Drug Injury Watch

Two Padcev SJS / TEN Case Reports Published Before March 2021 Padcev Label Change About These Skin Reactions

When Astellas Pharma First Knew About SJS / TEN Side Effects Is A Key Fact In This Still Developing Padcev Drug Safety Issue

 

(Posted by Tom Lamb at Drug Injury Watch)

 

About a month ago, on September 21, 2021, we posted this article, "Padcev Skin Reaction Side Effects SJS and TEN: From No Warning to "Black Box" in Less Than 2 Years". Since then we have found two Padcev skin reaction case reports involving Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) that we want to present now in order to raise the profile of these serious Padcev skin reactions, which can be fatal.

We start with a Case Report item published by the Journal of The American Academy of Dermatology (JAAD), "A rare presentation of enfortumab vedotin–induced toxic epidermal necrolysis".  Notably, this Padcev medical journal article was published a couple of months before the first Padcev drug label change that added warnings for the Padcev skin side effects Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which happened back in March 2021. As such, from the Introduction of that JAAD article, this Padcev patient case report starts as follows:

Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous reaction that involves more than 30% of the skin. TEN is not a recognized side effect of [Padcev (enfortumab vedotin)]. However, we present a rare case of [Padcev]–induced TEN in a 72-year-old man with metastatic urothelial carcinoma.

This man presented to the hospital for the evaluation of a rash that developed shortly after his day 8 infusion of Padcev. In more detail, from the JAAD Case Report:

The patient was scheduled to receive [Padcev (enfortumab vedotin)] on days 1, 8, and 15 of a 28-day cycle at the M.D. Anderson Cancer Center. He tolerated day 1 of his medication well; however, after his day 8 infusion, an erythematous rash with associated skin sloughing developed on <20% of his body (Fig 1). He was admitted to the M.D. Anderson Cancer Center for initial management, but as the rash progressed, he was transferred to the University of Texas Medical Branch's burn intensive care unit on day 12. He was hemodynamically stable on admission. Physical examination demonstrated tense bullae on a background of erythema on his bilateral axillae, back, genitalia, posterior aspect of the bilateral thighs (Fig 2), and bilateral heels and a single blister on the posterior aspect of his oral cavity, raising concern for Stevens-Johnson syndrome (SJS)/TEN. At the initial presentation to our hospital, his score of toxic epidermal necrolysis (SCORTEN) was 7, and ABCD-10 score was 5.

His medication list was reviewed for the identification of a potential cause of SJS/TEN.... Based on his recent initiation of [Padcev (enfortumab vedotin)] and his rapid-onset development of the rash, the drug was deemed to be the cause and was discontinued, and he was started on a topical steroid. A biopsy was performed, and the pathology revealed interface dermatitis with central areas of full-thickness epidermal necrosis, consistent with an SJS/TEN overlap (Fig 3).

... His rash progressed to involve >30% of his skin, and he was diagnosed with TEN.... The patient died 20 days after admission on February 27, 2020.

Our next medical journal article, which covers two Padcev skin reaction case reports, was published online March 4, 2021, which is a few weeks before the March 22, 2021, FDA Supplemental Approval letter (PDF) for first warnings about the Padcev being associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). 

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Published by Frontiers in Oncology, the lengthy title of that article is "Case Report: Enfortumab Vedotin for Metastatic Urothelial Carcinoma: A Case Series on the Clinical and Histopathologic Spectrum of Adverse Cutaneous Reactions From Fatal Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis to Dermal Hypersensitivity Reaction".  From that medical journal article, we focus on a Padcev SJS / TEN case report that was ultimately fatal. It concerns a 71-year-old male, whose case was described in relevant part as follows:

He received [Padcev (enfortumab vedotin)] 1.25 mg/kg on days 1 and 8 of the first cycle. Within 24 h of the day 8 infusion [of Padcev], he experienced diffuse pruritus. Four days after the infusion, he presented to the emergency department with fevers to 101°F and mouth pain but was otherwise hemodynamically stable with unremarkable cardiac and pulmonary exams. His dermatologic exam on admission revealed a small ulceration on the right lateral upper lip, well-demarcated erythema of the inferior tongue tip, and tender erythema of the axillae, flanks, inguinal region, and soles of feet (Figures 2A, B). He had flaccid ruptured bullae with approximately 11% of body surface area involvement that included the right heel, right posterior upper arm, and left forearm with positive Nikolsky sign. Eosinophil count and liver function tests were within normal limits. He was admitted and initiated on systemic steroids. Twelve days after [Padcev (enfortumab vedotin)] treatment and 4 days after symptom onset, a punch biopsy of the left axillae confirmed subepidermal bulla with detached epidermis with scattered dyskeratotic cells and mixed dermal inflammatory infiltrate composed of lymphocytes, neutrophils, eosinophils, and macrophages (Figure 2C). The clinical and histologic findings were compatible with early changes of SJS/TEN....

