Drug Injury Watch

Risk Of Actemra Associated Liver Injury Being Assessed By Health Canada, With Drug Label Change Likely To Follow

Drug-Induced Liver Injuries Reported In Patients Using Actemra, Including Cases Of Acute Liver Failure Requiring A Transplant

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In May 2019 we learned that Actemra has been associated with drug-induced liver injuries, which can be serious, life-threatening, or even fatal. This is according the Canadian drug regulatory agency, Health Canada, which issued this Dear Healthcare Professional Letter, "Important Safety Information on ACTEMRA® (tocilizumab) - Risk of Hepatotoxicity", on May 21, 2019.

From this Health Canada document we get the following:

ACTEMRA is known to cause transient or intermittent mild to moderate elevation of hepatic transaminases. This risk is increased when ACTEMRA is used in combination with potentially hepatotoxic drugs (e.g., methotrexate).

Following Health Canada’s request, [Hoffmann-La Roche Limited] performed a cumulative, comprehensive assessment of serious hepatic injury including hepatic failure reported with ACTEMRA across all available clinical and post-marketing data sources, including data from the Food and Drug Administration Adverse Event Reporting System (FAERS) and Eudravigilance (EV) databases and from the literature. Eight cases of ACTEMRA-related moderate to severe [drug-induced liver injury (DILI)] were identified. These events occurred between 2 weeks to more than 5 years after initiation of tocilizumab with median latency of 98 days. Two of these 8 cases required liver transplantation. The total world-wide ACTEMRA exposure is estimated to be 1,066,849 patients (corresponding to 882,370.3 Patient Years) up to April 10, 2018.

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As background, Actemra is a prescription medicine used to treat:

• adults with moderate to severe rheumatoid arthritis;
• adults with giant cell arteritis, an inflammation in the arteries, especially the ones in the temples; and,
• children older than 2 years with certain types of arthritis.

We have written about Actemra safety issues twice previously:

1.   "Actemra Side Effects: Pulmonary Hypertension, Interstitial Lung Disease, Pulmonary Alveolar Proteinosis" (August 2018)
2.   "Despite The High Number Of Actemra - Pancreatitis Cases Reported To FDA, No Warning Added To Drug Label" (June 2017)

We will watch to see whether the FDA issues a similar drug safety warning about Actemra-related liver injury and mandates a drug label change here in the US.

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

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Lemtrada Review By European Drug Regulatory Agency Covers Various Serious Side Effects In MS Patients

EMA Will Investigate Reports Of Associated Conditions Beyond Those That Were In November 2018 FDA Drug Safety Communication

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

We recently learned by means of this April 12, 2019 European Medicines Agency (EMA) press release, "Use of multiple sclerosis medicine Lemtrada restricted while EMA review is ongoing", that the multiple sclerosis (MS) drug Lemtrada (alemtuzumab) is facing more scrutiny from drug regulators.

As background, we reported in this December 4, 2018 post, "Lemtrada: Warnings About Strokes And Arterial Dissections / Blood Vessel Lining Damage Added To Drug Label", that in November 2018 an FDA Drug Safety Communication was issued and there was a Lemtrada label change, which included an increased risk of strokes warning being added to the "Black-Box Warning" for Lemtrada.

From this April 14, 2019 Medscape article, "PRAC Restricts Use of Alemtuzumab for MS Pending Ongoing Review", we get these details about the latest drug safety issues associated with Lemtrada:

New reports of serious side effects affecting the heart, blood vessels, lungs, and liver of patients with relapsing-remitting multiple sclerosis (MS) who are taking [Lemtrada (alemtuzumab)] have prompted the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) to launch a review and to place temporary restrictions on use of the drug while the review is ongoing.

In addition to the restrictions, PRAC has recommended an update of the product information for [Lemtrada (alemtuzumab)] to inform patients and healthcare providers about cases of immune-mediated conditions, including autoimmune hepatitis and hemophagocytic lymphohistiocytosis; problems with the heart and blood vessels that occur within 1 to 3 days of treatment, including bleeding in the lungs, heart attack, stroke, and cervicocephalic arterial dissection; and severe neutropenia.

