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FDA Concern About Whether Victoza Is Associated With Pancreatic Cancer

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.

[Read this article in full at original source]


Jardiance, Invokana, And Farxiga Double Risk Of Diabetic Ketoacidosis

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:

Invokana (canagliflozin)
Invokamet (canagliflozin and metformin)
Invokamet XR (canagliflozin and metformin extended-release)
Farxiga (dapagliflozin)
Xigduo XR (dapagliflozin and metformin extended-release)
Qtern (dapagliflozin and saxagliptin)
Jardiance (empagliflozin)
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.

[Read this article in full at original source]


No Link Seen Between Sovaldi Or Harvoni And Liver Cancer Recurrence

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.

[Read this article in full at original source]


Ocrevus Patient Gets Progressive Multifocal Leukoencephalopathy (PML)

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.

[Read this article in full at original source]


Health Canada Increases Warnings About Aranesp Skin Adverse Reactions

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).

[Read this article in full at original source]


Farxiga MDL Includes Diabetic Ketoacidosis And Kidney Damage Lawsuits

On April 6, 2017 the United States Judicial Panel On Multidistrict Litigation (JPML) issued this document, “IN RE: FARXIGA (DAPAGLIFLOZIN) PRODUCTS LIABILITY LITIGATION TRANSFER ORDER — MDL No. 2776”, from which we get the following information:

On the basis of the papers filed and the hearing session held, we find that these actions involve common questions of fact, and that centralization of these cases will serve the convenience of the parties and witnesses and promote the just and efficient conduct of this litigation. The actions share factual questions arising from allegations that taking Farxiga or Xigduo XR may result in patients suffering kidney-related injuries, such as diabetic ketoacidosis and kidney damage. The actions thus implicate numerous common issues concerning the development, manufacture, testing, regulatory history, promotion, and labeling of the drugs.

The JPML went on to assign this new Farxiga MDL to Judge Lorna G. Schofield, who will preside over this consolidated litigation in the Southern District of New York federal court.

The FDA is investigating a connection between Farxiga and Xigduo XR — as well as Invokana, Invokamet, Xigduo, Jardiance, Glyxambi, Synjardy, and Qtern — with several different serious side effects, including diabetic ketoacidosis (DKA) and kidney damage.

All of these diabetes drugs are Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors, a new class of diabetes medicines.

We will continue to monitor legal and drug safety developments regarding Farxiga, Xigduo XR, and the several other SLGT2 inhibitor diabetes drugs.

[Read this article in full at original source]


Children Who Developed Neuro-Psychiatric Problems After Taking MiraLAX

MiraLAX was initially approved by the FDA as a prescription drug laxative medicine.

In 2006 the FDA approved “over-the-counter use of MiraLAX (polyethylene glycol 3350) powder for solution for the treatment of occasional constipation (irregularity)”.

Despite the fact that MiraLAX is not intended for use by young children, pediatricians and other doctors have been prescribing or recommending MiraLAX use in that patient population for many years, apparently. Generally, this use of MiraLAX by children pursuant to their doctor’s guidance is called “off-label” use.

About 15 years to the day after MiraLAX was approved, and following many significant adverse events reports concerning children having been submitted to the FDA, it was finally decided that there should be a medical study done on the use of MiraLAX by young children.

This medical study, “The Use of Polyethylene Glycol in the Pediatric Population”, is currently underway at the Children’s Hospital of Philadelphia (CHOP).

What is remarkable, and sad, about the reason the FDA finally saw fit to establish and fund this investigative study of MiraLAX off-label use by children is presented in this February 14, 2017 report by Wendy Saltzman, of WPVI-TV in Philadelphia, “Action News Investigation: Parents Say Over-the-counter Medicine Sickening Kids”.

We get the following disturbing anecdotal reports of MiraLAX adverse reactions in children from the first part of that posted article by reporter Wendy Saltzman:

“We saw a lot of the anger, a lot of the rage, a lot of the aggression,” parent Mike Kohler said.

“Near psychiatric events with paranoia, mood swings, aggression, rage,” parent Jeanie Ward said.

“I feel like my son was absolutely robbed of most of his childhood,” parent Jessica Aman of Chester Springs, Pa. said.

“He had the rage, fears, phobias, anxieties,” parent Sarah Locatelli said.

Jeanie Ward’s daughter Nicole was placed on MiraLAX when she was just 3 1/2-years-old. Within ten days, she says Nicole turned manic, aggressive, and paranoid.

“It was horrifying to see my daughter change like that and to not come completely go back to normal,” Ward said.

We will be looking further into this possible drug-safety problem involving children who used MiraLAX and developed neurological side effects and/or significant psychiatric problems.

[Read this article in full at original source]


Can Hepatitis C Drugs Harvoni Or Sovaldi Cause Return Of Liver Cancer?

