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Sovaldi / Harvoni: “Black-Box” Warning About Hepatitis B Reactivation

In February 2017 a so-called “black-box” warning was added to the drug labels for Harvoni, Sovaldi, Technivie, Viekira Pak, and other direct-acting antivirals, warning doctors and patients that cases of hepatitis B virus (HBV) reactivation have been reported. Further, it states that some of those cases resulted in fulminant hepatitis, hepatic failure, and death.

For more details, we get the following from the Warnings and Precautions part of the February 2017 revised Sovaldi drug label:

5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death….

HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

Back in December 2016 Health Canada issued this document, “Summary Safety Review — Direct-acting antivirals ­– Assessing the Potential Risk of Hepatitis B Virus Reactivation”, from which we get the following key points:

  • Health Canada carried out a review of the potential risk of hepatitis B virus (HBV) reactivation with the use of DAAs. The review was triggered by reports that patients infected with both HBV and HCV may experience a reactivation of their HBV infection if DAAs are used to treat their HCV infection. These reports were identified by the European Medicines Agency (EMA).
  • Health Canada’s review concluded that there is a potential risk of HBV reactivation in patients co­infected with both HBV and HCV, and the use of DAAs. Health Canada has recommended that the safety information for all DAAs be updated to inform about this potential risk.

We will continue to monitor this aspect of the safety profile of Harvoni, Sovaldi, Technivie, Viekira Pak, and other direct-acting antivirals (DAAs) used increasingly in the US and elsewhere to treat the hepatitis C virus (HCV).

[Read this article in full at original source]


Eliquis MDL For Federal Lawsuits; In California, JCCP Petition Pending

In the federal court system, there are now more than 50 Eliquis lawsuits filed, and more of these drug injury and death cases are expected. Given this situation, in early February 2017 the United States Judicial Panel on Multidistrict Litigation (JPML) established this consolidation of all federal court Eliquis cases, IN RE: ELIQUIS (APIXABAN) PRODUCTS LIABILITY LITIGATION — MDL No. 2754.

From the February 7, 2017 JPML Order establishing this Eliquis federal court MDL we get this information about the litigation:

[W]e find that these actions involve common questions of fact, and that centralization will serve the convenience of the parties and witnesses and promote the just and efficient conduct of this litigation. All the actions share common factual questions arising out of allegations that plaintiffs suffered severe bleeding and related injuries as a result of taking Eliquis (apixaban), that defendants did not conduct sufficient testing of the drug, and that defendants’ warnings and instructions as to the alleged risks, including the unavailability of a reversal agent to counteract bleeding, were inadequate. Issues concerning the design, testing, manufacture, regulatory approval, labeling, and marketing of Eliquis thus are common to all actions….

We conclude that the Southern District of New York is an appropriate transferee district for this litigation. Common defendants BMS and Pfizer both have their corporate headquarters within the district, and therefore relevant documents and witnesses are likely to be located there. Sixteen actions on the motion and three potential tag-along actions are pending there.

In addition to the federal court Eliquis cases, there are a significant number of Eliquis lawsuits filed in the California state court system. As a result, a petition to coordinate those California Eliquis cases was submitted to the Chair of the Judicial Council seeking to establish a consolidation, there, which would be similar to the federal court Eliquis MDL.

In California, if that petition to coordinate the Eliquis lawsuits — which was submitted to the Chair of the Judicial Council (the Chief Justice) and then assigned to a motion judge for determination — is granted, its result would be called the California Eliquis JCCP (Judicial Council Coordination Proceedings).

It is currently expected that the determination about the creation of this California Eliquis JCCP will be made in the next couple of months.

[Read this article in full at original source]


Warnings About Significant Liver Injury Added To Tecfidera Drug Label

In January 2017 liver injury was added to the Warnings and Precautions part of the Prescribing Information document, or drug label, for Tecfidera (dimethyl fumarate), which was approved by the FDA in 2013 as a treatment of patients with relapsing forms of multiple sclerosis (MS).

We get background information and some commentary from this February 1, 2017 Medscape Medical News article, “Dimethyl Fumarate for MS: Liver Injury Warning Strengthened”:

The prescribing information for the oral multiple sclerosis (MS) medication dimethyl fumarate (Tecfidera, Biogen) has been updated to include a warning of potential liver injury that could require hospitalization.

The new information notes that clinically significant cases of liver injury have been reported in patients treated with the drug in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment….

