FDA Extends Xeljanz Safety Warnings to Other JAK Inhibitors

The FDA is requiring revisions about increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots and death to the labels of the Janus kinase (JAK) inhibitors indicated for inflammatory conditions: Pfizer Inc.’s Xeljanz/Xeljanz XR (tofacitinib), Eli Lilly and Co.’s Olumiant (baricitinib) and AbbVie Inc.’s Rinvoq (upadacitinib). The move follows the agency’s review of a large, randomized safety clinical trial of Xeljanz. The FDA also is limiting the approved uses for all the drugs to certain people who have not responded to or cannot tolerate at least one tumor necrosis factor (TNF) inhibitor. While some payers may already have had TNF inhibitors as a first step, they need to make sure that they have utilization management strategies in place to help ensure these drugs are used in the second-line setting, recommend industry experts.

The trial compared Xeljanz with TNFs in people with rheumatoid arthritis (RA) and showed an increased risk of blood clots and death with a lower 5 mg dose of Xeljanz. A prior study whose results Pfizer disclosed on Jan. 27, 2021, showed the same results but at a higher 10 mg dose. The study also showed a higher rate of lymphomas in people treated with Xeljanz as opposed to those treated with TNF inhibitors. In addition, it found a higher rate of lung cancers in current or past smokers on Xeljanz, as well as an increased risk of overall cancers in these patients, compared with those on TNF inhibitors.

The agency recommends that anyone on one of these therapies “should tell your health care professional if you are a current or past smoker, or have had a heart attack, other heart problems, stroke, or blood clots in the past as these may put you at higher risk for serious problems with the medicines. Patients starting these medicines should also tell your health care professional about these risk factors.” The FDA says it will require changes to “several sections” of the drugs’ prescribing information and patient medication guides.

While Olumiant and Rinvoq were not studied, they have the same mechanism of action as Xeljanz, so the FDA says they might have similar risks.

The FDA notes that it has approved two other JAK inhibitors: Incyte Corp.’s Jakafi (ruxolitinib) and Bristol Myers Squibb’s Inrebic (fedratinib). But because they are not indicated for inflammatory conditions, they do not have to update their prescribing information.

This isn’t the first time that the agency has warned about safety concerns with Xeljanz. On Feb. 5, 2019, the FDA issued a safety announcement around a clinical trial finding that showed people with RA on a 10-mg-twice-daily dose were at increased risk of blood clots in their lungs and death. The agency noted that it had approved this dosing regimen only in ulcerative colitis, not RA. On July 26, 2019, the agency issued another safety announcement, disclosing that it had approved a black box warning around this risk for Xeljanz’s label.

Still, as recently as last year, there were disagreements among rheumatologists as to JAK inhibitors’ place in the treatment of RA, points out Winston Wong, Pharm.D., president of the W-Squared Group. Articles from medwireNews and Rheumatology Advisor detailed the “Great Debate” of the American College of Rheumatology (ACR) Convergence 2020, held virtually Nov. 5-9, 2020, as being whether JAK inhibitors should be used before TNF inhibitors after an inadequate response to methotrexate:

“Introducing the topic, Elizabeth Wahl, from the University of Washington in Seattle, USA, said that the 2015 ACR guidelines recommend the use of tumor necrosis factor (TNF) inhibitors before JAK inhibitors following an inadequate response to conventional DMARDs [i.e., disease-modifying antirheumatic drugs), but ‘emerging data indicates that [JAK inhibitors] may be more effective than TNF inhibitors for the treatment of RA.’ Accordingly, in the 2019 update of the European RA treatment guidelines, EULAR [i.e., European Alliance of Associations for Rheumatology] did ‘not specify a treatment order between biologics or [JAK inhibitors]’ in RA patients with high-risk features and an inadequate response to conventional DMARD.”

In a poll after the debate, 69% of participants voted in favor of not using JAK inhibitors before TNFs, with 31% voting in favor of JAK use before TNF inhibitors.

The FDA initially approved Xeljanz as a tablet on Nov. 6, 2012, for the treatment of adults with moderately to severely active RA who have an inadequate response or intolerance to methotrexate. It’s now approved for three additional inflammatory conditions: for adults with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other DMARDs, for adults with moderately to severely active ulcerative colitis who have had an inadequate response or who are intolerant to TNF inhibitors and for active polyarticular course juvenile idiopathic arthritis in people at least 2 years old as an oral solution. An extended-release Xeljanz XR tablet also is available.

