Drug Injury Watch

Eliquis May Appear To Be Safer Than Xarelto, But There Is No Randomized Head-To-Head Clinical Trials Comparing The Two, Yet

One Unfortunate Fact These Two New Blood-Thinners Have In Common Is That Neither Has An FDA-Approved Antidote At Present Time

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Earlier this month the medical journal Chest published online (Epub ahead of print) this article, "Direct comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in nonvalvular atrial fibrillation".

Also earlier this month, JAMA Internal Medicine published online (Epub ahead of print) this article, "Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation."

In both of these medical study reports it seemed that Xarelto (rivaroxaban) was more likely to be involved in a serious bleeding event as an adverse reaction than was either Pradaxa (dabigatran) or Eliquis (apixaban).

We previously touched upon the significance of these two new medical journal articles about a year ago with this post, "Is Eliquis Safer Than Xarelto And Pradaxa If It Causes Fewer Dangerous Major Bleeding Events -- Perhaps, But Neither Eliquis Nor Xarelto Have Any Specific Reversal Agent To Stop An Acute Bleed Once It Starts; Only Pradaxa Does".

To set up this latest report on the safety controversy surrounding these non-vitamin K antagonist oral anticoagulants (NOACs), as they are sometimes referred to -- but see also this recent related report, "What's in a Name? Debate on What to Call Novel Oral Anticoagulants" -- we want to provide some market-share information. From an October 21, 2016 CardioBrief article by Larry Husten, "Eliquis Nipping At Heels of Top-Selling NOAC Xarelto":

According to recent data from IMS Health, [Xarelto (rivaroxaban)] now has 46.5% of the NOAC market, compared with a 42.5% share for [Eliquis (apixaban)]. This represents a decline in share for rivaroxaban from a peak of about 60% of the market, while [Eliquis (apixaban)] has enjoyed continuous growth in its market share over the last few years. By contrast, dabigatran (Pradaxa) has 10.5% of the market and edoxaban (Savaysa) a minuscule 0.5% of the market.

So here we will be focusing on the two market-share leaders in this increasing popular class of blood-thinning drugs.

 

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 Eliquis  ---  Savaysa  ---  Xarelto

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As for what we know now, and what we need to learn going forward, we get these insights from this October 7, 2016 article, "More NOAC Comparisons See Higher Bleeding Risk With Rivaroxaban: Is the ‘Writing on the Wall’?":

The two new studies [published in the medical journal Chest and JAMA Internal Medicine] come close on the heels of an analysis by Danish researchers comparing [Pradaxa (dabigatran)], [Xarelto (rivaroxaban)], [Eliquis (apixaban)], and warfarin. In that analysis, [Pradaxa (dabigatran)] and [Eliquis (apixaban)] were associated with a significantly decreased risk of ICH compared with warfarin, but [Xarelto (rivaroxaban)] was not, although all three NOACs were as effective as warfarin at reducing stroke in atrial fibrillation patients. Laila Stærk, MD (Herlev and Gentofte University Hospital, Denmark), who presented that data at the recent European Society of Cardiology Congress 2016, spoke about the new data with TCTMD today, choosing her words carefully.

“We know the limitations of registry studies, which include the possibility of unmeasured confounders,” Stærk observed. That said, she continued, “We are seeing a tendency—and we have seen it now in different countries—suggesting that maybe all NOACs are not the similar in terms of safety.”...

To date there are no randomized head-to-head trials comparing the new agents, but that is about to change. Stærk told TCTMD that a new prospective, cluster randomized trial has just been announced in Denmark that will involve “almost all” hospitals in the country. Designed to run for 4 years, each hospital will just use one of the four approved NOACs ([Pradaxa (dabigatran)], [Xarelto (rivaroxaban)], [Savaysa (edoxaban)], and [Eliquis (apixaban)]) for the period of 1 year, then the next the next year, and so forth. At the end of the 4-year period, every participating hospital will have 1 year’s experience with each of the approved NOACs, with follow-up to continue for several years thereafter. Dubbed DEN-NOAC, the trial will be led by Casper Bang, MD (Rigshospitalet, Copenhagen, Denmark).