ICU transfer with IV methylprednisolone treatment was initiated on day 3 for involvement of 18% total body surface area and high SCORETEN of 7.... He subsequently was transferred to the burn unit at a nearby hospital, but the patient expired several days later.

We will continue to monitor the medical literature for any additional Padcev skin reaction case reports involving Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

As stated in our initial article about serious Padcev skin reactions last month, we are investigating cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients using Padcev 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)

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Xeljanz Risks of Cardiovascular Events, as Well as Cancers, Cause More Xeljanz Use Limitations

October 2021 UK's MHRA Xeljanz Action Follows September 2021 FDA Xeljanz Drug Safety Communication Update

 

(Posted by Tom Lamb at Drug Injury Watch)

 

On September 1, 2021, we posted this article, "Xeljanz: FDA Warnings Updated: There are Higher Rates of Blood Clots and Deaths for Both Doses of Xeljanz, Now", in which we listed the five Drug Injury Watch articles we wrote earlier in 2021 about Xeljanz drug safety developments. Now we are covering the latest drug regulatory action taken due to the Xeljanz risk of cardiovascular events as well as the Xeljanz risk of cancers, or malignancies, this one by the UK's Medicines and Healthcare products Regulatory Agency (MHRA).

This Drug Safety Update document, "Tofacitinib (Xeljanz▼): new measures to minimise risk of major adverse cardiovascular events and malignancies", issued by the MHRA on October 6, 2021, states that Xeljanz should not be used by these patients in the groups identified below unless there is no suitable drug treatment alternative:

• people older than 65 years of age;
• people who are current or past smokers;
• people with other cardiovascular risk factors, such as diabetes or coronary artery disease;
• people with pre-existing cancer or malignancy risk factors.

As regards the Xeljanz side effects findings underlying these new Xeljanz use limitations, from the Safety Review part of this October 2021 MHRA Xeljanz document:

Study ORAL Surveillance (A3921133) was a large, randomised, active-controlled, clinical safety trial to evaluate the safety of tofacitinib versus tumour necrosis factor (TNF)-alpha inhibitors....

The co-primary endpoints of study A3921133 were adjudicated major adverse cardiac events and adjudicated malignancies (with the analysis excluding non-melanoma skin cancer)....

In 2021, final results from study A3921133 showed tofacitinib to be associated with an increased incidence of non-fatal myocardial infarction and malignancies, particularly lung cancer and lymphoma.

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About the Xeljanz risk of cardiovascular events, we find this important information in the October 2021 MHRA Xeljanz document:

Predictive factors for development of myocardial infarction (fatal and non-fatal) were identified using a multivariate Cox model with backward selection. These factors were age older than 65 years, male sex, current or past smoking, history of diabetes, and history of coronary artery disease (which includes past myocardial infarction, coronary heart disease, stable angina pectoris, or past coronary artery procedures).

And about the Xeljanz risk of cancers, that document provides this information:

Predictive factors for development of malignancies (excluding non-melanoma skin cancer) were identified using a multivariate Cox model with backward selection. These were age older than 65 years and current or past smoking.

We will watch for possible additional drug regulatory actions due to the Xeljanz risk of cardiovascular events as well as the Xeljanz risk of cancers, and report significant developments here.

Our law firm is handling Xeljanz drug injury lawsuits 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. Feel free to send me an email if we can be of assistance to you or someone you know.

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

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Imbruvica Heart-Related Side Effects Continue to Get Attention from Drug Safety Researchers

Recent Cardiotoxicity Case Reports for Patients Using Imbruvica Alone or When Combined With Other Drugs

 

(Posted by Tom Lamb at Drug Injury Watch)

 

Just about two years ago, in mid-October 2019, we posted these two articles, "Patients Treated With Imbruvica Had Increased Rate Of Fatal Cardiac Events Compared To Conventional Chemotherapy", and "Imbruvica-Related Hypertension And Associated Serious Side Effects Examined In New Medical Study."  Since then, we have seen various case reports of heart-related Imbruvica side effects in the medical literature, both when patients used only Imbruvica and when Imbruvica was used in combination with certain other drugs.

In this new article, we point out a few of the medical journal articles and news reports about heart-related Imbruvica side effects that have been published in the past 12 months.