MS experts contacted by Medscape Medical News did not think the labeling change would make much difference to its use.

“The incidence of liver function abnormalities appears to be rare, but the new labeling informs prescribers that monitoring will be necessary,” said Edward Fox, MD, MS Clinic of Central Texas, Round Rock. “I would expect that this will lead to more frequent laboratory testing early in the course of treatment, but would be very unlikely to affect prescribing patterns. Personally, it won’t change what I have already been doing. Most disease-modifying treatments for MS, including all approved oral therapies, have labeling reflecting a risk of hepatic injury.”…

But Mark S. Freedman, MD, Ottawa Hospital, Ontario, Canada, noted that this was another side effect to have shown up with the drug since it reached the market.

“Tecfidera is not the ‘honey’ it was reported to be from the clinical trials,” he commented. “Progressive multifocal leukoencephalopathy and other opportunistic infections (herpes), hepatotoxicity, renal toxicity, and other issues have all surfaced since the trials were reported.”

We will continue to monitor the medical literature and adverse event reports for significant cases of liver injury associated with the use of Tecfidera by MS patients.

[Read this article in full at original source]


Newer Hepatitis C Drugs Harvoni And Sovaldi Could Cause Liver Failure

A new Institute for Safe Medication Practices (ISMP) report, “New Safety Issues for Hepatitis C Antivirals”, appeared in the “ISMP QuarterWatch: January 25, 2017 — New data from 2016 Q2″ publication.

Here are some of the details from the full report on this recent ISMP research project which examined Harvoni, Sovaldi, and other hepatitis C medicines in the direct-acting antivirals (DAAs) class of drugs:

… [W]e searched the most recent 12 months of FAERS data for acute liver failure cases associated with these new drugs. Acute liver failure is a rare, dramatic, and catastrophic medical emergency that involves sudden damage to so much liver tissue that continued survival is at risk. While most organs are ultimately affected, one critical symptom is encephalopathy–a brain dysfunction that can involve psychiatric disturbances, motor problems, hyperventilation, and even coma…. [footnote omitted]

For the 12 months ending June 30, 2016, we identified 524 reported cases worldwide of liver failure in which one of the nine direct-acting antivirals was a primary or secondary suspect drug…. The 524 liver failure cases occurred more frequently in males (55%) and in patients with a median age of 61 years. In these reports, 165 cases (31.5%) had an outcome of death at the time the report was submitted. Overall, 90% of the reports were originated by health professionals, including 34 cases extracted from the medical literature with duplicate references excluded. Table 4 shows 55 cases involved liver transplants, but it was not clear whether the transplants were a treatment for liver failure, or whether the event might have occurred in a post-transplant population. These cases reflect the global reported adverse event experience, with 386 (73.7%) from outside the U.S.

And from the Executive Summary section of this January 2017 ISMP QuarterWatch publication, we get these additional facts about the liver failure cases associated with Sovaldi, Harvoni, and other “Hep C” DAAs:

The 524 reported cases of liver failure included all the approved direct-acting antivirals as either primary or secondary suspect drugs, often in combination with each other or with ribavirin. Almost half the cases also included the hallmark symptom of liver failure, encephalopathy, which is a form of brain injury resulting in delirium, personality changes, suicidal behavior, sleep-wake reversal, and coma. Overall, 165 (31.5%) had died at the time of the report. While it was challenging to separate cases to which complications of hepatitis C might have contributed, 90% of the cases were submitted by healthcare professionals, who would be likely to understand the natural progression of the disease.

We will continue to monitor this new drug safety issue and are interested in hearing from or about any hepatitis C patients treated with Sovaldi or Harvoni who developed liver failure or were diagnosed liver injury, which might have been caused by these drugs.

[Read this article in full at original source]


Leukemia Drug Iclusig Had More Safety Warnings Added In November 2016

Here is overview of this rather significant and substantial November 2016 Iclusig Prescribing Information revision which was mandated by the FDA.

In the Boxed Warning section of the Iclusig drug label there was some additional safety information put in the pre-existing parts about (1) various types of arterial occlusions and (2) heart failure. Also, there is a new part entitled Venous Thromboembolism which addresses venous occlusive events.

