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In August 2017 the United States Judicial Panel on Multidistrict Litigation (JPML) granted a second motion for centralization or consolidation of federal court lawsuits brought by plaintiffs in proton-pump inhibitors (PPIs) cases alleging kidney injury.
In more detail, the JPML established IN RE: PROTON-PUMP INHIBITOR PRODUCTS LIABILITY LITIGATION (NO. II) – MDL No. 2789. From the JPML’s Transfer Order filed on August 2, 2017 we get these details:
In the complaints in these 161 personal injury and wrongful death actions, plaintiffs allege that as a result of taking one or more proton-pump inhibitors (PPIs), they or their decedents suffered kidney injury (e.g., chronic kidney disease (CKD), acute interstitial nephritis, end stage renal disease, or kidney failure). Plaintiffs allege that defendants failed to adequately warn of the negative effects and risks associated with PPIs….
Notably, during this second time around only one drug company, Takeda. was still opposed to the creation of any PPIs federal court MDL. But the JPML was not convinced by Takeda’s various arguments in opposition, as seen from this excerpt from the Transfer Order:
And, although it is true that AstraZeneca is sued in far more actions than Takeda, a significant number of actions are “mixed use” cases in which the plaintiffs allege use of more than one PPI, and sue Takeda and one or more other PPI manufacturers, including AstraZeneca. The prospect of additional cases against Takeda does not seem far-fetched . Given these circumstances, including the seemingly indivisible nature of plaintiffs’ alleged injuries in the “mixed use” cases, we decline to carve out from the MDL cases or claims against Takeda. [footnotes omitted]
Lastly, this point – which may have been a factor for the JPML when ruling this time on the Prilosec / Prevacid / Nexium federal court MDL consolidation – was mentioned in a footnote for the August 2017 Transfer Order: “The variety of alleged kidney injuries arguably has diminished, as most plaintiffs allege that they suffer from [chronic kidney disease (CKD)]….”
We continue to monitor legal and medical developments regarding the drug injury aspects of Nexium, Prevacid, and Prilosec.
A British medical journal, The Lancet Diabetes & Endocrinology, published this Correspondence item on July 18, 2017, “SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System”.
The main point of that article is set forth in this excerpt:
In summary, this pharmacovigilance analysis confirms that use of canagliflozin, but not dapagliflozin or empagliflozin, might be associated with an increased risk of amputations. However, [the US Food and Drug Administration (FDA) adverse event Reporting System (FAERS)] data analysis has important limitations because there is no definite causal link between drug exposure and adverse event…. [footnote omitted]
In early August 2017 an article with some additional contextual information, “FDA Reports Further Support for Canagliflozin-Amputation Link”, was published on the Medscape website (free registration required). From that article we get the following points:
Among 66 reports of SGLT2-inhibitor–associated amputations, 57 (86%) involved canagliflozin. Moreover, two-thirds of those reports were among people with no discernible risk factors for amputation, “which, worryingly, points to an unpredictable effect of the drug,” [Gian Paolo Fadini, MD, PhD, of the division of metabolic diseases, department of medicine, University of Padova, Italy] told Medscape Medical News….
Thus far, the FDA has not extended the label warning about amputations to other drugs in the class [e.g., Jardiance (empagliflozin) and Farxiga (dapagliflozin)], although the European Medicines Agency (EMA) has, pending further investigation.
“Our data are the first to confirm the warning originated from CANVAS and tends to suggest this is not a class effect,” Dr Fadini told Medscape Medical News.
We are currently investigating possible drug injury cases against the responsible drug company, Janssen Pharmaceuticals, where a patient who used Invokana or Invokamet had to have a lower limb amputation.
The European Medicines Agency (EMA) recently announced it is taking regulatory action on certain magnetic resonance imaging (MRI) contrast drugs containing gadolinium a couple of months after the U.S. Food and Drug Administration (FDA) decided otherwise.
We start with the timeline of events giving rise to the EMA’s suspension of the MRI drugs Magnevist, Omniscan, and OptiMARK in July 2017.
In this July 7, 2017 EMA document, “PRAC confirms restrictions on the use of linear gadolinium agents”, which included this statement: “No specific conditions linked to gadolinium deposition in the brain have been identified, but the clinical consequences are unknown.”
And in its July 21, 2017 document, “EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans”, we get this further elaboration on that statement:
There is currently no evidence that gadolinium deposition in the brain has caused any harm to patients; however EMA has recommended restrictions for some intravenous linear agents in order to prevent any risks that could potentially be associated with gadolinium brain deposition….
We turn now to the FDA’s treatment of this drug-safety assessment of Magnevist, Omniscan, and OptiMARK, as well as the several other gadolinium-based contrast agents (GBCAs).