In April 2017 this news report, “The Link Between Direct-Acting Antiviral Therapy for Hepatitis C Virus and Liver Cancer Risk Continues To Be Debated”, was published on the PracticeUpdate website.

This recent report draws upon eight new medical studies which were presented at the International Liver Congress 2017, from April 19 to 23, 2017, in Amsterdam.

By means of the following excerpt from this report we get an update on the possible association between Sovaldi and Harvoni with liver cancer recurrence or return:

While remarkable progress has been made in the development of successful antiviral therapies for hepatitis C virus infection, recent studies suggest that curing patients of their hepatitis C virus does not eliminate their risk of developing liver cancer. An unexpectedly high rate of hepatocellular carcinoma recurrence is becoming apparent in patients whose tumor was treated successfully and had received direct-acting antiviral drugs.

The claim was further supported by a study led by Maria Reig, MD, of the Hospital Clinic Barcelona. Patients with hepatitis C virus and hepatocellular carcinoma who had been cured of hepatocellular carcinoma and received direct-acting antiviral therapy experienced a hepatocellular cancer recurrence rate of 31.2% (24/77). Of those who received treatment for hepatocellular carcinoma at recurrence, 30% (6 of 20) of patients presented progression in the immediate 6-month follow-up.

Dr. Reig said, “Our study results offer further support to previous findings of an unexpectedly high recurrence rate of hepatocellular carcinoma associated with direct-acting antiviral drugs. This association may result in a more aggressive pattern of recurrence and faster tumor progression. The data indicate that further research is needed to clarify the mechanism for the association between liver cancer recurrence and direct-acting antiviral therapy.”

This April 2017 news report also pointed out that several other medical studies presented at the same conference in Amsterdam suggested there is no link between Sovaldi or Harvoni use and liver cancer returning.

Accordingly, the issue of whether liver cancer recurrence is associated with Harvoni, Sovaldi, or other direct-acting antiviral” (DAA) hepatitis C drugs has not been definitively determined but, rather, remains under debate in the medical realm.

We will continue to monitor the medical literature for reports relevant to the safety profile of Harvoni and Sovaldi, as well as other “Hep-C” drugs in the DAA class, such as Viekira Pak, Technivie, Olysio, Daklinza, Epclusa, and Zepatier.

[Read this article in full at original source]


Breast Implants Lymphoma Cancer: Diagnosis And Treatment Developments

The medical literature about breast implant-associated ALCL (BIA-ALCL) grew considerably in 2015, and reflected a better understanding of the diagnosis and treatment aspects of this rare form of lymphoma.

In February 2015 this article, “Breast Implant-associated Anaplastic Large Cell Lymphoma: Updated Results from a Structured Expert Consultation Process”, was published in Plastic and Reconstructive Surgery-Global Open. From the Abstract for this article:

[A multidisciplinary panel] agreed that (1) this disease should be called “BIA-ALCL”; (2) late seromas occurring >1 year after breast implantation should be evaluated via ultrasound, and if a seroma is present, the fluid should be aspirated and sent for culture, cytology, flow cytometry, and cell block to an experienced hematopathologist; (3) surgical removal of the affected implant and capsule (as completely as possible) should occur, which is sufficient to eradicate capsule-confined BIA-ALCL; (4) surveillance should consist of clinical follow-up at least every 6 months for at least 5 years and breast ultrasound yearly for at least 2 years; and (5) BIA-ALCL is generally a biologically indolent disease with a good prognosis, unless it extends beyond the capsule and/or presents as a mass. They firmly disagreed with statements that chemotherapy and radiation therapy should be given to all patients with BIA-ALCL.

Next, in the March 2015 edition of Plastic and Reconstructive Surgery, came this report, “Anaplastic large cell lymphoma occurring in women with breast implants: analysis of 173 cases”, which provided this information:

[Anaplastic large cell lymphoma (ALCL)] lesions first presented as late peri-implant seromas, a mass attached to the capsule, tumor erosion through the skin, in a regional node, or discovered during revision surgery. The clinical course varied widely from a single positive cytology result followed by apparent spontaneous resolution, to disseminated treatment-resistant tumor and death. There was no preference for saline or silicone fill or for cosmetic or reconstructive indications. Where implant history was known, the patient had received at least one textured-surface device.

In October 2015 Clinics in Plastic Surgery published “Coming of Age: Breast Implant-Associated Anaplastic Large Cell Lymphoma After 18 Years of Investigation”, from which we get this excerpt:

Breast implant associated anaplastic large cell lymphoma (BIALCL) is a distinct clinical entity that can present in patients receiving either reconstructive or cosmetic breast implants. Presenting symptoms include onset of a delayed (>1 year after implantation) fluid collection, mass of the capsule, or lymphadenopathy. Treatment has progressed in recent years and most commonly includes implant removal and total resection of the tumor, including capsule, mass, and involved lymph nodes.