Lastly, as regards the current "no antidote" situation, you can read this relatively recent report, "Xarelto / Savaysa / Eliquis: Antidote Drug AndexXa Is Rejected By FDA In August 2016, Surprising Many Pharma Industry Observers (And Doctors?)".

Of course, we will continue to monitor the still-emerging safety issues surrounding Eliquis, Savaysa, and Xarelto.

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

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Viagra MDL For Melanoma Side Effect Legal Claims May Expand To Include Cialis Lawsuits, Soon, And Levitra Cases, Later

There Is An Apparent Melanoma Skin Cancer Link For Each Of These ED Drugs Given How PDE5 Inhibition Augments Tumor Cell Invasiveness

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

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UPDATE: IN RE: Viagra (Sildenafil Citrate) and Cialis (Tadalafil) Products Liability Litigation, MDL-2691 --  As of the first part of January 2017 there were 263 Viagra and Cialis cases filed according to the document "MDL Statistics Report - Distribution of Pending MDL Dockets by District -- Report Date: 1/17/2017", issued by the United States Judicial Panel on Multidistrict Litigation.

(2/16/17)

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Viagra (sildenafil) was the first drug prescribed for male erectile dysfunction (ED) associated with an increased risk for malignant melanoma, starting back in 2014.

In the past year there have been medical articles published suggesting that the four other brand name ED drugs which are phosphodiesterase 5 (PDE5) inhibitors -- Cialis (tadalafil), Levitra (vardenafil), Staxyn (vardenafil), and Stendra (avanafil) -- are associated with an increased risk of melanoma skin cancer, too. Essentially, the active ingredients sildenafil, tadalafil, vardenafil, and avanafil which are found in these drugs act by inhibiting the phosphodiesterase 5 (PDE5). In turn, PDE5 inhibition augments tumor cell invasiveness, which promotes the development of malignant melanoma.

As regards drug injury lawsuits concerning this melanoma side effect of ED drugs, that litigation began with Viagra cases being filed against Pfizer, the drug company responsible for Viagra. By April 2016 there was a sufficient federal court Viagra lawsuits filed that the Judicial Panel on Multidistrict Litigation (JPML) decided to create the so-called Viagra MDL, known fully as IN RE: VIAGRA (SILDENAFIL CITRATE) PRODUCTS LIABILITY LITIGATION -- MDL No. 2691. This federal court consolidation of Viagra lawsuits was assigned to Judge Richard Seeborg, of the Northern District of California. To date, more than 200 Viagra cases are pending before Judge Seeborg in San Francisco related to individuals being diagnosed with melanoma after using Viagra.

Not unexpectedly, the filing of Viagra lawsuits has been followed by the filing of Cialis lawsuits on behalf of men who have developed malignant melanoma, some of whom have died, unfortunately.

 

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In September 2016 the plaintiffs in some of those federal court Cialis cases asked the JPML to add their lawsuits to the Viagra MDL for various reasons, including the need for judicial economy, consistency in rulings, and the commonality among the Viagra and Cialis melanoma claims. That motion for what would then be a Viagra - Cialis MDL is currently pending.

Next, it is likely that there will be Levitra - melanoma lawsuits filed in the next few months. And, further, once the number of Levitra cases filed in federal court reaches a certain level, one anticipates a motion filed with the JPML requesting that those melanoma cases get added to an expanded federal court Viagra MDL.

For a brief history of how this melanoma drug injury litigation has developed, starting with the medical literature, here is a list of some of our past articles:

• Viagra / Cialis / Levitra – Melanoma: July 2016 Medical / Legal Update
• Melanoma Skin Cancer Side Effect Linked To Viagra / Cialis / Levitra
• Viagra – Melanoma MDL Motion For Federal Court Lawsuits Against Pfizer
• Cialis / Levitra / Viagra – Melanoma: Possible Drug Safety Issue Was Raised And Left Open In A 2011 Medical Journal Article
• The Link Between Popular Erectile Dysfunction (ED) Drug Viagra And Melanoma Has A Potential Molecular Basis According To Medical Expert Who Reviewed Recent Study
• Viagra May Increase Risk Of Melanoma In Men Who Have Used This ED Drug, According To An April 2014 Medical Journal Article

At the present time there are five ED pills in the phosphodiesterase 5 (PDE5) inhibitors class of drugs: Viagra; Cialis; Levitra; Staxyn; and, Stendra.