From its “FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue” we get this explanation of why no regulatory action is necessary — at least not yet:
All GBCAs may be associated with some gadolinium retention in the brain and other body tissues. However, because we identified no evidence to date that gadolinium retention in the brain from any of the GBCAs, including GBCAs associated with higher retention of gadolinium, is harmful, restricting GBCA use is not warranted at this time. We will continue to assess the safety of GBCAs and plan to have a public meeting to discuss this issue in the future….
We will be watching for the “public meeting to discuss this issue in the future” mentioned by the FDA — which, perhaps, will be a so-called Advisory Committee Meeting.
In addition, we will monitor the medical literature for “any risks that could potentially be associated with gadolinium brain deposition” mentioned by the EMA.
In the final week of July 2017, the FDA issued a notification that it had approved a revised drug label for Invokana and Invokamet, as well as a revised Medication Guide for these two diabetes drugs from Janssen Pharmaceuticals.
From the most recent drug label, or Full Prescribing Information, for Invokana (accessed 7/27/17), here is the text of the so-called Black-Box Warning:
WARNING: LOWER LIMB AMPUTATION
• An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
• Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
• Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
• Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur [see Warnings and Precautions (5.1)].
And from the Invokana Medication Guide revised in July 2017, in the “Amputations” section, we get this information directed to patients who are taking this drug, or Invokamet:
You may be at a higher risk of lower limb amputation if you:
o have a history of amputation
o have heart disease or are at risk for heart disease
o have had blocked or narrowed blood vessels, usually in your leg
o have damage to the nerves (neuropathy) in your leg
o have had diabetic foot ulcers or sores
We are currently investigating possible drug injury cases against the drug company, Janssen Pharmaceuticals, where a patient who used Invokana or Invokamet had to have a lower limb amputation. If you or someone in your family has had a toe, foot, or leg amputation, you can get Free Case Evaluation for such a case.
A developing drug safety issue is presented in this news report, “FDA Considers Label Changes for Keytruda, Opdivo and Yervoy”, which was posted July 12, 2017 on the Regulatory Affairs Professional Society (RAPS) website.
Here are some contextual details provided by reporter Zachary Brennan in this article:
The consideration for changing the labels of Yervoy, Opdivo and Keytruda comes as FDA says it has completed post-marketing reviews for sight-threatening complications such as retinal detachment and vision loss with the three treatments.
Tralisa Colby, an FDA public affairs specialist, explained to Focus: “Regulatory discussions are ongoing regarding PD-1 pathway blocking antibodies in attempts to improve the consistency and effectiveness of the information regarding immune-mediated ARs provided in the labels. Those labeling changes may include additional characterization of ocular inflammatory conditions; however, the current term, uveitis, should convey the severity and potential ocular complications to oncology physicians.”
Further, this July 12 RAPS news report states that the Prescribing Information documents, or drug labels, for Yervoy, Opdivo, and Keytruda have uveitis listed as a potential immune-mediated adverse reaction (AR).
Of course, we will continue to monitor the safety profile of Yervoy, Opdivo, and Keytruda, with special attention to any label changes mandated by the FDA as regards retinal detachment and/or vision loss.
An insightful article by reported Charles Piller, “Failure to warn: Hundreds died while taking an arthritis drug, but nobody alerted patients”, published June 5, 2017 online by STAT, put the spotlight on some serious but little-known side effects associated with this medicine from Genentech, Inc.
From that recent article we get this rather alarming safety information about Actemra:
… STAT analyzed more than 500,000 side-effect reports on rheumatoid arthritis drugs, and found clear evidence that the risks of heart attacks, strokes, heart failure, and other conditions were as high or higher for Actemra patients than for patients taking some competing drugs.
Most of those medications warn about these risks on their labels. Actemra does not.
Consumers are barraged every day with drug ads accompanied by numbing lists of side effects, but STAT’s investigation shows that the risks to patients might be greater than they are led to believe. The Food and Drug Administration has received reports on 1,128 people who died after taking Actemra, and has reviewed its safety several times since it was approved. But the agency doesn’t have sophisticated tools to determine whether the drug was a culprit or a bystander in those deaths….
Experts who examined the data at STAT’s request said the FDA should immediately consider warnings for heart failure and pancreatitis — an inflammation of the pancreas that in its acute form can kill up to 50 percent of patients. They said the evidence that Actemra might increase the risk of heart attacks, strokes, and interstitial lung disease, a sometimes-fatal scarring of lung tissue, is less convincing but warrants further review.
This focus on Actemra side effects and the lack of warnings about these adverse reactions shines the light on the apparent inadequate standards of post-marketing surveillance for drugs approved by the FDA.
We are interested in hearing about patients who were diagnosed with pancreatitis or some other serious side effect while using Actemra. You can do this by submitting a Quick Contact Form or by using the Email link found in the sidebar.
