A WHITE PAPER REPORT BY MASS TORT NEXUS
(The following information and conclusions are based on opinions formed after a review of relevant facts and data by John Ray and edited by Lisa Powell, Mass Tort Nexus www.masstortnexus.com)
XARELTO LABEL CHANGE AND CLINICAL TRIAL BACKGROUND
On October 11, 2018, Janssen Pharmaceuticals, Inc. (a division of Johnson & Johnson) changed its Xarelto® drug safety label as follows:
Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) for anti-factor XA (FXa) activity is not recommended.
Rivaroxaban is an anticoagulant medication. Anticoagulants thin blood. Rivaroxaban is sold under its trade name, Xarelto®. Xarelto® is used to prevent and/or treat blood clots that could result in strokes in patients with non-valvular atrial fibrillation, in patients undergoing knee and hip reconstruction or replacement surgery, and for secondary prevention in patients who have had an Acute coronary syndrome event.
Prior to FDA approval in 2011, clinical trials were conducted to test the safety and efficacy of Xarelto® and to compare it to other anticoagulants. Trial administrators measured both the medication’s effectiveness in thinning the blood and how long it took to be within the therapeutic range. A blood test is used to measure the international randomized ratio (INR). The INR was used to determine the appropriate dose and dosage (i.e., amount and rate of administration) specific to each patient; or, in this case, each trial participant.
The safety label update made last week by the drug maker, Janssen Pharmaceuticals, Inc. (a division of Johnson & Johnson) in effect states that the INR test used to gain FDA approval—and that doctors continue to use to dose and monitor the effects of Xarelto® in their patients—is arguably defective. Not only would this render the clinical trial results invalid but also bolster plaintiffs’ new and existing claims that the drug maker(s) failed to adequately inform doctors that there was no means by which to determine the correct dose and dosage for any given patient. Essentially a doctor would have to wait until the patient bleeds out or throws a clot before determining that the patient may not be on the right dose and/or dosage. In other words, the INR test likely has no diagnostic value and is no more effective than a shot in the dark.
Summary of Facts and Subsequent Findings
- On October 11, 2018, the Xarelto® drug safety label was changed to “not” recommend INR testing to monitor the effects Xarelto® on patients
- INR testing was used in clinical trials to establish the safety and efficacy of Xarelto® and to compare it to other anticoagulants prior to FDA approval and market release in 2011
- Title 21 of the U.S. Code of Federal Regulation requires that drug labels include a summary of essential scientific information including a statement of the recommended or usual dosage
- Results from Xarelto® clinical trials using INR testing are at best, questionable, and at worst, invalid
- A change to the Xarelto® drug safety label likely indicates that the drug makers failed to adequately warn that there was no means by which to determine correct dosage for any given patient
- A pharmaceutical product for which correct dose and dosage cannot be established for a given patient is arguably defective in a significant way
- Physicians that rely on INR testing without knowing that it may render inaccurate results could lead them to incorrectly dose Xarelto® potentially causing significant harm to their patients
Methodology Flaws in the Xarelto Clinical Trials
INR testing was used in the original Xarelto® clinical trials known as the ROCKET-AF and EINSTEIN DVT/PE trials. These trials were paid for by the drug makers—Bayer Healthcare and Janssen Pharmaceuticals, Inc. (a division of Johnson & Johnson). These trials were conducted to establish the safety and efficacy of Xarelto® and to compare it to other anticoagulants.
The following is an excerpt from the EINSTEIN DVT/PE clinical trial results:
EINSTEIN DVT/PE trial design: Randomized, phase 3, multicenter, open-label, parallel group,
active-controlled, event-driven noninferiority studies (EINSTEIN DVT and EINSTEIN PE) with patients receiving XARELTO® at an initial dose of 15 mg twice daily with food for the first 3 weeks, followed by XARELTO® 20 mg once daily with food or enoxaparin 1 mg/kg twice daily for at least 5 days with VKA, then VKA only after target INR (2.0-3.0) was reached. Patients were treated for 3, 6, or 12 months at HCP discretion.
