Drug Injury Watch

Xeljanz: Drug-induced Peripheral Neuropathy as Possible Xeljanz Side Effect in 2 RA Patients

Reports of Rheumatoid Arthritis Patients on Xeljanz Experiencing Secondary Neurological Adverse Events

 

(Posted by Tom Lamb at Drug Injury Watch)

 

As we have written about previously, according to the FDA, some of the generally recognized Xeljanz side effects and Xeljanz adverse events are:

Heart Attacks
Myocardial Infarction (MI)
Strokes — Ischemic / due to a blood clot
Deep Vein Thrombosis (DVT)
Pulmonary Embolism (PE)
Arterial Thrombosis
Lymphoma
Lung Cancer
Other Cancers
Death

Now, as reported in this Letters to the Editor item, "Tofacitinib and Risk of Peripheral Neuropathy? Experience of 2 Cases in Patients With Rheumatoid Arthritis", patients treated with Xeljanz (tofacitinib) for their rheumatoid arthritis (RA) may be at risk of neurological adverse events, such as peripheral neuropathy.  That item about neurological adverse events associated with Xeljanz use was published in the March 2021 edition of JCR: Journal of Clinical Rheumatology.

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It was a September 23, 2021 article, "Report: 2 Patients With RA Experienced Peripheral Neuropathy on JAK Inhibitor", published online by The American Journal of Managed Care (AJMC), however, which just recently brought this possible new Xeljanz drug safety issue to our attention. From that recent AJMC article we get this overview of those two Xeljanz - peripheral neuropathy case reports:

The first patient in the report, a 37-year-old woman, had a history of 6 years of active seropositive RA. Due to her active disease and severe radiographic damage to her hips, hands, and knees, she was prescribed [Xeljanz (tofacitinib)].

“After 2 weeks of use, although pain and stiffness improved, she started complaining of limb dysesthesias and decrease in muscle strength causing legs motor deficit but preserved osteotendinous reflexes,” Tobón and colleagues said.

Non-superior/inferior motor neuron compromise was also present, and mixed polyneuropathy was confirmed by electromyography and nerve conduction studies, the authors said. The patient’s cerebrospinal fluid was normal, and other potential causes were ruled out.

The patient eventually progressed to bed confinement. Her [Xeljanz (tofacitinib)] was discontinued; she was instead prescribed tocilizumab (Actemra) to treat her joint condition. She was able to walk again within a month.

In the second case, a 59-year-old patient with a history of benign renal tumor back in 2012 and unilateral nephrectomy was confirmed to have RA. Her mild renal dysfunction contra-indicated methotrexate, and so she was given chloroquine. When she failed to respond to that, she was given [Xeljanz (tofacitinib)]. Within a month, she was experiencing muscle weakness and decreased sensitivity in her lower limbs, Tobón and colleagues said.

After additional tests, she was given intravenous immunoglobulin (IVIG), which led to clinical improvement. She was thus continued on [Xeljanz (tofacitinib)] with close monitoring, for almost 2 years, the authors said.

We will continue to monitor the medical literature for developments regarding serious Xeljanz side effects and Xeljanz adverse events, including any additional Xeljanz - peripheral neuropathy case reports.

At the present time, our law firm is investigating Xeljanz lawsuits filed against Pfizer, the pharmaceutical company responsible for Xeljanz, for patients with cases of Xeljanz causing heart problems such as heart attacks, strokes, pulmonary embolism (PE), and deep vein thrombosis (DVT), as well as Xeljanz causing lymphoma, lung cancer, and other cancers. Please feel free to contact us if we can help you or someone you know with a Xeljanz drug injury case.

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

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Padcev Skin Reaction Side Effects SJS and TEN: From No Warning to "Black Box" in Less Than 2 Years

Bladder Cancer Drug Padcev is Linked to Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) in 2021

 

(Posted by Tom Lamb at Drug Injury Watch)

 

Padcev (enfortumab vedotin-ejfv), an injection drug for intravenous use, was approved by the FDA in December 2019 for the treatment of certain adult patients with locally advanced or metastatic urothelial cancer (mUC).  Urothelial carcinoma, also known as transitional cell carcinoma (TCC), is by far the most common type of bladder cancer. As such, if you have bladder cancer it is almost certain to be a urothelial carcinoma.  It is important for bladder cancer patients and their families to know that the Padcev skin side effects Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious skin reactions that can be life-threatening and even fatal.