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Returning to the April 2019 EMA press release about their Lemtrada safety investigation, we get the following from the "Information for patients" section:

• New cases of side effects have been reported with Lemtrada, including some affecting the heart, blood vessels, lungs and liver.
• You should get medical help immediately if you experience symptoms of:

-- acute (sudden) heart problems (usually within 1–3 days of receiving the medicine): such as trouble breathing and chest pain
-- bleeding in lungs: such as trouble breathing and coughing up blood
-- stroke and tears in blood vessels supplying the brain: such as drooping of the face, sudden severe headache, weakness on one side, difficulty with speech or neck pain
-- liver problems: such as yellow skin or eyes, dark urine, and bleeding or bruising more easily than normal
-- an inflammatory condition known as haemophagocytic lymphohistiocytosis: such as fever, swollen glands, bruising and skin rash.

Looking forward, the PRAC’s final recommendations about Lemtrada will be forwarded to the Committee for Medicinal Products for Human Use (CHMP) for their consideration.

We will continue to monitor drug regulatory actions regarding Lemtrada in the US, Europe, and elsewhere.

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

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Pradaxa-Related Liver Injury: Health Canada's Drug Safety Review Of Pradaxa Concludes There Is A Link

Remains Unknown Whether Pradaxa Label Change About Liver Damage In Canada Will Be Followed By Similar FDA Action In US

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In May 2018 Health Canada announced that their Pradaxa drug safety review evaluating the risk of liver injury associated with Pradaxa concluded that there may be a link. Accordingly, Health Canada is working with the responsible pharmaceutical company to update the Canadian product monograph, or drug label, for Pradaxa (dabigatran) to inform healthcare professionals and patients about this increased risk of liver injury.

In more detail, from this Health Canada document, "Summary Safety Review - PRADAXA (dabigatran etexilate) - Assessing the potential risk of liver injury":

 Safety Review Findings

• At the time of the review, Health Canada had received 27 Canadian reports of severe liver injury related to the use of Pradaxa. Of these reports, 4 were further assessed as they were suspected to be linked to the use of Pradaxa. 3 of the 4 reports, including 1 death, showed a possible link between liver injury and the use of Pradaxa.  [footnote omitted]
• This review also looked at 105 international reports of severe liver injury related to the use of Pradaxa. Of these reports, 16 were further assessed as they were suspected to be linked to the use of Pradaxa. 13 of these 16 reports, including 2 deaths, showed a possible link between liver injury and the use of Pradaxa.
• In most reports that were further assessed by Health Canada, other medical conditions and medications could have caused the liver injury.
• This safety review looked at information from 2 published cases of liver injury suspected to be linked to the use of Pradaxa. These 2 cases were not further reviewed because severe liver injury was not confirmed.
• A review of the scientific literature did not find any published studies that showed an increased risk of liver injury in patients treated with Pradaxa.
• Product labels in the United States and the European Union do not contain any information specific to liver injury.

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That relatively recent Health Canada Pradaxa Safety Review document goes on to point out: "The Pharmaceuticals and Medical Devices Agency of Japan issued a risk communication and updated the product label on September 12, 2017 to include liver injury (i.e. 'acute hepatic failure, hepatic function disorder, and jaundice')." [footnote omitted].

Here are the two related drug safety documents about Pradaxa issued by Japan's Pharmaceuticals and Medical Devices Agency (PMDA):

(1) "Summary of investigation results -- [Pradaxa] -- Dabigatran etexilate methanesulfonate"

(2) "Revision of Precautions -- [Pradaxa] --  Dabigatran etexilate methanesulfonate"

We will watch to see whether the FDA and/or European drug regulators require a Pradaxa label change adding a new warning about an increased risk of liver injury, e.g., acute liver failure, abnormal liver function, and jaundice.

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

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Ocaliva Black-Box Warning About Liver Failure Due To Incorrect Doses Added In Early 2018

This Ocaliva Label Change Follows September 2017 Dear Doctor Letter Sent By Intercept Pharmaceuticals

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

An earlier blog post, "Will Ocaliva Get Black-Box Warning For Liver Injury Side Effects After September 2017 FDA Report?", received its answer last week.