Other JAKs Are Seeing FDA Decision Delays

While the FDA was reviewing the Xeljanz data, it also delayed decisions on additional anti-inflammatory indications for currently marketed JAK inhibitors, as well as ones with initial applications at the agency. Decisions on Olumiant in atopic dermatitis, Xeljanz in ankylosing spondylitis and Rinvoq in atopic dermatitis, psoriatic arthritis and ankylosing spondylitis have been delayed throughout the year, as has a decision on the application for Pfizer’s abrocitinib in atopic dermatitis.

Renee Rayburg, R.Ph., vice president of specialty clinical consulting at Pharmaceutical Strategies Group, an EPIC company, points out that Rinvoq and abrocitinib both have marketing authorization for atopic dermatitis in the UK.

One anti-inflammatory JAK inhibitor, however, recently gained FDA approval following a delayed agency decision in June: Incyte’s Opzelura (ruxolitinib). On Sept. 21, the agency approved the drug — which is a topical version of Jakafi — for the short-term and non-continuous treatment of mild-to-moderate atopic dermatitis in non-immunocompromised people at least 12 years old whose disease is not adequately controlled with topical prescription therapies or when those treatments are not advisable. The product also has a black box warning around safety issues seen among JAKs used for inflammatory conditions.

Jakafi also received an additional indication on Sept. 22, but that was for chronic graft-versus-host disease.

“Although Opzelura is topically administered, with limited systemic absorption and distribution in pharmacokinetic/pharmacodynamics studies, the FDA still added the JAK inhibitor classwide boxed warning to its label,” observes Dea Belazi, Pharm.D., M.P.H., president and CEO of AscellaHealth. He notes that the product has a “somewhat narrow and restrictive label.” In addition to its short-term use in the mild-to-moderate setting, the label advises against its use with certain other agents. With its limits on use, the drug “will not likely be a therapeutic first-line option,” he says.

Opzelura’s labeling “implies that the safety issues associated with JAK inhibitors goes beyond the systemic route of administration (e.g., injectables and orals) for these products,” says Lynn Nishida, R.Ph., head of clinical operations at Evio. “And with even topical administration and acute treatment with a JAK inhibitor, the FDA is likely to err on the conservative side and view this as a class issue in requiring similar box warnings for cancer and cardiovascular risks regardless of how it’s administered.”

“Given there is a difference in systemic exposure with ruxolitinib cream vs. oral JAKs, approval of ruxolitinib does not shed much light as to the fate of the oral JAKs seeking an indication for” atopic dermatitis, says Robert Kinyua, Pharm.D., senior director of clinical program development at Prime Therapeutics LLC. “Additionally, ruxolitinib is for mild-to-moderate disease while oral JAKs were evaluated for moderate-to-severe disease, meaning the risk vs. benefit considerations are different between the cream and oral JAKs.”

However, asserts Belazi, “as the first JAK inhibitor approved after the FDA’s Drug Safety Communication, Opzelura’s labeling has set a precedent. JAK Inhibitors awaiting approval likely will be issued with the same JAK-inhibitor class-wide box warning with guidance for limiting use in specific patient populations as second-line therapy.”

Renee Baiano, Pharm.D., C.S.P., clinical program manager at AllianceRx Walgreens Prime, says it’s possible that the FDA could approve some JAK inhibitors in more severe inflammatory diseases but reject others in less severe inflammatory conditions. “A risk vs. benefit analysis is an important part of all new drug approvals,” she says.

According to Kinyua, if those drugs are approved, “they will likely be indicated for those with moderate-to-severe disease. What the FDA might do is require that they are used after failure of safer agents.”

Agency Has Been Under Scrutiny Lately

In treating the Xeljanz data as a class effect, Wong says he can’t say whether the FDA is being “overly cautious,…but given the amount of scrutiny they have been under lately since the approval of aducanumab, can you blame them?

“What is unknown, and in my opinion requires further investigation, is whether there is a difference in incidence based upon the specificity of the four JAK receptors being inhibited, as well as the strength of the inhibition,” he continues. And “should the warning be applied to the bone marrow disorders as well? Bottom line is that as the FDA sorts out the risk of adverse events, the current JAK inhibitors standing before the FDA for approval will most likely be delayed and, when approved, will most likely carry the ‘class’ black box and indication.”