In addition, Cialis is prescribed sometimes when doctors see the signs and symptoms of benign prostatic hyperplasia (BPH).

Two other PDE5 inhibitors are Revatio (sildenafil) and Adcirca (tadalafil). These drugs are prescribed for the treatment of pulmonary arterial hypertension (PAH).

We are currently investigating cases of melanoma in men who used Viagra, Cialis, Levitra, Staxyn, or Stendra, as well as men and women who used Revatio or Adcirca. These cases are possible drug injury lawsuits against the responsible pharmaceutical companies, not the prescribing doctors.

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

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Risk of Hepatitis B Reactivation Associated With Gleevec, Iclusig, And Other BCR-ABL Tyrosine Kinase Inhibitors, According To Health Canada

While Mechanism And Frequency Currently Unknown, This Situation Can Involve Acute Hepatic Failure Or Fulminant Hepatitis Leading To Liver Transplantation Or Death

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Back in May 2016 Health Canada issued a safety warning, "BCR-ABL Tyrosine Kinase Inhibitors [GLEEVEC (imatinib mesylate), TASIGNA  (nilotinib), BOSULIF (bosutinib), SPRYCEL (dasatinib), ICLUSIG (ponatinib hydrochloride)] - Risk of Hepatitis B Reactivation",  which did not receive much public attention in the US.

According to this May 4, 2016 Health Canada document, BCR-ABL tyrosine kinase inhibitors (TKIs) are used for the treatment of  specific types of blood cancers, including Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) and Ph+ acute  lymphoblastic leukemia (ALL), and less commonly, other types of cancers.

The currently available medicines in this BCR-ABL TKIs class of drugs include:

• Gleevec (imatinib mesylate) -- Novartis Pharmaceuticals Canada Inc.
• Tasigna (nilotinib) -- Novartis Pharmaceuticals Canada Inc.
• Bosulif (bosutinib) -- Pfizer Canada Inc.
• Sprycel (dasatinib) -- Bristol-Myers Squibb Canada
• Iclusig (ponatinib hydrochloride) -- ARIAD Pharmaceuticals, Inc.

Further, according to Health Canada, this apparent side effect of HBV reactivation in chronic HBV carriers is considered to be a class-effect of BCR-ABL TKIs.

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Gleevec / Iclusig

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From that May 2016 Health Canada document, we get the following detailed safety information about these drugs:

A recent review of clinical trials and reports received in the post-marketing period as well as published medical literature  indicate that cases of HBV reactivation have occurred in patients who are carriers for the virus after receiving BCR-ABL TKIs. In some of the cases, HBV reactivation caused acute liver failure or fulminant hepatitis requiring liver transplantation or death.  HBV reactivation occurred at different points during therapy, with cases reported worldwide between three weeks and more than 8 years after starting treatment.

Although no mechanism for HBV reactivation has been identified to date, based on a review of the available evidence, HBV reactivation is considered to be a class effect of BCR-ABL TKIs.

This document goes on to note that the Canadian Product Monographs for all BCR-ABL TKIs drugs will be updated to reflect this new safety information concerning hepatitis B reactivation.

For patients, it is important to know the symptoms of hepatitis include weight loss, fever, abdominal pain, and nausea or vomiting followed by yellowing of the skin (jaundice).

We will continue to monitor this still relatively new safety development for Gleevec and Islusig, as well as Tasigna, Bosulif, and Sprycel. In particular, we will watch for developments regarding (1) the mechanism and (2) the frequency of HBV reactivation during treatment, both of which Health Canada says are not known at present.

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

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

Harvoni, Sovaldi, Viekira Pak, And Other Direct-Acting Antivirals Get Black-Box Warning: Risk Of Hepatitis B Virus Reactivation

October 2016 FDA Drug Safety Communication Warns About These Relatively New Drugs Which Are Increasingly Popular For Treating Chronic Hepatitis C

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

UPDATE:   "New Safety Issue: Direct-Acting Antivirals Drugs For Hepatitis C Such As Harvoni And Sovaldi Could Cause Liver Failure"

(1/30/17)

 

In April 2016 we posted this article, "European Drug Regulators Consider Whether Harvoni, Sovaldi, And Other New "Hep-C" Drugs May Cause Liver Cancer Return, Hepatitis B Reactivation".