On February 1, 2018 the FDA issued this Safety Alert, "Ocaliva (obeticholic acid): Drug Safety Communication - Boxed Warning Added To Highlight Correct Dosing", from which we get this information:

ISSUE: FDA is warning that the liver disease medicine Ocaliva (obeticholic acid) has been incorrectly dosed daily instead of weekly in patients with moderate to severe primary biliary cholangitis (PBC), a rare chronic liver disease, increasing the risk of serious liver injury. To ensure correct dosing and reduce the risk of liver problems, FDA is clarifying the current recommendations for screening, dosing, monitoring, and managing PBC patients with moderate to severe liver disease taking Ocaliva. FDA is adding a new Boxed Warning, FDA’s most prominent warning, to highlight this information in the prescribing information of the drug label. FDA is also requiring a Medication Guide for patients to inform them about this issue.

As a condition of approval, FDA required the manufacturer of Ocaliva, Intercept Pharmaceuticals, to continue studying the medicine in patients with advanced PBC. These clinical trials are currently ongoing and FDA expects to receive results in 2023. FDA is adding the additional warnings to the drug label after receiving reports that Ocaliva is being given to PBC patients with moderate to severe liver impairment more often than is recommended in the prescribing information, resulting in liver decompensation, liver failure, and sometimes death. FDA will continue to monitor this medicine and will update the public if new information becomes available.

BACKGROUND: This is an update to the MedWatch safety alert for Ocaliva (obeticholic acid) - Increased Risk of Serious Liver Injury, issued 09-21-2017.

 

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From the Full Prescribing Information for Ocaliva (accessed 2/1/18), here is the so-called "Black-Box Warning" text being added:

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR C OR DECOMPENSATED CIRRHOSIS

• In postmarketing reports, hepatic decompensation and failure, in some cases fatal, have been reported in patients with primary biliary cholangitis (PBC) with decompensated cirrhosis or Child-Pugh Class B or C hepatic impairment when OCALIVA was dosed more frequently than recommended [see Warnings and Precautions (5.1)].

• The recommended starting dosage of OCALIVA is 5 mg once weekly for patients with Child-Pugh Class B or C hepatic impairment or a prior decompensation event [see Dosage and Administration (2.2)].

From a February 1, 2018 BioPharmaDIVE news report, "FDA adds black box warning to Intercept's Ocaliva", we get additional details about this Ocaliva drug safety development:

Ocaliva (obeticholic acid) is Intercept's sole marketed product, winning approval in May 2016 for a rare type of chronic liver disease known as primary biliary cholangitis or PBC. Few other treatments exist for the progressive disease, which can lead to cirrhosis and liver failure.... 

In September, the company issued a so-called "Dear Health Care Provider" letter warning of complications including liver failure and death when patients with moderate to severe PBC received higher-than-intended doses of Ocaliva.  [Note: Added link to this Intercept Pharmaceuticals letter about Ocaliva dated 9/8/17.]

The FDA followed that up with a drug safety communication outlining similar concerns. By the regulator's tally, nineteen patients receiving Ocaliva died over the 13 months from the drug's launch through last September. Seven out of the eight fatal cases with available information on cause of death showed the patients had incorrectly received daily doses, instead of the weekly administration recommended for those with moderate to severe declines in liver function.

Lastly, according to Intercept Pharmaceutical’s February 1, 2018 press release, the company is also working with the European Medicines Agency to update the Ocaliva drug label in Europe and will issue a Direct Healthcare Professional Communication to educate physicians on the appropriate Ocaliva dosage for patients with advanced cirrhosis.

We are investigating drug-induced liver injury and hepatic / liver failure cases as possible drug injury lawsuits against Intercept Pharmaceuticals.

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

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Drug-Induced Liver Injury Warning Added To OFEV Label In Canada As Done Earlier In US

This Relatively New Idiopathic Pulmonary Fibrosis (IPF) Pill Is Clearly On The Radar Of Drug Safety Regulators

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

OFEV (nintedanib) capsules were approved by the FDA in 2014 for treatment of idiopathic pulmonary fibrosis (IPF). Boehringer Ingelheim Pharmaceuticals, Inc. is the drug company responsible for OFEV in the US.

On January 11, 2018 Health Canada issued a Dear Healthcare Professional Letter communication titled "OFEV (nintedanib) - Risk of Drug-Induced Liver Injury and the Need for Regular Monitoring of Liver Function".

From the Background Information section of that new Health Canada document we get this overview of the safety issue:

OFEV (nintedanib) is used to treat idiopathic pulmonary fibrosis (IPF).