Belazi agrees. “In the near future, the FDA is likely to stick with its decision to treat all JAK inhibitors the same. As a class, they will be considered to have the same potential risks as Xeljanz until proven otherwise regardless of disease severity.”

For the Managed Care Biologics and Injectables Index: Q2 2021, between May 18, 2021, and July 13, 2021, Zitter Insights polled 40 commercial payers with 129.5 million covered lives about the earlier study of the higher Xeljanz dose and its impact on their management of psoriatic arthritis and of the JAK/STAT inhibitors. Payers with almost 50% of covered lives said the study was highly influential.

Zitter Insights and AIS Health are both MMIT companies.

During the same time period, Zitter Insights polled 50 rheumatologists on how the study would impact their prescribing. They reported a higher impact than payers, with 64% saying it was highly influential on their psoriatic arthritis prescribing, and 56% said the same for JAK/STAT inhibitors.

The FDA’s action “in general…will cause pause by prescribers and patients for treatment with any of these” JAK inhibitors, says Nishida. “To that end, there will be ongoing dissension on whether topical Opzelura should have been included with systemic JAK inhibitors in receiving the same black box warning or not.”

Plans May Need to Alter Prior Authorization

Plans that placed the JAK inhibitors — which have a “slightly lower” cost than the TNF inhibitors before rebates — on par with the anti-TNFs will need to change their prior authorization criteria, states Wong.

Kinyua notes that the updated labels have not yet been published, and payers’ actions “will be heavily influenced by the language” in those labels.

In managing the JAK inhibitors in inflammatory conditions, Theresa James, Pharm.D., C.S.P., sales solutions director at AllianceRx Walgreens Prime, advises that payers “stay the course — most, if not all, payers currently require step therapy and/or prior authorizations for approval of JAK inhibitors for inflammatory indications.” Kinyua notes that guidelines do not recommend using JAKs before TNF inhibitors.

In addition to step therapy and prior authorization, James says that quantity limits are another strategy payers can implement to make sure the JAK inhibitors are used in the second-line setting.

Belazi also says that “current patients on JAK inhibitors should be re-evaluated to ensure that the patient is receiving an optimal drug therapy regimen for their medical condition.”

With the JAKs in inflammatory conditions, “payers need to construct their coverage policies to identify patients who may best benefit vs. when use may pose risk,” recommends Nishida. “It comes down to identifying unique situations of a patient’s medical circumstances and risks, realizing that we cannot treat everyone the same way with a one-size-fits-all medication treatment.” Using traditional utilization management tactics, as well as technology available at the point of prescribing, payers can “identify patients with comorbid conditions that may contribute to exacerbation of adverse events and the patient’s ability to tolerate the medications,” she explains.

JAK Use ‘Is Expected to Decline’

According to James, “due to the updated warnings and restrictions limiting the use of JAK inhibitors to second-line therapy, utilization is expected to decline.” Rayburg and Belazi say they agree that a decrease in the treatments’ use is anticipated.

Payers use treatment guidelines to put together utilization management criteria when managing the inflammatory therapeutic class in general, with an eye on keeping spend in check, says James. These strategies can ensure that people use traditional nonspecialty drugs before moving to specialty agents, “which not only come with high costs but can also be associated with increased side effects.”

Management of the class “will vary among different payers and is also dependent on the diagnosis,” says Belazi. “Typically, as part of payers’ utilization management programs, prior authorization and/or step therapy are generally used to ensure appropriate use to the payers or approved guidelines. Generally, the guidelines will vary slightly by indication or medical use but will utilize first-line agents, such as oral DMARDs, NSAIDs or corticosteroids, and then a TNF inhibitor, followed by other biologic therapies.”

When a person initiates treatment with methotrexate or another nonbiologic DMARD, explains Wong, “at this point in time, outside of an ICD-10 code on the medical claim, payers would not even be aware of these patients. Specifically from a pharmacy perspective, the immunologic patient is identified as the biologic therapy is initiated. Due to the cost of these medications, these drugs will all fall under a prior authorization program and specialty pharmacy distribution.”

Overall in the inflammatory conditions, “most payers have selected one or two products to represent different mechanisms of action,” says Nishida. “Very rarely would there be step therapy that required a JAK inhibitor before a TNF. Most payers recognize by medical policies the unique safety profiles for TNFs and JAK inhibitors and criteria that allows exceptions to be made for nonpreferred products because of patient individual circumstances and risk factors.”