As background, from "Stevens-Johnson syndrome/toxic epidermal necrolysis", a MedlinePlus document provided by the U.S. National Library of Medicine, we get the following:

Although Stevens-Johnson syndrome and toxic epidermal necrolysis were once thought to be separate conditions, they are now considered part of a continuum. Stevens-Johnson syndrome represents the less severe end of the disease spectrum, and toxic epidermal necrolysis represents the more severe end.

In more detail, in people who have developed Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) is diagnosed when more than 30% of the skin surface is affected and the moist linings of the body (mucous membranes) have extensive damage. Put otherwise, toxic epidermal necrolysis (TEN) is a severe form of Stevens-Johnson syndrome (SJS). And, significantly, TEN is such a serious skin reaction that it can be fatal, causing patient deaths in some situations.

Now we will look at the timeline as to how the Padcev Prescribing Information, or drug label, went from having no warning about Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) when approved by the FDA in December 2019 to the Padcev drug label having a "Black-Box" warning about the SJS and TEN skin side effects, now, less than 2 years after Padcev came on the market.

In the initial Padcev drug label ("Revised: 12/2019") there was a warning about general, low-level Padcev skin side effects in the Warnings and Precautions section at 5.4 Skin Reactions.

The first label change to add warnings for the Padcev skin side effects Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) came in March 2021. From the "Revised: 3/2021" Padcev drug label at 5.1 Skin Reactions:

Severe cutaneous adverse reactions, including fatal cases of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later.

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But only four months later, in July 2021, the FDA mandated increased warnings about the Padcev skin side effects Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), in the form of a so-called "Black Box" warning with the bolded title WARNING: SERIOUS SKIN REACTIONS. There was also this bulked-up 5.1 Skin Reactions warning in the "Revised: 7/2021" version of the Padcev drug label:

Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later.

Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials. Twenty-three percent (23%) of patients had maculopapular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 13% of patients, including maculo-papular rash, rash erythematous, rash or drug eruption, symmetrical drugrelated intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmarplantar erythrodysesthesia. In clinical trials, the median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients [see Adverse Reactions (6.1)].

For an overview of the data which led to these two Padcev label changes in 2021, we point out this article, "Postmarketing Cases of Enfortumab Vedotin–Associated Skin Reactions Reported as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis", published online by the JAMA Dermatology medical journal on September 8, 2021. Notably, this "Research Letter" was written by FDA staff in the Division of Pharmacovigilance, Office of Surveillance and Epidemiology. It begins with this introduction:

During routine surveillance, the US Food and Drug Administration (FDA) Division of Pharmacovigilance identified postmarketing cases of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with [Padcev (enfortumab vedotin)] from the FDA Adverse Event Reporting System (FAERS). To investigate a potential association between [Padcev (enfortumab vedotin)] and SJS/TEN, we evaluated all sources for postmarketing cases of SJS/TEN and report our findings.

Our law firm is investigating cases for patients who have suffered the Padcev skin side effects Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) as possible drug injury lawsuits to be filed against Astellas Pharma US, Inc., the manufacturer of Padcev.

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free. Confidential. No Obligation.  (Case review is done by attorney Tom Lamb)

Elmiron and Maculopathy: Increased Risk of Ocular Complications in Long-Term, High-Dose Elmiron Use

Two Recent Medical Articles on Vision Side Effects of Elmiron (pentosan polysulfate sodium, or PPS) for Interstitial Cystitis

 

(Posted by Tom Lamb at Drug Injury Watch)

 

Chronic use of Elmiron (pentosan polysulfate sodium, or PPS) for interstitial cystitis, also known as bladder pain syndrome, has been associated with maculopathy in patients. The mechanism for this link between Elmiron and maculopathy, however, is still not fully understood. And the diagnostic means for identifying a case of Elmiron and maculopathy early on is still evolving. In this post, we look at some relatively recent research regarding the still-emerging drug safety issue of Elmiron and maculopathy.