In advance of the June 20, 2017 FDA Advisory Committee meeting to discuss Novo Nordisk’s supplemental New Drug Application (sNDA) for approval of Victoza® (liraglutide) injection, we reviewed the FDA Briefing Document for this Endocrinologic and Metabolic Drugs Advisory Committee Meeting (EMDAC), which includes a section titled “ONCOLOGY CONSULT: PANCREATIC CANCER”.
In that FDA Briefing Document the results of the so-called LEADER trial: “Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A long-term, multi-center, international, randomized double-blind, placebo-controlled trial to determine liraglutide effects on cardiovascular events.” are discussed.
As regards the Victoza – pancreatic cancer safety issue, there is this discussion:
Pancreatic adenocarcinoma is an aggressive malignancy with a high mortality rate. It is most commonly diagnosed at an advanced stage; only 30% of patients are eligible to undergo resection with curative intent. Despite the advanced presentation at diagnosis and aggressive clinical course typically observed in patients with pancreatic cancer, quantitative analysis of the timing of genetic evolution suggests that at least a decade takes place between the initial mutation and development of the first malignant (nonmetastatic) pancreatic cancer cell and that approximately 5 additional years are required for the primary tumor to develop metastatic potential…. This suggests that a direct causal role for [Victoza (liraglutide)] in the initial development of pancreatic cancer in patients participating in the LEADER trial is unlikely given the short latency period between exposure and diagnosis of pancreatic cancer. There is insufficient information available to elucidate whether [Victoza (liraglutide)] treatment plays a role in accelerating the evolution of primary or metastatic disease following occurrence of the initial mutation that will ultimately lead to clinically evident pancreatic cancer, given the relative short follow-up period (median follow-up of 3.5 years).
This part of the document goes on to indicate that the FDA is still concerned about pancreatic cancer being a possible side effect of Victoza:
In summary, taking into consideration the totality of information available, the additional information provided in LEADER does not appear to substantively alter the original FDA and EMA conclusions regarding the lack of sufficient information to conclusively determine whether long term exposure to GLP-RAs increase the risk of pancreatic cancer. Longer follow-up (e.g., 10 years) is recommended to further characterize the relationship between GLP-1 RAs [e.g., Victoza] and the development of pancreatic cancer.
We will continue to follow this pancreatic cancer safety issue for Victoza, watching for any actions taken by the FDA and other drug regulators as well as monitoring the relevant medical journals.
The June 8, 2017 edition of The New England Journal of Medicine (NEJM) has a “To the Editor” letter, titled “Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor”, which is likely causing some concerns among doctors and type 2 diabetes (T2D) patients. It is about the safety of Jardiance, Invokana, Farxiga, and other diabetes medicines in the SGLT2 inhibitor class of diabetes drugs.
A June 7, 2017 MedPage Today article, “Study Warns of Diabetic Ketoacidosis With SGLT2 Inhibitors in T2D”, provides a summary and some commentary about the recent medical study which is described in this June 2017 NEJM letter to the editor:
The newest class of drugs for treating type 2 diabetes carries a greater risk for diabetic ketoacidosis compared to other classes of drugs, a new study suggests.
Newly initiated use of an SGLT2 inhibitor was associated with a roughly twofold greater risk of diabetic ketoacidosis versus new initiation of a DPP4 inhibitor (HR 2.2, 95% CI 1.4 to 3.6), according to Michael Fralick, MD, of Brigham and Women’s Hospital, and colleagues….
It is important to know that if diabetic ketoacidosis (DKA) is not treated, it can lead to severe illness or death. In more detail, possible complications of DKA include these medical conditions:
- Cerebral Edema (fluid buildup in the brain)
- Bowel Necrosis (death of bowel tissue due to low blood pressure)
All of these newer diabetes medicines are part of the Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors class of drugs:
Invokamet (canagliflozin and metformin)
Invokamet XR (canagliflozin and metformin extended-release)
Xigduo XR (dapagliflozin and metformin extended-release)
Qtern (dapagliflozin and saxagliptin)
Glyxambi (empagliflozin and linagliptin)
Synjardy (empagliflozin and metformin hydrochloride)
Synjardy XR (empagliflozin and metformin hydrochloride)
We are currently investigating possible drug injury lawsuits against the responsible pharmaceutical companies for diabetes patients who have developed diabetic ketoacidosis (DKA), with or without cerebral edema and bowel necrosis.
We continue to monitor the safety profile of Harvoni and Sovaldi, which have been associated with the possibility of liver cancer recurrence.
The May 2017 edition of Health Product InfoWatch included this report, “Summary Safety Review – Direct-Acting Antivirals – Assessing the Potential Risk of Liver Cancer Recurrence”, which was issued on April 27, 2017 by Health Canada.