Under the Warnings and Precautions section of the Iclusig drug label there were some additional facts and new information put in the following pre-existing parts, which are presented the order in which they were set forth on the FDA CDER SLC page for Iclusig:

5.1 Arterial Occlusion
5.10 Hemorrhage
5.11 Fluid Retention
5.12 Cardiac Arrhythmias
5.13 Myelosuppression
5.14 Tumor Lysis Syndrome
5.17 Embryo-Fetal Toxicity
5.2 Venous Thromboembolism
5.3 Heart Failure
5.4 Hepatotoxicity
5.5 Hypertension
5.6 Pancreatitis
5.8 Neuropathy
5.9 Ocular Toxicity

Further, under Warnings and Precaution, there is this new part: 5.15 Reversible Posterior Leukoencephalopathy Syndrome (RPLS).

Iclusig (ponatinib) is a kinase inhibitor approved by the FDA as a treatment for certain types of leukemia in adult patients.

Finally as regards this limited Iclusig label changes overview, under the Adverse Reactions section of the Iclusig drug label there was some additional facts and new information put in this pre- existing part, 6.1 Clinical Trial Experience.

The complete set of new side effects warnings can be seen on the FDA’s Drug Safety Labeling Changes (SLC) page for Iclusig.

We will continue to monitor the safety profile of the leukemia drug Iclusig and to report significant future developments.

[Read this article in full at original source]


Is The Risk Of Liver Cancer Increased From Use Of Harvoni Or Sovaldi?

As regards the liver cancer risks that have been mentioned in connection with the hepatitis C drugs Sovaldi and Harvoni, during the past nine months there have been mixed messages about whether there is an apparent side-effect situation or not.

We start our update on this still emerging drug safety issue with this April 2016 Medscape news report, “Liver Cancer Found in Hepatitis C Patients on New Antivirals”, from which we get this excerpt:

In a surprising number of patients with hepatitis C and cirrhosis, hepatocellular carcinoma develops within weeks of starting treatment with direct-acting antivirals, new research suggests.

“I do not think that direct-acting antivirals are directly responsible,” said lead investigator Stefano Brillanti, MD, from the University of Bologna, Italy.

“The hypothesis is that immune surveillance may be reduced too rapidly,” he told Medscape Medical News. “You have an immediate drop in viremia, but also attenuation of inflammation. I think inflammation is a bad thing in terms of hepatitis progression, but it may be a good thing in terms of controlling cancer.”

Then we move forward to this November 2016 article published by PracticeUpdate as part of their Gastroenterology section, “Direct-Acting Antiviral Medications for Hepatitis C Virus Infection Do Not Raise Cancer Risk”, from which we get this more recent information:

Patients with hepatitis C who take direct-acting antiviral medications have been found to be at no higher risk of developing liver cancer than those who do not take the medication. If they do develop liver cancer, however, they might be at an increased risk of more aggressive, infiltrative patterns of cancer.

This finding of a retrospective database study was reported at The Liver Meeting 2016, from November 11 – 15.

Alfredo Alberti, MD, of the University of Padova, Italy, explained, “Data on clinical outcomes in cirrhotic patients with hepatitis C treated with direct-acting antiviral agents are still scanty and controversial. This is the case concerning the development of a liver cancer, one of the most frequent and deadly complications of hepatitis C virus infection.”

We will continue to monitor the medical literature and watch for any drug regulatory agency action concerning the possible association between direct-acting antiviral hepatitis C drugs like Sovaldi and Harvoni with liver cancer diagnoses, be it the initial incidence or a recurrence of the hepatocellular carcinoma.

[Read this article in full at original source]


Invokana Has New Warning About Risk Of Lower Limb Amputation In Canada

We continue to monitor the drug safety regulators as well as the medical literature concerning the possible link between an increased risk of these amputations and the use of SGLT2 inhibitors such as Invokana, Invokamet, Farxiga, Xigduo XR, and Jardiance.

From the Health Product InfoWatch newsletter — formerly The Canadian Adverse Reaction Newsletter (CARN) — put out by Health Canada in December 2016, under the “Product monograph updates” heading, we get this drug safety development:

Invokana (canagliflozin) and Invokamet (canagliflozin and metformin hydrochloride)

The risk of lower limb amputation, primarily of the toe, has been added to the Adverse Reactions section of the Canadian product monographs for Invokana (canagliflozin) and Invokamet (canagliflozin and metformin hydrochloride).

