November 2017 Volume 16 Issue 11 Quarter Watch ™ (2017 Quarter 1 Data) Safety signals for two novel drugs, Nuplazid and Entresto The latest issue of ISMP’s Quarter Watch ™ (see box) provides a review of Liraglutide dosage unit confusion. We drug safety issues identified through 297,010 new adverse drug event re - were notified recently by Surescripts, the ports submitted to the US Food and Drug Administration (FDA) Adverse electronic prescribing network that links Event Reporting System (FAERS) during the first quarter of 2017, including more clinicians, hospitals, pharmacies, and phar - than a quarter (26.8%) describing fatal or serious events in the US. In this report, we macy benefit managers, that some new focus on early adverse event data reported during the first quarter of 2017, along prescriptions for VICTOZA(liraglutide) and with data from three previous quarters, for two new drugs with novel mechanisms SAXENDA (liraglutide) pen injectors have of action that are intended for difficult-to-treat patient populations: contained inaccurate dosage information. The issue is the inappropriate use of “mL,” NUPLAZID (pimavanserin), approved in April 2016, provides a new biochemical “milliliters,” or “cc” as dosing units, rather approach to treating hallucinations and other symptoms of psychosis in Parkin - than “mg,” in the patient directions. For ex - son’s disease. We investigated a signal that the drug could be making the ample, Surescripts has identified orders symptoms worse in some patients. such as “inject 1.2 mL sub-q EVERY DAY” ENTRESTO (sacubitril and valsartan), approved in July 2015, targets a new instead of 1.2 mg. Since the concentration pathway involved in the regulation of blood pressure and appears to improve of liraglutide in both products is 6 mg/mL, mortality and cardiovascular outcomes in heart failure patients with reduced prescribing 1.2 mL instead of 1.2 mg results ejection fraction. However, hypotension-related events were reported in more in a 6-fold overdose (7.2 mg). The pen in - than 1,500 patients. jectors only display the dose in “mg,” al - though with both pens, the “mg” markings Nuplazid (pimavanserin) and Hallucinations are difficult to see ( Figure 1). (Note: Both Nuplazid was approved to treat hallucinations, delusions, and other symptoms of psychosis among patients with Parkinson’s disease after an internal FDA debate about whether its benefits outweigh its risks. The drug is now being tested for use in larger populations, including patients with Alzheimer’s disease and schizophrenia. Hallucinations in Parkinson’s. Approximately 1 million people in the US, mostly over age 65, have Parkinson’s disease, a movement disorder in which dopamine- Figure 1. The “mg” markings with the dosing producing neurons are progressively lost. Hallucinations can be induced by the windows on both the Victoza (top) and Saxenda drugs commonly used to treat Parkinson’s, notably levodopa, a drug typically given (bottom) pens are difficult to see. in combination with carbidopa, and dopamine agonists (e.g., pramipexole [ MI - Victoza and Saxenda pens allow doses to RAPEX ]). This, along with progression of the disease, means that approximately be dialed and modified, whereas other 50% of people with Parkinson’s will develop hallucinations and other symptoms of glucagon-like peptide-1 [GLP-1] receptor psychosis. The antipsychotics used to treat hallucinations in schizophrenia block the agonists have fixed doses.) normal function of dopamine, a problem for Parkinson’s patients who are already losing dopamine function. In addition, antipsychotics induce parkinsonian symptoms Surescripts has asked electronic health continued on page 2 —Quarter Watch > record (EHR) vendors to ensure that the dose creation tools provided to end-users do not allow “mL” as a dose unit option for What is Quarter Watch ™? Victoza or Saxenda. Should a free-text pre - Quarter Watch ™ is the publication of an independent ISMP surveillance program scription be necessary, the patient direc - that monitors adverse drug events reported to FDA by manufacturers, health tions should be typed accordingly with the professionals, and the public. The agency releases, for research and data analysis, dose unit in “mg,” and never in “mL” so excerpts of all domestic and foreign reports it receives into the FDA Adverse that correct labeling, counseling, and ad - Event Reporting System (FAERS). The goal is to identify signals that may represent ministration of the intended dose is en - important drug safety issues which often require further investigation to determine sured. Orders for Victoza or Saxenda with their frequency and establish a causal relationship to the suspect drug. continued on page 2— SAFETY briefs > November 2017 Volume 16 Issue 11 Page 2 > Quarter Watch —continued from page 1 in about 35% of patients and are not recommended for the elderly because of in - cont’d from page 1 creased mortality. Nuplazid was developed as an alternative that does not block