Drug Injury Watch

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

January 2017 ISMP Report: FDA Database Has 524 Cases Of Liver Failure, Including 165 Deaths, And 1,058 Reports Of Severe Liver Injury

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

A January 24, 2017 article published by The New York Times, "Are New Drugs for Hepatitis C Safe? A Report Raises Concerns", sets the stage for and captures the essence of this emerging drug safety issue for a relatively new class of drugs:

The drugs covered in the new report include two blockbusters, Sovaldi and Harvoni, both made by Gilead Sciences and priced at $1,000 a pill, with billions of dollars in sales. Sovaldi was approved in 2013, and Harvoni in 2014. These drugs and other antivirals can cure the disease in 12 weeks in many patients.

Earlier drugs were less effective, had to be taken for much longer and had harsh side effects that left many patients unable to finish the course of therapy.

About 250,000 people took the newer drugs in 2015, the report said, at tremendous expense: $55,000 to $125,000 per patient. In those treated during the year ending June 30, 2016, the report identified 524 with liver failure, 165 of whom died. Of those with liver failure, 386 were from outside the United States. An additional 1,058 had severe liver injury, and in 761 the drugs appeared not to work.

But whether the drugs were to blame is not known. The problems were observed by doctors who suspected drugs were the cause, but that does not prove cause and effect. And details about the patients’ medical histories were not available....

Thomas J. Moore, a senior scientist at the Institute for Safe Medication Practices [(ISMP)] and an author of the report, said the study reflected a larger question about the drug approval process. Approval for the newer hepatitis C drugs was expedited because better treatments were so badly needed. But does the rush to market come at a price?

“Gosh, here is something that really qualifies as a breakthrough, and we have policies to get it into use as quickly as possible, which means we know less about it,” Mr. Moore said. “Benefits and side effects evolve over the long term, not over 12 weeks.”

The underlying report, "New Safety Issues for Hepatitis C Antivirals", appeared in the "ISMP QuarterWatch:  January 25, 2017 — New data from 2016 Q2" publication.

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Harvoni / Sovaldi / Technivie / Viekira Pak

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From that document, we learn that after the FDA identified the first new major safety problem linked to the nine new direct-acting antiviral drugs for hepatitis C -- namely, that treatment with the likes of Sovaldi and Harvoni opened the door to reactivation of hepatitis B -- the ISMP undertook this project.

Here are some of the details from the resulting full report on their research:

... [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 and Harvoni:

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.  

In addition, we are interested in cases of hepatitis B reactivation in patients after using Solvaldi or Harvoni.

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

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Iclusig: Leukemia Drug With Many Different Serious Side Effects Had More Warnings Added In November 2016

Black-Box Warning Now Includes Venous Thromboembolism As Well As Various Types Of Arterial Occlusions, And There Are More New Safety Issues

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

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

On November 28, 2016 we learned about several alerting and wide-ranging safety labeling changes for Iclusig which were recently approved by the FDA Center for Drug Evaluation and Research (CDER).

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

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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, this new part now appears: 5.15 Reversible Posterior Leukoencephalopathy Syndrome (RPLS).

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

We point out there were more revisions mandated by the FDA in November 2016, which can be viewed on the FDA CDER SLC page for Iclusig.

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

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Is Liver Cancer Associated With Harvoni, Sovaldi, And Other Direct-Acting Antiviral Medications For Hepatitis C?

Conflicting Findings From Different Medical Studies Leave The Extent Of This Drug Safety Issue Uncertain At Present Time

 

(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)

 

Back 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".

As regards the liver cancer risks that have been mentioned in connection with the hepatitis C drugs Sovaldi and Harvoni, during the nine months since our earlier article, there have 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."

The study by Dr Brillanti's team, presented here at the International Liver Congress 2016 [Abstract LBP506. Presented April 14, 2016], suggests that patients with hepatitis C should be closely monitored after treatment with direct-acting antivirals. Two days earlier, a study conducted by a team from the University of Barcelona in Spain suggested the same thing (J Hepatol. Published online April 12, 2016).

Both studies indicate that patients with a history of hepatocellular carcinoma have the highest risk of developing a tumor after direct-acting antiviral therapy, but new diagnoses were also reported.

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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.”

Recent studies have suggested the possibility of increased risk of developing hepatocellular carcinoma during and after direct-acting antiviral treatment in patients infected with hepatitis C virus....

Dr. Alberti concluded, “The results, while confirming that direct-acting antiviral treatment doesn’t increase the overall risk of hepatocellular carcinoma, indicate that even successful antiviral therapy does not prevent hepatocellular carcinoma, at least during the first 6 to 12 months after initiation of treatment.”

He continued, “During this interval, microscopic and initially invisible foci of hepatocellular carcinoma might even be boosted in growth as consequence of profound immunological and molecular changes in the liver microenvironment following abrupt cessation of hepatitis C virus replication. It is mandatory, therefore, that patients treated with direct-acting antiviral medications with advanced liver disease continue to be monitored for hepatocellular carcinoma.”

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.

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

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Diabetes Medicine Invokana Gets New Warning About Lower Limb Amputation Added To Drug Package Insert In Canada

This December 2016 Label Change Mandated By Health Canada, However, Does Not Apply To Jardiance, Farxiga, And The Rest Of SGLT2 Inhibitors Class Of Drugs

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

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UPDATE: Invokana "Black-Box Warning" For Leg And Foot Amputations 

"FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR)"

[5-16-2017] Based on new data from two large clinical trials, the U.S. Food and Drug Administration (FDA) has concluded that the type 2 diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. We are requiring new warnings, including our most prominent Boxed Warning, to be added to the canagliflozin drug labels to describe this risk.

See also: "Risk of Lower Limb Amputations Doubled with Invokana and Invokamet Use" from our Drug Safety Developments blog.

(5/18/17)

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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).

Key messages for healthcare professionals:

• In an ongoing cardiovascular study† of 4 327 patients with type 2 diabetes, with known or at high risk for cardiovascular disease, the incidence rates of lower limb amputation, primarily of the toe, were 7.3, 5.4 and 3.0 per 1 000 patient years of exposure to canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, with the imbalance occurring as early as the first 26 weeks of therapy.
• In other type 2 diabetes studies with canagliflozin, which enrolled a general diabetes population of 8 111 patients, no difference in lower limb amputation risk was observed relative to control.

† Study details available at https://clinicaltrials.gov/ct2/show/NCT01032629.

[Footnotes omitted]

 

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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.

In April 2016, PRAC launched a safety review of canagliflozin based on an increase in amputations — mostly of the toes — seen in the ongoing long-term Canagliflozin Cardiovascular Assessment Study (CANVAS).

A 4.5-year interim analysis by the independent monitoring committee for the trial found that the rate of amputations per every 1000 patients was equivalent to seven for 100 mg/day and five for 300 mg/day of canagliflozin compared with three per 1000 patients taking placebo.

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".

From the Safety Announcement section of that document we get this information:

The U.S. Food and Drug Administration (FDA) is alerting the public about interim safety results from an ongoing clinical trial that found an increase in leg and foot amputations, mostly affecting the toes, in patients treated with the diabetes medicine canagliflozin (Invokana, Invokamet). We have not determined whether canagliflozin increases the risk of leg and foot amputations. We are currently investigating this new safety issue and will update the public when we have more information.

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.

We will 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.

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)