Will Recent ISMP QuarterWatch Report Prompt FDA Regulatory Action, Including Possible Drug Label Change By Novartis?
(Posted by Tom Lamb at DrugInjuryWatch.com)
The FDA approved Entresto™ (sacubitril and valsartan) tablets in July 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
In the original and still current Prescribing Information for Entresto (Revised 8/2015 and accessed 11/21/17), at Part 5 “Warnings and Precautions”, already has some text and data about incidents of low blood pressure in some patients using this rather unique heart failure drug:
5.3 Hypotension
ENTRESTO lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at greater risk. In the double-blind period of PARADIGM-HF, 18% of patients treated with ENTRESTO and 12% of patients treated with enalapril reported hypotension as an adverse event [see Adverse Reactions (6.1)], with hypotension reported as a serious adverse event in approximately 1.5% of patients in both treatment arms. Correct volume or salt depletion prior to administration of ENTRESTO or start at a lower dose. If hypotension occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia). If hypotension persists despite such measures, reduce the dosage or temporarily discontinue ENTRESTO. Permanent discontinuation of therapy is usually not required.
Despite this cautionary language, the November 1, 2017 edition of ISMP QuarterWatch, a publication from the Institute for Safe Medication Practices, reports that a so-called “drug safety signal” has been detected recently for Entresto as regards hypotension being a serious side effect which warrants more attention — and, perhaps, and an increased warning.
Relying upon “New data from 2017 Q1” of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), this leading drug safety publication ends its recent report on Entresto with these statements in the final Conclusions section:
This large volume of reports of hypotension confirms the concerns of FDA reviewers that the [Entresto (valsartan-sacubitril) clinical trial results in carefully selected patients underestimated the risk of hypotension in normal clinical practice. As we noted, the risk is so prominent that about 1 out of 4 patients started on [Entresto] will experience a hypotension-related event.
We recommend that the FDA and [Novartis Pharmaceuticals Corporation] the manufacturer [of Entresto] more clearly communicate the full risk of hypotension, including appropriate steps for monitoring patients, and examine whether a more gradual escalation of dose to the recommended level would reduce the risk.
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This November 2017 ISMP QuarterWatch Entresto safety analysis article provides more detail about the number of hypotension reports made to the FDA in the section titled “The FAERS Data”:
In the 12 months ending March 2017, we identified 6,770 adverse drug event reports for [Entresto (sacubitril-valsartan)], including 681 (10%) patient deaths on one extreme, but 4,131 (61%) cases that were coded as occurring but with no medically serious consequences. The reported adverse reactions included medically important adverse events also seen in the large clinical trial, including renal failure and impairment (n = 317 PRR = 3.19), angioedema (n = 152 PRR = 5.63), and hyperkalemia (n = 87; PRR = 11.51). However, the most frequently reported adverse reactions were hypotension-related events (n = 1,684 PRR = 4.8).
At an easier to understand level, this new Entresto drug safety issue is presented in the Executive Summary part of this November 2017 ISMP QuarterWatch publication as follows:
[T]he signal investigated for this report suggested that many patients starting on this new drug [Entresto] were experiencing hypotension (low blood pressure), and the reported complications ranged from dizziness to blackouts and other consequences serious enough to require hospitalization. We identified 1,684 adverse event reports indicating a hypotension-related event, more than for any other cardiovascular drug we monitored over the 12 months ending in 2017 Q1. They occurred in older patients (median age 70 years), and although there were 69 reported deaths, in two-thirds of the cases, the health consequences were not severe.
Further investigation showed this adverse event was known, but likely underestimated in the single large clinical trial that supported [Entresto’s] FDA approval. In that study, 24.4% of carefully selected patients experienced a hypotension-related adverse event. But FDA reviewers noted this was likely an underestimate because this enriched trial was conducted only with patients already known to tolerate the study drugs without experiencing adverse events severe enough to cause discontinuation.
We will be watching the see whether the FDA takes any regulatory actions concerning Entresto or whether Novartis requests permission from the FDA to make a label change strengthening the warning about the apparent increased risk of this hypotension Entresto side effect.
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