According to "Screening needed for pentosan polysulfate sodium-associated maculopathy", published on September 2, 2021, by Ocular Surgery News:

In most cases, retinal findings do not appear until a patient has been on [Elmiron] for 10 to 15 years, according to Elliott Sohn, MD, of the University of Iowa. Because patients generally start to present with interstitial cystitis in their 40s, once they start to develop maculopathy, it is easily confused with macular degeneration.

“The maculopathy appears to be dose dependent and most often seen when the patient has been on [Elmiron] for a total cumulative dose of 1,500 g,” Sohn said. “A lot more research needs to be done to better understand why and how this is happening, as well as the prevalence of it.”

Two medical journal articles published in 2021 have presented some of this needed research about Elmiron and maculopathy.

First, from the Abstract for this study report published in the February 11, 2021 edition of the medical journal Clinical Ophthalmology, "Maculopathy Secondary to Pentosan Polysulfate Use: A Single-Center Experience":

• Aim:  To investigate the prevalence of retinal pathology in patients with a history of exposure to [Elmiron (pentosan polysulfate sodium, or PPS)].
• Results:  A total of 131 patients who were exposed to [Elmiron] and seen at the Northwestern Ophthalmology clinic were identified in the EHR. Forty patients of 131 had imaging. Patients with imaging or fundus examination suspicious for [Elmiron] maculopathy were placed into the suspect group. Of the 40 patients that had imaging, 5 (12.5%) had features suspicious for [Elmiron] maculopathy. Of the remaining 91, 5 (5.4%) had macular pigmentary changes described on fundus exam. Among the 10 patients in the suspect group, the average duration of [Elmiron] use was 4.2 years (range 0.3-11.6 years, interquartile range 5.5 years) and the average cumulative dose [of Elmiron] was 380g (range 29-1092g, interquartile range 132g).
• Conclusion:  A novel drug-induced maculopathy has been associated with [Elmiron] use with a distinct clinical constellation that can be accurately identified with multimodal imaging.

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Second, from the Abstract for this study report published in the September 1, 2021 edition of The Journal of Urology, "PD01-09 PATIENT PERCEPTION OF OCULAR RISK IN PENTOSAN POLYSULFATE USE FOR INTERSTITIAL CYSTITIS":

• RESULTS:  A total of 735 patients treated with [Elmiron] were identified, of which 95 completed screening at the Stein Eye Institute. Of the 95, 64 patients consented to the study. Of the 64 patients included in analysis, 37 were no longer taking [Elmiron]. Patients with maculopathy (n=10) were more likely to have discontinued [Elmiron] (n=8) compared to patients without maculopathy (p=0.03). Patients with confirmed ocular complications reported daily doses [of Elmiron] in excess of recommended 300 mg daily dose (590 mg versus 290 mg in those without, p<0.00001) and significantly greater mean lifetime cumulative doses [of Elmiron](671 g versus 3894 g, p=<0.00001). There were no significant differences in age, daily dose, lifetime [Elmiron] dose exposure, or perception of maculopathy risk in those continuing [Elmiron] compared to those who had discontinued [Elmiron]. Primary reasons for discontinuation of [Elmiron] were concern for ocular injury (41%), lack of efficacy or decreased benefit (32%), cost (16%), and other side effects (11%).
• CONCLUSIONS:  While the mechanism of maculopathy in [Elmiron] use is not fully understood, this risk must be weighed against its potential benefit as a treatment for interstitial cystitis. Physicians should counsel patients on risk of ocular complication in long term and high dose [Elmiron] use, and consider alternative therapies and early ophthalmologic referral in patients with lifetime cumulative doses [of Elmiron] greater than 500 g.

Of course, we will continue to monitor this still-emerging drug safety issue of Elmiron and maculopathy.

Our law firm is investigating possible Elmiron drug injury lawsuits for cases of Elmiron causing eye problems such as retinal pigmentary changes and pigmentary maculopathy resulting in vision loss.