Given the developments medical researchers have made in understanding this breast implants lymphoma cancer situation, in March 2017 the FDA provided a summary of updated information it had collected in a new document, “Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL)”.

We continue to monitor the medical literature for articles about the diagnosis and treatment of BIA-ALCL as well as the various theories about how this rare form of lymphoma (blood cancer) develops in some women with breast implants.

[Read this article in full at original source]


Pradaxa And Xarelto May Double The Risk Of Heart Attacks Some Patients

In March 2017 the British Journal of Clinical Pharmacology published this article, “Risk of myocardial infarction in patients with atrial fibrillation using vitamin K antagonists, aspirin or direct acting oral anticoagulants”, which reports on the first retrospective cohort study to compare the risk of acute myocardial infarction (AMI), or heart attack, with use of direct-acting oral anticoagulants (DOACs) with that associated with vitamin K antagonists (VKAs), e.g., warfarin.

The bottom line is that the medical researchers conducting this study found a two-fold increase in the risk of heart attacks with use of Pradaxa (dabigatran) and Xarelto (rivaroxaban) in comparison with warfarin in patients using those drugs for atrial fibrillation (AF) therapy.

Specifically, from the Results section of the Abstract for this March 2017 medical journal article: “The risk of AMI was doubled when we compared current use of DOACs with current use of VKAs [adjusted HR 2.11; 95% confidence interval (CI) 1.08, 4.12]….”

And from the Discussion part of the full article:

In conclusion, our cohort study identified a twofold increase in the risk of AMI when using DOACs, [Xarelto (rivaroxaban)] or [Pradaxa (dabigatran)], in comparison with VKAs, in AF therapy in real-world patients. In addition, our results showed that in AF patients, the risk of AMI with current use of aspirin as monotherapy is higher than with current use of VKAs. VKAs probably have greater beneficial effects on AMI than DOACs. Ongoing research is needed as the use of DOACs increases in the population.

While this observational study reports that there is a correlation between the use of Xarelto (rivaroxaban) or Pradaxa (dabigatran) with an increased risk for myocardial infarction (MI), or heart attack, it is important to keep in mind that correlation does not prove causation.

Rather, in order to definitively answer the question “Do direct oral anticoagulants (DOACs) increase the risk for myocardial infarction (MI), or heart attack”, we will need a well-designed study. One hopes that Boehringer Ingelheim Pharmaceuticals (Pradaxa) or Janssen Pharmaceuticals (Xarelto), as the responsible drug companies, have such a drug-safety study currently underway or planned to begin soon.

[Read this article in full at original source]


March 2017 FDA Report: Breast Implants Linked To Lymphoma Blood Cancer

You may have heard about the March 2017 FDA update report concerning a little-known and rare type of lymphoma, or blood cancer, which has been developing in some women who have had breast implant procedures done for augmentation or reconstruction purposes.

From this March 21, 2017 article, “9 Deaths Are Linked to Rare Cancer From Breast Implants”, published by The New York Times (NYT), we get some basic information regarding this still-emerging health problem:

About 290,000 women in the United States had implants for breast enlargement in 2016, and 109,000 received them for reconstruction after breast cancer, according to the American Society of Plastic Surgeons.

In many cases when the lymphoma occurs, just removing the implant and the tissue around it eliminates the disease. But some women may need chemotherapy and radiation.

In more detail, the FDA updated its “Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL)” information page in March 2017.

The most notable new facts are found in the Medical Device Reports part of this FDA breast implants – lymphoma page, specifically the most-current figures on the number of BIA-ALCL cases:

As of February 1, 2017, the FDA has received a total of 359 medical device reports (MDRs) of BIA-ALCL, including nine deaths. There are 231 reports that included information on the implant surface. Of these, 203 were reported to be textured implants and 28 reported to be smooth implants. Most of the reports contained no information about the surface textures of any previous implants. In addition, 312 of the 359 reports included information on implant fill types. Of these, 186 reported implants filled with silicone gel and 126 reported implants filled with saline.

The earlier referenced March 21 NYT news story also provides some contextual information which seems to help us understand the timing of this recent FDA announcement about breast implants and lymphoma:

A spokeswoman for the F.D.A., Stephanie Caccomo, said Tuesday’s announcement was made because “in 2016, there were several advances in the description of the disease and treatment recommendations, including recognition of the disease by the World Health Organization and publication of diagnosis and treatment guidelines by the Plastic Surgery Foundation and National Comprehensive Cancer Network.”

Of course we will continue to monitor the medical literature and regulatory realm for further developments concerning breast implant-associated anaplastic large cell lymphoma (BIA-ALCL).

[Read this article in full at original source]



All content by attorney Tom Lamb

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