In other words, Xarelto® was administered to trial participants and after a target INR was reached, they received a different anticoagulant—a VKA (i.e., vitamin K antagonist).
Given the drug safety update added to the Xarelto® label by Janssen on October 11, 2018:
Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) for anti-factor Xa (FXa) activity is not recommended.
Results from Xarelto® clinical trials using INR testing are at best, questionable, and at worst, invalid.
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In May 2017—17 months before Janssen changed the Xarelto® label—Clinical Therapeutics, an international peer-reviewed journal, published an article entitled, “International Normalized Ratio Is Significantly Elevated with Rivaroxaban and Apixaban Drug Therapies: A Retrospective Study Published.” An excerpt from the article follows (emphasis added):
Direct factor Xa inhibitors such as rivaroxaban or apixaban may prolong prothrombin time (PT) and elevate international normalized ratio (INR). However, these tests are not reliable for assessing the anticoagulation effects of these agents. PT assay sensitivity is relatively weak at therapeutic drug concentrations and is subjected to significant variations depending on the reagent used. Conversion of PT to INR may even increase the variability. We conducted a retrospective cross-sectional study aiming to assess the prevalence and extent of INR elevation in hospitalized patients receiving rivaroxaban or apixaban as part of their home medications and to find out whether other existing factors could elevate INR apart from the drug entity itself. [Emphasis added.]
The data collected from 218 hospitalized patients׳ charts included PT and INR taken on admission, patients׳ characteristics, laboratory results, other medications regularly used, and coexisting clinical conditions.
No statistically significant association between INR elevation and the parameters examined was found in our study. INR was significantly elevated in both drug groups (P < 0.001), with 84.2% of rivaroxaban patients and 78.3% of apixaban patients presenting with INR levels above the higher limit of the normal range. Furthermore, INR was significantly higher in the rivaroxaban group than in the apixaban group (P < 0.001).
Both of the reviewed drugs significantly elevated INR. Moreover, rivaroxaban elevates INR significantly more than apixaban, and there are apparently no other factors affecting INR but the drugs themselves. Larger prospective studies are needed to confirm and clarify the clinical significance of these results.
In that the common tests used to determine the correct administration of Xarelto® are not recommended by the drug maker, how are doctors to determine what dose and dosage of Xarelto® is correct vs. what dose and dosage may render a patient over anticoagulated and more likely to experience severe bleeding, or under anticoagulated, leaving patients more likely to suffer the adverse events Xarelto® is intended to treat?
In other words, doctors have relied on—and may continue to rely on—the test that the makers of Xarelto® now say is not recommended to determine the blood-thinning effects of the drug without knowing that these tests were likely rendering inaccurate results which could lead to their treating patients in a manner likely to cause them significant harm.
If the means to determine the correct dosage to administer to a given patient does not exist, the product is arguably defective. In addition, it would be impossible for a drug maker to comply with the requirements of Title 21, as follows:
21 CFR § 201.56 (a)(1): The labeling must contain a summary of the essential scientific information needed for the safe and effective use of the drug.
21 CFR § 201.100(b)(2): Requires labels for prescription drugs bear a statement of the recommended or usual dosage.
Janssen’s Misleading Advertising Campaign
There are three types of anticoagulants used in the United States. Xarelto® is a direct factor Xa inhibitor type. Benefits claimed by its U.S. manufacturer, Janssen Pharmaceuticals, Inc., include once daily administration of an oral pill, no dietary restrictions, and less testing requirements resulting in fewer blood draws. Warfarin, another type of anticoagulant, is a vitamin K inhibitor. If a patient’s blood becomes too thin after taking warfarin, vitamin K is administered to reverse its blood-thinning effects (i.e., an antidote or reversal agent). While the INR measurement is an effective test to dose and monitor warfarin in patients, Janssen’s advertising campaign touting less testing requirements for Xarelto® as a benefit is laughable given that the INR test used repeatedly to demonstrate the safety and efficacy of Xarelto® “is not recommended.” Until early 2018—approximately seven years after its market release–Xarelto® did not have a reversal agent, and to date, there is not a “recommended” test for doctors to accurately dose and monitor the effects of Xarelto® in their patients.