As background, from this July 2016 Medscape Medical News report, “EMA Extends Amputation Investigation to All SGLT2 Inhibitors” (free registration required to access article):

The European Medicines Agency (EMA)’s Pharmacovigilance Risk Assessment Committee (PRAC) has extended the scope of its investigation into the possible link between the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana, Vokanamet, Janssen) and amputations to include other drugs of the same class.

Now, the PRAC’s review will include the other SGLT2 inhibitor medicines dapagliflozin (Farxiga, Xigduo XR, AstraZeneca), and empagliflozin (Jardiance, Boehringer Ingelheim), based on the determination that the potential risk may be relevant for them as well.

And back in mid-May 2016 there was this item, “FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate”.

Since then, we have not heard again from the FDA about the results of this investigation regarding leg, foot, and toe amputations possibly caused by the use of Invokana and Invokamet.

[Read this article in full at original source]


December 2016: FDA Requires Safety Warnings Label Change For Jardiance

After the December 2, 2016 decision by the FDA to expand the health benefits for the relatively new diabetes medicine Jardiance (empagliflozin) to include preventing fatal heart attacks and strokes in type 2 diabetes patients, we saw news reports about its expected effect on Jardiance sales in the U.S.

From this December 9, 2016 Reuters article, “New diabetes guidelines imminent, Jardiance sales may surge”, we get this information:

Two leading U.S. medical societies are poised in the coming weeks to issue new diabetes treatment guidelines reflecting the lifesaving cardiovascular effects of Eli Lilly’s Jardiance in a move expected to drive up the drug’s sales.

The forthcoming guidelines from the American Diabetes Association and the American Association of Clinical Endocrinologists….

[Ashtyn Evans, an analyst with the Edward Jones investment company,] predicted that doctors would now favor Jardiance for new patients over other similar drugs called SGLT-2 inhibitors, including Johnson & Johnson’s Invokana and AstraZeneca’s Farxiga, until they complete their own heart-protection studies in the next two years.

What did not get this same type of media coverage was the other part of the FDA’s December determination, a “Revised: December 2016” Jardiance Prescribing Information document — also called the package insert or drug label — which contains increased warnings about some serious side effects.

From that new Jardiance drug label (accessed 12/12/2016), at “5 Warnings and Precautions”, we get this updated safety information:

5.2 Ketoacidosis

Fatal cases of ketoacidosis have been reported in patients taking JARDIANCE.

5.3 Acute Kidney Injury and Impairment in Renal Function

JARDIANCE causes intravascular volume contraction and can cause renal impairment. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including JARDIANCE; some reports involved patients younger than 65 years of age.

We point out that similar drug safety information was added back in August 2016 to the drug label for Invokana (canagliflozin), another diabetes medicine in the SGLT-2 inhibitors class of drugs.

Of course, we will continue to watch for reports of Jardiance adverse drug reactions (ADRs) made to the FDA or included in future medical journal articles.

[Read this article in full at original source]


Long-Term Use Of Prevacid, Prilosec, and Nexium May Lead To Strokes

In November 2016 we learned about a new study that suggests these popular category heartburn medications, known as proton pump inhibitors (PPIs), may increase the risk of ischemic strokes.

From a press release from the American Heart Association, “Popular heartburn medication may increase ischemic stroke risk”, we get the following facts:

A popular group of antacids known as proton pump inhibitors, or PPIs, used to reduce stomach acid and treat heartburn may increase the risk of ischemic stroke, according to preliminary research presented at the American Heart Association’s Scientific Sessions 2016….

Ischemic stroke, the most common type of stroke, is caused by clots blocking blood flow to or in the brain.

… Researchers determined if the stroke occurred while patients were using 1 of 4 PPIs: omeprazole (Prilosec), pantoprazole (Protonix), lansoprazole (Prevacid) and esomeprazole (Nexium).

For ischemic stroke, researchers found:

Overall stroke risk increased by 21 percent when patients were taking a PPI.

At the lowest doses of the PPIs, there was slight or no increased stroke risk.

At the highest dose for these 4 PPI’s, stroke risk increased from 30 percent for lansoprazole (Prevacid) to 94 percent for pantoprazole (Protonix).

We will continue to monitor the various side effects that have been associated with the use of Nexium, Prilosec, and Prevacid, as well as proton pump inhibitors (PPIs) heartburn drugs and acid reflux medicines.