Today, about six months later, the FDA indicated their concern for these relatively new chronic hepatitis C treatment drugs -- including Harvoni, Sovaldi, and Viekira Pak -- by issuing a Drug Safety Communication which started with this statement:

The FDA is warning about the risk of hepatitis B virus (HBV) becoming an active infection again in any patient who has a current or previous infection with HBV and is treated with certain direct-acting antiviral (DAA) medicines for hepatitis C virus. In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death. HBV reactivation usually occurred within 4-8 weeks.

As a result, FDA is requiring a Boxed Warning, our most prominent warning, about the risk of HBV reactivation to be added to the drug labels of these DAAs directing health care professionals to screen and monitor for HBV in all patients receiving DAA treatment. This warning will also be included in the patient information leaflet or Medication Guides for these medicines.

As background, direct-acting antivirals (DAAs) are a class of prescription medicines that are FDA-approved to treat adults with hepatitis C virus (HCV) infection. These medicines are available as single-ingredient products and also in combination with other HCV medicines.

Here is a list of direct-acting antivirals currently available in the US:

Daklinza (daclatasvir) -- Bristol-Myers Squibb
Epclusa (sofosbuvir and velpatasvir) -- Gilead Sciences
Harvoni (ledipasvir and sofosbuvir) -- Gilead Sciences
Olysio (simeprevir) -- Janssen
Sovaldi (sofosbuvir) -- Gilead Sciences
Technivie (ombitasvir and paritaprevir and ritonavir) -- Abbvie
Viekira Pak (dasabuvir and ombitasvir and paritaprevir and ritonavir) -- Abbvie
Viekira Pak XR (dasabuvir and ombitasvir and paritaprevir and ritonavir) -- Abbvie
Zepatier (elbasvir and grazoprevir) -- Merck Sharp Dohme

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Harvoni / Sovaldi / Technivie / Viekira Pak

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Returning to the "FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C", which was issued on October 4, 2016:

FDA identified 24 cases of HBV reactivation reported to FDA and from the published literature in HCV/HBV co-infected patients treated with DAAs during the 31 months from November 22, 2013 to July 18, 2016. This number includes only cases submitted to FDA, so there are likely additional cases about which FDA is unaware. Of the cases reported, two patients died and one required a liver transplant. HBV reactivation was not reported as an adverse event in the clinical trials submitted for the DAA approvals because patients with HBV co-infection were excluded from the trials.

And from that same FDA Drug Safety Communication about Harvoni, Sovaldi, and Viekira Pak, as well as other direct-acting antiviral (DAA) medicines for the hepatitis C virus, we get this more precise medical information:

• Hepatitis B virus (HBV) reactivation has occurred in patients co-infected with hepatitis C virus (HCV) while undergoing treatment with DAAs for HCV infection. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. This risk has been observed with DAAs used without interferon to treat HCV infection.
• HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of hepatitis B surface antigen (HBsAg) in a person who was previously HBsAg negative and hepatitis B core antibody (anti-HBc) positive. Reactivation of HBV replication is often followed by hepatitis, i.e., an increase in transaminase levels and, in severe cases, an increase in bilirubin levels, hepatic failure, and death.
• The mechanism through which HBV reactivation occurs is currently unknown.
• Cases of HBV reactivation have been reported in HCV patients treated with DAAs who are hepatitis B surface antigen (HBsAg) positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive), and were not receiving HBV antiviral treatment.

Finally, the FDA has advised patients using any of these DAA medicines for treat chronic hepatitis C virus (HCV) infection to contact their health care professional immediately if they develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or light-colored stools, as these may be signs of serious liver problems.

Of course, we will continue to monitor the safety profiles of Harvoni, Sovaldi, and Viekira Pak, as well as the several other direct-acting antiviral (DAA) medicines, and report further significant developments.

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

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