Cases of [drug-induced liver injury (DILI)] have been observed with OFEV treatment in the post-marketing setting since the product was launched in 2014. The overall cumulative [idiopathic pulmonary fibrosis (IPF)] patient exposure to OFEV from marketing experience is estimated to be over 32,000 patient-years. As of October 15, 2017, 32 cases of DILI have been reported worldwide in patients treated with OFEV, including one in Canada. In 24 of the 32 cases, the outcome of the DILI events was reported. In the majority (17) of these cases, the DILI event resolved when the dose was reduced or treatment was stopped. In 6 cases, the patient had not recovered at the time of reporting. One case resulted in fatal outcome.

That document went on to state "Health Canada is working with the manufacturer to update the Canadian Product Monograph [for OFEV] with this safety information."

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This forthcoming label change for OFEV in Canada follows similar regulatory action taken in the US several months ago, as indicated by an August 4, 2017 letter from the FDA to Boehringer Ingelheim Pharmaceuticals Inc.

As regards the OFEV - liver drug safety issue, the following text was added to the Warnings and Precautions part of the Full Prescribing Information for OFEV document (accessed 1/11/18) as a result of that August 2017 FDA letter: 

5.2 Elevated Liver Enzymes

Cases of drug-induced liver injury have been observed with OFEV treatment [see Adverse Reactions (6.2)]. In the post-marketing period, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcome, have been reported. The majority of hepatic events occur within the first three months of treatment. In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT) and bilirubin. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases. The majority (94%) of patients with ALT and/or AST elevations had elevations <5 times ULN. The majority (95%) of patients with bilirubin elevations had elevations <2 times ULN [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Patients with a low body weight (<65 kg), Asian, and female patients may have a higher risk of elevations in liver enzymes. Nintedanib exposure increased with patient age, which may also result in a higher risk of increased liver enzymes [see Clinical Pharmacology (12.3)]. Conduct liver function tests (ALT, AST, and bilirubin) upon initiation of treatment with OFEV, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with OFEV, promptly interrupt therapy [see Dosage and Administration (2.1, 2.3)].

We will continue monitor the medical literature, FDA, and Health Canada for further developments regarding this drug-induced liver injury issue for OLEV.

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

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FDA Recommends A Recall For Limbrel "Medical Food" Product But Primus Pharmaceuticals Is Not Complying

Reports Of Drug-Induced Liver Injury And Hypersensitivity Pneumonitis Are At Center Of This Unusual Drug Safety Controversy

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

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UPDATE: Primus Pharmaceuticals Inc. Finally Removes Its Osteoarthritis Capsule Limbrel From The Market

... "We are not shipping. We're not promoting. We're not sampling doctors," said Primus President and CEO James Weir. "We have terminated all of those activities in good faith even though we don't believe our product is life threatening."

Primus sells Limbrel as a "medical food," but the FDA said last month that the product is an unapproved drug linked to 194 adverse events over the last decade.

[Article continues at original source]

(1/5/18)

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According to the "What is Limbrel?" page of the Limbrel.com website (accessed 12/8/17) which is presented by Primus Pharmaceuticals, Inc.:

Limbrel contains flavocoxid, a proprietary blend of natural ingredients from phytochemical food source materials. Flavocoxid is comprised primarily of the flavonoids such as baicalin and catechin.

From the "FDA Limbrel Alert" page of the Limbrel.com website (accessed 12/8/17):

Limbrel has not been recalled though the FDA has asked Primus to make a voluntary recall. Primus is waiting to obtain the documents on which FDA has based its safety alert and recall request prior to making a final decision, although the opinions of independent experts and the medical literature conflict with FDA’s safety alert and request for recall.

We first reported about the November 21, 2017 FDA warning about Limbrel last month in this post, "Osteoarthritis 'Medical Food' Limbrel Tied to Life-Threatening Events".

Since then there was this December 4, 2017 FDA statement:

The U.S. Food and Drug Administration recommended that Primus Pharmaceuticals, Scottsdale, Arizona, voluntarily recall Limbrel, a capsule marketed to manage the metabolic processes associated with osteoarthritis. The company has not yet acted to remove the product from the market. Although the product is marketed as a medical food, the preliminary determination of the FDA investigation is that Limbrel is an unapproved new drug. The agency does not have mandatory recall authority over drug products.

