escitalopram 29 OLANZapine 14
DULoxetine 26 Other 61
citalopram 22
vortioxetine 21
PARoxetine 20 linezolid 17
buPROPion 18 methylphenidate 12
Opioids 47 ondansetron 11
traMADol 37 lithium 11
tapentadol 10 sodium oxybate 10

 

The 7 antipsychotics that are strong suspects for NMS are shown in Table 4. ARIPiprazole accounted for the largest proportion of cases. We found a few dozen additional reported cases with strong signals for drugs whose primary mechanism of action does not directly block dopamine receptors, including valproic acid, lithium, sertraline, mirtazapine, and PARoxetine. NMS occurs at normal therapeutic doses, usually within a few days of starting treatment with (or switching between) antipsychotics or other drugs that affect neurotransmission. The syndrome can also occur upon abrupt withdrawal of drugs that block dopamine receptors. The hallmark symptoms are disturbed mental functioning, lead pipe muscle rigidity, and fever.

Table 4. Strong signals for neuroleptic malignant syndrome, 2017
Suspect Drugs Cases
Antipsychotics 497
ARIPiprazole 189
OLANZapine 95
QUEtiapine 77
risperiDONE 50
haloperidol 34
cloZAPine 31
paliperidone 21

 

Confusion between syndromes. The similarity in symptoms between the two syndromes often leads to confusion in diagnosis. The cases are also confounded by polypharmacy, such as consumers taking both an antidepressant and antipsychotic drug. Still another layer of complexity arises because some antipsychotic drugs have active effects on both dopamine and serotonin receptors, notably ARIPiprazole. Furthermore, FDA warnings for antidepressant drugs, such as PARoxetine, express uncertainty as to which of the two syndromes are expected to occur.

Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)

Causes and symptoms. SJS/TEN is a rare autoimmune disorder that causes T-cells and natural killer cells to attack and kill dermal cells, destroying the skin and causing a disfiguring and painful condition similar to severe burns. The outer skin layers slough off even when gently rubbed. The difference between SJS and TEN is the extent of body surface area (BSA) affected, with SJS limited to less severe cases in which less than 10% of the BSA is compromised. Recent studies suggest mortality rates range from 12% for the least severe cases to 49% for TEN cases with a larger BSA affected.

Suspect drugs. Drugs are the primary but not exclusive cause of SJS/ TEN, with more than 100 drugs implicated in published studies. In the 2017 adverse drug event data we identified 20 drugs with strong signals for SJS/TEN (Table 5). LamoTRIgine was the most frequent suspect drug. Cases were also reported for some of the most widely used over-the-counter therapeutic drugs (ibuprofen, acetaminophen, and omeprazole), several antibiotics/antifungals, and 3 recently approved oncology drugs (nivolumab, pembrolizumab, and cobimetinib) with smaller patient populations. While our strongest signals were linked to 20 drugs, we identified 134 additional drugs with 2 to 9 reported cases of SJS/TEN, including 4 of the most widely used antibiotics (amoxicillin, levoFLOXacin, clarithromycin, and azithromycin).

Table 5. Strong signals for Stevens-Johnson syndrome/toxic epidermal necrolysis, 2017
Suspect Drugs Cases Suspect Drugs Cases
Anticonvulsants 210 Analgesics 91
lamoTRIgine 128 ibuprofen 39
carBAMazepine 34 acetaminophen 39
phenytoin 22 diclofenac 13
valproic acid 13 Antineoplastics 72
levETIRAcetam 13 nivolumab 23
Antibiotics/Antifungals 105 pembrolizumab 20
sulfamethoxazole/ trimethoprim 50 lenalidomide 17
vancomycin 18 cobimetinib 12
Antipsychotics 16
ciprofloxacin 15 ARIPiprazole 16
Other 59
fluconazole 12 allopurinol 43
clindamycin 10 omeprazole 16

 

Progressive Multifocal Leukoencephalopathy (PML)

Causes and symptoms. PML is an often fatal viral infection of the brain that occurs when immunosuppressive drugs or HIV compromise the body’s ability to hold in check the widely prevalent John Cunningham virus (JCV), which lurks harmlessly in 50-70% of the population after initial infection, which usually occurs during childhood. Initial infection and later latency are without symptoms until the body is immunocompromised. This is caused mostly by monoclonal antibodies, which disables the body’s defense to JCV in some people and allows the virus to attack the brain’s white matter. Changes in behavior, confusion, aphasia, impaired gait, and visual disturbances follow. Published studies of small patient populations report incidence from about 1 per 1,000 patients taking natalizumab, to 1 per 32,000 patients taking riTUXimab.