In 2014, the FDA required Janssen to add new language to its official warnings and precautions including an update to its “black box” because the test equipment used to measure the INR during clinical trials was deemed faulty. The black box is the strongest and most urgent FDA warning added to an official drug label. The update notifies patients and caregivers about certain risks and potentially dangerous side effects from Xarelto®. A year earlier, the FDA cited Johnson & Johnson for its misleading advertising campaign in contradiction to U.S. laws and regulations.
According to Recall Center, a consumer protection organization:
Since the drug’s release, there have been multiple updates to the label warning users of possible risks. In 2013, the FDA issued a determination letter to Johnson & Johnson advising them that their print advertising published in WebMD magazine earlier that year was misleading. They cited the following deficiencies:
- Effects of the drug to potential patients were downplayed
- Efficacy claims appeared to be disassociated from the potential risks
- Assertions that Xarelto has “no dosage adjustments,” which the FDA noted is inaccurate according to the product information’s section on warnings and precautions, as well as its section on dosage and administration.
Because of these allegations, the FDA declared Johnson & Johnson to be in violation of U.S. laws and regulations that oversee drug marketing. [U.S. Food & Drug Administration. “Letter to Roxanne McGregor-Beck, RE: NDA #202439.” (June 6, 2013) FDA.gov. Accessed Oct. 27, 2014]
According to a 2017 PR Newswire press release published by Business Insider (emphasis added):
Johnson & Johnson (NYSE: JNJ), Janssen Pharmaceuticals and Bayer Healthcare (OTC: BAYRY) are accused of downplaying the risks of taking Xarelto and aggressively marketing the drug as an alternative for warfarin in patients needing blood thinners to reduce the risk of dangerous clots. The companies positioned the drug as more convenient, calling for a once-a-day dose and eliminating the need for regular monitoring of a patient’s blood. However, the lawsuits charge that doctors and patients were not fully informed of the risks.
While Janssen’s Xarelto® advertising campaign claims:
And with XARELTO® you can
- Spend your time how you want to spend it, with no regular blood monitoring
MISLEADING. A more accurate statement would arguably be:
Regular blood monitoring would be useless because it will not identify whether a patient is under anti-coagulated [i.e. clotting too much] or over anti-coagulated [i.e., bleeding too much].
- Enjoy a full variety of healthy foods with no known dietary restrictions
- Know it’s working, with no frequent dosage adjustments
MISLEADING. A more accurate statement would arguably be:
There is no means by which to determine if a dosage adjustment is needed in that the common tests to make such a determination are inaccurate in patients who have been administered Xarelto®.
It bears repeating:
A pharmaceutical product for which correct dosage cannot be established or determined for any given patient is arguably defective in a significant way.
With Testing, Rat Poison Can Be Correctly Dosed for Benefit
There may be no better example of why correctly dosing an anticoagulant is important than warfarin. Warfarin first came into commercial use as a rat poison in 1948. Correctly dosed, warfarin is an effective anticoagulant for humans; incorrectly dosed, warfarin is poison.
Unlike Xarelto®, INR testing is reliable for dosing warfarin. To optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required. During the initial stage of treatment, the INR is checked daily. Intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose. Newer point-of-care testing is available and has increased the ease of INR testing in the outpatient setting. Instead of a blood draw, the new INR point-of-care test involves a simple finger prick.
Therefore, an anticoagulant that cannot be accurately dosed is arguably not as safe as rat poison.
The foregoing is an observation of statistics and data related to Xarelto®. The conclusions contained herein are based on opinions formed by the author after a review of the relevant data. We acknowledge that others could draw differing conclusions and opinions based on the same observations.