From the Safety Review Findings part of same report we get this detailed information:
At the time of the review, Health Canada had received 3 unique Canadian reports of liver cancer recurrence related to DAAs use (2 with Sovaldi and 1 with Holkira Pak [(known as Viekira Pak in the US)]). All 3 reports were considered to be related to the use of DAAs. However, other factors present in the cases may have played a role in the liver cancer recurrence, such as serious scarring of the liver (cirrhosis), previous history of liver cancer and other treatments known to be associated with a higher risk of liver cancer recurrence, including surgery and a cancer treatment using radio waves (radiofrequency ablation).
This safety review also looked at information from 14 international reports of liver cancer recurrence related to DAAs use: 9 reports involved Sovaldi, 4 reports involved Harvoni and 1 report involved Holkira Pak [(known as Viekira Pak in the US)]. All 14 reports were considered to be related to DAAs use. However, factors known to be associated with a higher risk of liver cancer recurrence may have played a role.
A search of the scientific literature identified 7 relevant studies describing the recurrence of liver cancer related to DAA use. The safety review could not conclude whether the use of DAAs played a role because the lengths of time the patients were monitored were different between the studies. The patients also had a variety of risk factors for liver cancer, including HCV infection, cirrhosis, previous history of liver cancer and advanced age.
Some studies have found that liver cancer recurrence was more likely to happen in patients who underwent surgery or radiofrequency ablation compared to those patients that received a liver transplant.
Besides the possibility of liver cancer recurrence, Harvoni, Sovaldi, and Viekira Pak as well as the several other newer hepatitis C medicines which are part of the Direct-Acting Antivirals (DAAs) class of drugs have been associated with acute liver injury, liver failure, and reactivation of hepatitis B.
A May 24, 2017 Reuters news report, “Deadly brain infection in German MS patient prompts Roche investigation”, brings some unwanted attention to a potential drug safety issue for Ocrevus (ocrelizumab injection) which may negatively affect this projected sales success. From this recent Reuters article:
A person in Germany treated with Roche Holding AG’s new multiple sclerosis drug Ocrevus has been diagnosed with an often-deadly brain infection after switching from another medication earlier this year, the Swiss drugmaker said on Wednesday.
Roche said it was investigating a case of Progressive Multifocal Leukoencephalopathy (PML) in a patient previously being treated for three years with Biogen Inc’s Tysabri and who had received a single dose of Ocrevus in February.
Roche is trying to determine the source of the illness but MS drugs that suppress the immune system can increase the risk of serious infections.
Ocrevus was approved in the United States in March.
Roche said the case of the rare brain disease that is usually fatal or disabling was reported as a carry-over from Tysabri, also known as natalizumab, by the physician who had been treating the patient.
Biogen issued a statement that made no mention of the possible Tysabri connection to the case….
Roche has said no PML cases emerged during its trials of Ocrevus, but the company included warnings to patients taking the medication that there was a risk they could get the disease.
In the Prescribing Information for Ocrevus (accessed 5/25/17), in the Warnings and Precautions section, at part 5.2 Infections, one finds a warning about Progressive Multifocal Leukoencephalopathy (PML).
We will continue to follow this possible safety issue for Ocrevus, a new multiple sclerosis (MS) drug from Genentech and Roche.
On May 5, 2017 the Canadian drug regulatory agency issued this Dear Healthcare Professional Letter: “ARANESP – Risk of Severe Skin Reactions: Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis”.
From this recent Health Canada Aranesp alert we get this updated drug safety information:
In some patients, ARANESP has been associated with severe skin reactions, including life-threatening reactions called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS/TEN are serious life-threatening conditions that often begin with flu-like symptoms including fever, tiredness, muscle and joint pain which are followed by a widespread rash with reddening and blistering of the skin and moist lining of the mouth, eyes, nose, throat, or genital area. This often leads to peeling and shedding of the affected skin which looks like a severe burn. Patients should discuss any skin reaction with their doctor, and seek immediate medical attention if they experience any of the SJS/TEN symptoms.
As of October 31, 2016, cumulative exposure to ARANESP was estimated to be over 6 million patient-years in the post-marketing setting. The potential risk of SJS/TEN with ARANESP use was evaluated using the global safety databases. As of April 5, 2017, 11 cases of SJS and 4 cases of TEN have been reported internationally in patients treated with ARANESP. To date no Canadian cases of SJS/TEN related to ARANESP treatment have been identified.
This so-called “Dear Doctor” letter about Aranesp also informed that Health Canada is currently working with the manufacturer, Amgen Canada Inc., to include this safety information in the Canadian Product Monograph for Aranesp.
Aranesp (darbepoetin alfa) products for subcutaneous and intravenous use are approved by the FDA for two indications: (1) anemia due to chronic kidney disease; and, (2) anemia due to chemotherapy in patients with cancer.
We will be watching to see whether the FDA takes any similar regulatory action regarding the possible Aranesp side effects of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
All content by attorney Tom Lamb