Suspect drugs. In 2017 we identified 419 reported cases of PML with a fatality rate of 29%, the highest for any of the four disorders. Four drugs had strong signals (Table 6). Natalizumab was initially withdrawn from the market in 2005 after 3 patients died of PML during clinical trials but was reintroduced in 2006 with prominent and dire warnings and a restricted distribution program. Thus, it is likely that a greater proportion of PML cases for natalizumab are reported to FDA. RiTUXimab has a boxed warning for PML (and SJS/TEN, for which 9 reports were received in 2017). Fingolimod is available without the same highly prominent warnings or restrictions. PML is included as 1 of 11 warnings about severe adverse effects. Mycophenolate is associated with reactivation of numerous viral infections, including JCV, cytomegalovirus, and hepatitis B and C. Overall, 35 additional drugs were possible suspects, accounting for 2 to 9 case reports. 

Table 6. Strong signals for progressive multifocal leukoencephalopathy, 2017
Suspect Drugs Cases
natalizumab 154
riTUXimab 59
fingolimod 20
mycophenolate 10

 

Conclusion

This issue of QuarterWatch examined four of the most distinctive and severe adverse drug events. We found the strongest signals for more than 75 drugs associated with these disorders from a wide array of therapeutic classes, including some of the most widely used medications. More research is needed to identify why certain patients are vulnerable to these life-threatening disorders. However, the risks associated with a few drugs appear so disproportionate that safer alternative treatments should be considered. These drugs include:

  • Natalizumab, which led all other drugs in reported cases linked to PML
  • LamoTRIgine, which led all other drugs in reported cases linked to SJS/TEN and has also been linked to several other forms of hypersensitivity, sudden unexplained deaths, suicidal behavior and ideation, and blood disorders
  • ARIPiprazole, which ranked first as a suspect drug for NMS and was also a leading suspect for SS, rhabdomyolysis, and SJS/TEN, in addition to the toxicity it shares with other antipsychotic drugs

Several other findings stood out during the analysis. Atorvastatin, simvastatin, and rosuvastatin were most frequently associated with rhabdomyolysis; however, drug harm to skeletal muscle cells could be an underestimated risk, especially if the disorder does not lead to renal failure. Both consumers and physicians should be alert to less severe signs and symptoms of harm to skeletal muscle, including milder cases of muscle pain and elevation of creatine kinase. TraMADol was a suspect drug associated with SS, although physicians are often unaware that this opioid is also a serotonin reuptake inhibitor, sharing that mechanism of action with many antidepressants. Physicians should be alert to the possibility that concomitant use with most antidepressants could result in life-threatening episodes of SS.

FDA has devoted substantial scrutiny to these potentially lethal risks and insists that most suspect drugs include clear warnings in the prescribing information and consumer Medication Guides. However, the agency has no published method for assessing how frequently these adverse events occur, and which drugs are most often the suspect. Because these events are distinctive, severe, and mostly drug-related, they are excellent candidates for study in the agency’s Sentinel System or other electronic health record data system.

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

What is QuarterWatch™?

QuarterWatch is an independent ISMP surveillance program that monitors adverse drug events reported to the FDA Adverse Event Reporting System (FAERS).  The goal is to identify signals that may represent important drug safety issues. The sheer number of case reports have scientific weight, but because of variation in reporting rates, they reveal little about how frequently events occur and do not prove that the suspect drug caused the event described—only that an observer suspected a relationship. Thus, identified safety issues often require further investigation to determine their frequency and establish a causal relationship to the suspect drug.