The TNF inhibitors class is well-established in the U.S., with Remicade (infliximab) from Janssen Biotech, Inc., a Johnson & Johnson company, first gaining approval on Aug. 24, 1998, for Crohn’s disease, followed by Amgen Inc.’s Enbrel (etanercept) approval on Nov. 2, 1998, for RA and then AbbVie Inc.’s Humira (adalimumab) for RA on Dec. 31, 2002. UCB, Inc.’s Cimzia (certolizumab pegol) was approved for Crohn’s on April 22, 2008, and Janssen’s Simponi (golimumab) for RA, psoriatic arthritis and ankylosing spondylitis on April 24, 2009.

“While TNF inhibitor medications are good options with well-established safety profiles, not all patients respond or tolerate this class of medication,” says Baiano. “For example, about 20% to 40% of RA patients treated with a TNF inhibitor fail to achieve a 20% improvement according to criteria set out by the American College of Rheumatology.”

Belazi notes that among people initially responding to a TNF inhibitor, “secondary loss of response may prompt discontinuation of treatment in up to 50% of patients after 12 months on therapy. In RA, it was found that up to one-third of patients showed poor response to this treatment.” In addition, “anti-TNF agents are generally well tolerated, but it may also depend on the disorder. A comparison of two prospective safety cohorts of patients with RA and psoriasis found a much lower rate of serious adverse/mortal events in the psoriasis group compared to the RA group. Patients with RA had higher rates of infections, cardiac/respiratory disorders and infusion reactions (higher use of infliximab), while those with psoriasis had more skin/subcutaneous and hepatobiliary disorders.”

Because Jakafi and Inrebic were not included in the labeling updates, changes in payer management of those therapies are not expected, as it was already common practice to require prior authorization for these medications, says Jill Distad, Pharm.D., B.C.G.P., sales solutions director at AllianceRx Walgreens Prime. However, “ultimately…these drugs will likely be viewed by payers and providers through a different lens moving forward.”

“These two JAK inhibitors are used for myelofibrosis and polycythemia,” explains Wong. “At this time, I do not believe there will be any impact to these two agents, simply because we do not know if the risk carries over. From a pathophysiology perspective, there may be factors associated with immunologic conditions that create the additional risk for serious heart-related effects that may not be present in bone marrow dysfunction patients.”

In its Drug Safety Communication, the FDA said that if it “becomes aware of any additional safety information or data that warrants updates to the prescribing information for these medicines [i.e., Jakafi and Inrebic], we may take further action and will alert the public.”

Payers Should Reach Out to Prescribers, Pharmacists, Members

Asked if payers should be reaching out to members and providers about the FDA warning, Distad replies that “it’s best practice for payers to make providers (both prescribers and pharmacies) aware when the FDA issues Drug Safety Communications. As for member outreach, payers certainly don’t want to cause the patient any distress or concern. Patients and providers should discuss the safety of the drug and whether or not it is an appropriate treatment. Payers and pharmacies both should be prepared to answer questions from concerned members, always ensuring them it’s best to follow up with their provider to further discuss their course of treatment.”

“This is a black box warning; thus, I do believe patients should be notified,” says Wong. “This message should be clear that the FDA has identified the risk of serious adverse effects; however, they should not stop taking their medication without first consulting their physician. Health plans should also be providing a list of patients to whom they had prescribed a JAK inhibitor for an immunologic condition.”

Belazi agrees that payers should reach out to providers over the JAKs’ safety risks to “help reinforce their education regarding the adverse events seen with this class of drugs and to ensure appropriate use of this class of drugs for their patients.” In addition, reaching out to members on one of these drugs “is also encouraged and will help patients consult with physicians on the appropriate treatment course for the patient.”

“As with any new drug that comes to market or when new safety warnings are added, patients who have questions should not hesitate to talk with their provider,” says Distad. Specialty pharmacies also can answer patient questions, including ones around dosing or possible side effect, and can direct people to programs that can help with their adherence and, in turn, improve their outcomes.

For more information on the Zitter data, contact Jill Brown Kettler at jbrown@aishealth.com.

Contact Baiano, Distad and James via Adrienne Foley at Adrienne.foley1@alliancerxwp.com, Belazi through Caroline Chambers at cchambers@cpronline.com, Kinyua through Karen Lyons at KLyons@primetherapeutics.com, Nishida at lynn@evio.com and Wong at w2sqgroup@gmail.com.

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