[Read this article in full at original source]


Defendants BMS And Pfizer Ask For Eliquis Lawsuits Federal Court MDL

On October 13, 2016 attorneys for Bristol-Myers Squibb Company and Pfizer Inc. filed with the United States Judicial Panel on Multidistrict Litigation (JPML) this court document, “BRISTOL-MYERS SQUIBB COMPANY AND PFIZER INC.’S MOTION FOR TRANSFER OF RELATED ELIQUIS (APIXABAN) PRODUCTS LIABILITY ACTIONS FOR COORDINATED PRETRIAL PROCEEDINGS PURSUANT TO 28 U.S.C. § 1407, which will refer to as “Defendants’ MDL Motion” hereafter.

As for why these two drug companies think that Eliquis lawsuits filed in the federal court system should be consolidated as a Multidistrict Litigation (MDL) case, we get this statement from the aforementioned Defendants’ MDL Motion:

While the claims vary slightly among the various complaints, the crux of the Related Actions is that each Plaintiff experienced bleeding while taking Eliquis, and that Defendants should be held liable for Plaintiffs’ injuries under a variety of theories, including that: (1) Defendants failed to warn adequately about the risk of bleeding; and (2) Defendants should not have sold Eliquis without precautions for blood monitoring or an additional drug to reverse its anticoagulant effect. Thus, Plaintiffs’ claims are based on a common set of core facts.

In a separate court document, “BRISTOL-MYERS SQUIBB COMPANY AND PFIZER INC.’S MEMORANDUM OF LAW IN SUPPORT OF THEIR MOTION FOR TRANSFER OF RELATED ELIQUIS (APIXABAN) PRODUCTS LIABILITY ACTIONS FOR COORDINATED PRETRIAL PROCEEDINGS PURSUANT TO 28 U.S.C. § 1407”, the two drug companies suggest to the JPML that this possible Eliquis MDL be assigned to U.S. District Judge Lewis A. Kaplan of the Southern District of New York.

It is currently anticipated that the Defendants’ MDL Motion will be considered by the JPML at the upcoming hearing session scheduled for January 26, 2017, in Miami, Florida.

Be assured we will be watching for the JPML’s determinations about the requested creation and suggested assignment of this federal court Eliquis MDL case.

[Read this article in full at original source]

Is Eliquis A Safe Alternative To Warfarin For Patients On Dialysis?

In this article published online by Pharmacy Times in August 2016, “Is Apixaban Safe and Effective for Patients on Hemodialysis?”, Brandon Dyson, PharmD, BCPS, who is a clinical pharmacist at an academic medical center, puts some scrutiny on Eliquis, an increasingly popular blood-thinner drug:

[Eliquis (apixaban)] is the only [novel oral anticoagulants (NOAC)] approved for use with creatinine clearance <15 mL/min. In fact, according to its package insert, there isn’t even a dose adjustment….

[T]he clinical trials for [Eliquis (apixaban)] didn’t include hemodialysis (HD) patients, but they’re able to recommend [Eliquis (apixaban)] use in HD patients with no dose adjustment. How?

You must dig deep to find the answer. The [Eliquis] package insert mentions a single-dose pharmacokinetic study in HD patients. If you dig a little further, you’ll eventually find it, and you’ll find out it only involved 8 patients….

What happens if you give multiple doses? [Eliquis (apixaban)] dosing is 5 mg BID in most patients. Does it accumulate in HD? We don’t know; it hasn’t been studied.

All we currently have is data from a single-dose trial in 8 patients. And that’s the point I’m trying to make. [Eliquis (apixaban)] may very well be safe and effective in HD, but we don’t actually know. It might be safe, but not effective, or it might be effective, but not safe. It also may be neither.

As for his mention of that eight (8) patient study, he referenced this medical journal article, “Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.”, published in the May 2016 print edition of The Journal of Clinical Pharmacology.

Of course, this clinical pharmacist’s concern about — or skepticism of, perhaps — Eliquis use in the setting of hemodialysis piqued our interest.

The only thing we were able to readily find on-point was this item, “Apixaban in Hemodialysis”, on the website, which provided us some rather limited information:

  • This study has been completed.
  • Sponsor: Jewish General Hospital
  • First received: January 12, 2016
  • Last updated: August 29, 2016
  • No Study Results Posted on for this Study

So, it seems, there is not much publicly available data about the safety of using Eliquis in the setting of hemodialysis. Yet, such use was apparently approved by the FDA.

[Read this article in full at original source]


All content by attorney Tom Lamb

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