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

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Xeljanz: FDA Warnings Updated: There are Higher Rates of Blood Clots and Deaths for Both Doses of Xeljanz, Now

JAK Inhibitors Xeljanz, Olumiant, and Rinvoq Get Drug Label Changes and Drug Use Limitations in September 2021

 

(Posted by Tom Lamb at Drug Injury Watch)

 

On September 1, 2021, the FDA released this alerting news about the association of Xeljanz use with adverse events involving blood clots and death: The increased risk of blood clots and death has been linked to the lower dose of Xeljanz as well as the higher dose of Xeljanz; put otherwise, both FDA-approved doses of Xeljanz are linked to these "side effects", or adverse drug reactions.

This September 2021 document, "FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions", begins with the following new information:

Based on a completed U.S. Food and Drug Administration (FDA) review of a large randomized safety clinical trial, we have concluded there is an increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death with the arthritis and ulcerative colitis medicines Xeljanz and Xeljanz XR (tofacitinib). This trial compared Xeljanz with another type of medicine used to treat arthritis called tumor necrosis factor (TNF) blockers in patients with rheumatoid arthritis. The trial’s final results also showed an increased risk of blood clots and death with the lower dose of Xeljanz. A prior DSC based upon earlier results from this trial, reported an increased risk of blood clots and death only seen at the higher dose.  [Emphasis added.]

And here is what the FDA doing "new", now, in September 2021 -- after some earlier FDA regulatory actions pertaining to Xeljanz over the past couple of years:

We are requiring revisions to the Boxed Warning, FDA’s most prominent warning, for Xeljanz/Xeljanz XR, Olumiant, and Rinvoq to include information about the risks of serious heart-related events, cancer, blood clots, and death. Recommendations for health care professionals will include consideration of the benefits and risks for the individual patient prior to initiating or continuing therapy. In addition, to ensure the benefits of these three medicines outweigh the risks in patients who receive them, we are limiting all approved uses to certain patients who have not responded or cannot tolerate one or more TNF blockers....

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In more detail, from the Data Summary section of the above-referenced September 2021 document, here are the most recent FDA findings as regards various Xeljanz side effects:

There was an increased risk of death, MACE, malignancies, and thrombosis associated with both regimens of Xeljanz. The data showed evidence of a dose-dependent increased risk for [major adverse cardiovascular events (MACE) -- defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke], all-cause mortality, and thrombosis at both doses of Xeljanz when compared to treatment with [tumor necrosis factor (TNF) blockers]. Additionally, the data showed evidence of a non-dose-dependent increased risk for malignancy excluding [nonmelanoma skin cancer (NMSC)] at both doses of Xeljanz when compared to TNF blockers. Lymphomas and lung cancers were observed at a higher rate in patients treated at both doses of Xeljanz compared to those treated with TNF blockers. In particular, a higher rate of lung cancers was observed in current or past smokers treated with Xeljanz. Current or past smokers had an additional increased risk of overall cancers.

Other JAK inhibitors [specifically, Olumiant (baricitinib) and Rinvoq (upadacitinib)] have not been studied in similar large safety clinical trials, so the risk with these medicines has not been evaluated. However, since [Olumiant and Rinvoq] share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks as seen in the safety clinical trial with Xeljanz.

However, this September 2021 FDA regulatory action regarding Xeljanz is not altogether unexpected, as can be seen by these five Drug Injury Watch articles about Xeljanz drug safety developments which we wrote earlier this year:

1. Possible FDA Advisory Committee Meeting for Xeljanz, Rinvoq, and Other Janus Kinase (JAK) Inhibitors  (July 6, 2021)
2. Xeljanz and Other JAK Inhibitors: Drug Safety Concerns Indicated by Recent FDA Actions  (April 15, 2021)
3. Possible Ramifications of Recent FDA Alert About Xeljanz Heart Problems and Xeljanz-related Cancers  (March 23, 2021)
4. Xeljanz Has A New Drug Safety Issue, We Just Don't Know How Significant It Is, Yet  (February 17, 2021)
5. Xeljanz FDA Drug Safety Communication in February 2021 Puts Heightened Scrutiny on Pfizer  (February 11, 2021)
   
   

Our law firm is investigating Xeljanz lawsuits filed against Pfizer, the pharmaceutical company responsible for Xeljanz, for cases of Xeljanz causing heart problems such as heart attacks and strokes as well as Xeljanz causing cancers.

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free. Confidential. No Obligation.  (Case review is done by attorney Tom Lamb)