or a “mL” dosage amount need to be clarified stimulate dopamine receptors, but instead blocks serotonin receptors (5-HT 2A ) that with the prescriber to verify the dose. may also contribute to hallucinations. However, these same serotonin receptors also play a central role in learning, memory, and cognition, and blocking normal sig - Differentiating insulin types by touch naling could result in significant adverse effects. and separate storage. A pharmacist told us about an insulin mix-up that her visually FDA approval. Initial FDA approval of Nuplazid was based on a single clinical trial impaired mother-in-law experienced. Her (normally two or more are required) that indicated a small treatment effect using a mother-in-law uses insulin pens for both new measurement scale. Three previous trials had failed to demonstrate a benefit in rapid-acting (insulin lispro) and long-acting reducing hallucinations and other symptoms of psychosis. FDA’s medical reviewer (insulin glargine) insulins at home. She recommended against the approval of Nuplazid. The reviewer noted that, although stores them together although she admin - other psychiatric drugs were often approved with limited evidence of benefit, in the isters the rapid-acting insulin 3 times a day case of Nuplazid, treatment had more than doubled the risk of death and/or serious with meals and the long-acting insulin at adverse events in its only positive trial. Despite these concerns, FDA approved the night. On two occasions, she has acciden - drug, explaining that while deaths and serious adverse events were increased in the tally given herself 50 units of the rapid-act - treatment group, the results were not definitive and occurred across numerous organ ing insulin instead of the long-acting insulin systems rather than through one or more identifiable drug-related mechanisms. at night. While 50 units is the correct dose for her long-acting insulin, it is a very large FAERS data. The leading adverse events reported during the 12 months ending in dose of the rapid-acting insulin given all at March 2017 were remarkably similar to the concerns previously raised by the FDA once. Both times, the pharmacist’s mother- medical reviewer and seen in previous clinical trials: hallucinations (n = 487), confu - in-law recognized her mistake and had to sional state (n = 258), deaths (n = 244), and complaints that the drug was ineffective stay up until early in the morning drinking (n = 333). In the case of hallucinations, which could be mistaken for a symptom of juice and checking her blood glucose levels worsening disease, we considered this a credible signal in part because the number frequently. The pharmacist happened to of reports outnumbered similar reports for all other drugs, including antipsychotics. be visiting the last time it happened. Despite It was also notable that 74% of the reports came from health professionals, who readings of about 100 mg/dL about 2 hours would be expected to be familiar with the symptoms and mortality of patients with after the mistake, her mother in-law still Parkinson’s disease psychosis, and therefore less likely to report these events unless woke up (fortunately) at 4 a.m. with a low a drug role was suspected. blood glucose value of 50 mg/dL. We also identified a new safety concern: concomitant use of antipsychotic drugs. After the first incident, the pharmacist and The reports revealed 318 cases of heavily medicated Parkinson’s patients (a median her mother-in-law talked about separating of 10 drugs) where Nuplazid had been added to other antipsychotic drugs (all but 7 the pens to prevent accidental mix-ups, cases were QUE tiapine [ SEROQUEL ]). No antipsychotic drugs have been approved but for logistical reasons, this would have for psychosis in Parkinson’s patients, although QUE tiapine is widely used. Now, it been challenging. She now wraps a hair appears that Nuplazid is being prescribed along with QUE tiapine, although combi - tie around the long-acting insulin pen so it nation therapy has never been tested ( QUE tiapine was banned in the Nuplazid “feels” different to her. While reading the clinical trials). In addition, both drugs are suspected of increasing mortality, and label each time is important, patients who each blocks a key signaling pathway in the brain, either serotonin or dopamine. have vision problems may have difficulty seeing the labels or stickers well. We shared our preliminary results with the manufacturer, Acadia Pharmaceuticals. The company said the large number of reports was in part due to its extensive Many years ago, various types of rapid- contact with health professionals and consumers through a specialty pharmacy net - acting, intermediate-acting, and long-act - work and patient support program. The company also suggested that the reports of ing insulins were packaged in vials that hallucinations might have occurred before the drug became fully effective 4 weeks were different from one another in shape after treatment started.