We start with a June 2021 report from ThePharmaLetter, "Imbruvica: new safety signal for use with rituximab and ACE inhibitors" about the European Medicines Agency (EMA) issuing a new safety signal for Imbruvica with rituximab:

As part of its advice on safety-related aspects to other European Medicines Agency committees, the Pharmacovigilance Risk Assessment Committee (PRAC) last week discussed a direct healthcare professional communication (DHPC) containing important safety information for Imbruvica (ibrutinib).

This DHPC aims to inform healthcare professionals about a new safety signal of sudden or cardiac death with Imbruvica when used in combination with rituximab and angiotensin-converting enzyme (ACE) inhibitors. The signal was recognized following a review of the findings of a clinical trial....

An interim analysis of the clinical trial suggested that the risk of sudden or cardiac death in patients on an ACE inhibitor when entering the study was increased in patients randomized to [Imbruvica (ibrutinib)] and rituximab, compared to those randomized to fludarabine, cyclophosphamide and rituximab.

While the PRAC is reviewing the signal, as a precautionary measure, for patients with [chronic lymphocytic leukemia (CLL)] currently receiving [Imbruvica (ibrutinib)] plus rituximab together with an ACE inhibitor, the PRAC advises healthcare professionals to reconsider the treatment strategy.

Next is a September 2021 MedPage Today news report, "Ibrutinib for CLL Tied to Higher Heart Risks vs Chemotherapy", about there being increased risks for atrial fibrillation, bleeding, and heart failure seen in a Canadian cohort of patients using Imbruvica:

Use of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) was linked with cardiovascular risks in patients with chronic lymphocytic leukemia (CLL), according to results of a population-based cohort study.

Over 3 years, the incidence of atrial fibrillation (AF)-related healthcare contact was 22.7% in patients treated with [Imbruvica (ibrutinib)] compared with 11.7% in patients who received chemotherapy, risk of hospital-diagnosed bleeding was 8.8% and 3.1%, respectively, and risk of heart failure (HF) was 7.7% and 3.6%, reported Husam Abdel-Qadir, MD, PhD, of Women's College Hospital in Toronto, and colleagues.

There were no significant differences in the risk of ischemic stroke or acute myocardial infarction between the two groups, they noted in the Journal of Clinical Oncology.

For more details about these heart-related Imbruvica side effects, we refer you to the underlying medical study article, "Cardiovascular Risk Associated With Ibrutinib Use in Chronic Lymphocytic Leukemia: A Population-Based Cohort Study", which was published online on August 31, 2021, by the Journal of Clinical Oncology.

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Lastly, there is this November 2020 Healio article, "Link between ibrutinib-related hypertension, heart problems necessitates close monitoring", which provides some key findings from several different medical journal articles about research focused on heart-related Imbruvica side effects. From the Conclusions part of that Healio article:

[Chronic lymphocytic leukemia (CLL)] is a disease of the elderly. Real-world evaluations suggest many patients initiated on [Imbruvica (ibrutinib)] have significant comorbidities, many of them cardiovascular.

Hypertension — an important risk factor for the development of atrial fibrillation — may occur at a much higher rate in real-world practice settings than reported in clinical trials.

Patients should be monitored for the development of new or worsened hypertension, particularly early in the therapy course.

Intervention with antihypertensive medications for patients with hypertension may prevent [major adverse cardiac events (MACE)], including atrial fibrillation. It does not appear that any class of antihypertensives is preferred for hypertension management among these patients.

Treatment of new-onset hypertension, as well as prevention of worsening hypertension and atrial fibrillation development, makes it easier for patients to remain on [Imbruvica (ibrutinib)] without dose modification or interruption.

But if you still want to learn more about this cardiotoxicity drug safety issue for Imbruvica, we give you this "extra" item to consider, "Ibrutinib's Cardiotoxicity-An Opportunity for Postmarketing Regulation", published by JAMA Oncology in February 2021, which starts as follows:

[Imbruvica (ibrutinib)] is an irreversible inhibitor of Bruton tyrosine kinase (BTK) that is indicated for multiple hematological malignancies, including previously untreated chronic lymphocytic leukemia (CLL). This drug is known to have cardiotoxic properties, probably due to off-target inhibition of another kinase. While in randomized trials ibrutinib has been demonstrated to increase survival, some studies have demonstrated fatal toxic effects associated with the drug. This was most obvious in a 3-arm study of CLL in which the 2 [Imbruvica (ibrutinib)] arms were associated with a 7% rate of death during treatment or within 30 days after treatment cessation, compared with a 1% rate of death in the control arm.

We will continue to monitor the medical literature for more analysis of heart-related Imbruvica side effects, as well as watch for possible action by drug safety regulators such as the FDA and the EMA in the future.

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

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