The FDA reminds consumers not to use any Limbrel products because of the risk of drug-induced liver injury, and a lung condition called hypersensitivity pneumonitis. Consumers taking any Limbrel products should stop immediately and contact their health care provider. Health care providers who are aware that their patients are taking Limbrel should advise them to stop using it.

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More information about the apparent stand-off between the FDA and Primus Pharmaceuticals can be found on that same web page, "FDA Alerts Consumers About Potentially Life-Threatening Health Problems Linked to Limbrel", which includes these three points in the "Fast Facts" section:

• The FDA continues to investigate a rise in reports of serious adverse events, including drug-induced liver injury and a lung condition called hypersensitivity pneumonitis, involving Limbrel, a product in capsule form currently marketed to “manage the metabolic processes associated with osteoarthritis.”
• On November 30, 2017, the FDA reiterated to Primus Pharmaceuticals the agency’s safety concerns and serious health risks associated with continued use of the product. The FDA recommended a voluntary recall, but so far the company has declined to take the product off the market.
• The FDA is advising consumers not to use any Limbrel products because of the risk of drug-induced liver injury and a lung condition called hypersensitivity pneumonitis. If you are taking this product, discontinue it immediately and contact your health care provider. Health care providers who are aware that their patients are taking Limbrel should advise them to stop using it.

On that same FDA page, the next section, "What is the Problem and What is Being Done About It?", provides some additional information about this unfolding Limbrel situation:

On November 8, 2017, the FDA first contacted Primus Pharmaceuticals regarding the adverse events and requested information about the formula for Limbrel. The formula is being reviewed by the FDA. The FDA also obtained product samples from the company and the samples are undergoing testing.

The FDA continues to investigate Primus Pharmaceuticals and the manufacturing process for Limbrel, and will share updates as they become available.

We will continue to follow this developing drug safety issue. Further, we welcome anyone with insights to the Limbrel situation to post their information in a Comment below or share it with us privately by sending me an email.

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

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Will Ocaliva Get Black-Box Warning For Liver Injury Side Effects After September 2017 FDA Report?

19 Patients Have Died While Using This New Liver Disease Drug, Some When Prescribed Higher-Than-Recommended Doses

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

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UPDATE: "FDA adds Boxed Warning to highlight correct dosing of Ocaliva (obeticholic acid) for patients with a rare chronic liver disease"

 

(2/1/18)

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Intercept Pharmaceuticals Inc's Ocaliva (obeticholic acid) was approved by the FDA in May 2016 for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.

While this relatively new liver disease medication has not been widely prescribed yet, there are expectations it could become a very significant drug product for Intercept.

From this September 21, 2017 article, "FDA Warns Doctors After 19 Deaths on Intercept Liver Drug", by reporter Robert Langreth, we get the following sales-related information:

About 15,000 prescriptions for Ocaliva have been written since it was introduced, according to data from Symphony Health Solutions compiled by Bloomberg Intelligence. The drug is Intercept’s only commercial product and was approved in the U.S. in May last year. It brought in $30.4 million in sales last quarter.

Rival treatments in testing at other drugmakers could threaten Ocaliva’s market potential if they don’t have the same risks. Intercept is in the final stages of testing Ocaliva for nonalcoholic steatohepatitis, or NASH, which is associated with being overweight.

Three percent to 12 percent of Americans have NASH, according to the U.S. National Institutes of Health -- a huge potential market. Analysts have projected that the drug will become a blockbuster, with more than $1 billion in sales by 2021, though the disclosure of deaths may change that.

This liver side effects issue for Ocaliva was presented in this document, "FDA Drug Safety Communication: FDA warns about serious liver injury with Ocaliva (obeticholic acid) for rare chronic liver disease", issued on September 21, 2017.

From the Safety Announcement part of that document:

The Food and Drug Administration (FDA) is warning that the liver disease medicine Ocaliva (obeticholic acid) is being incorrectly dosed in some patients with moderate to severe decreases in liver function, resulting in an increased risk of serious liver injury and death. These patients are receiving excessive dosing, particularly a higher frequency of dosing than is recommended in the drug label for them. Ocaliva may also be associated with liver injury in some patients with mild disease who are receiving the correct dose.... [emphasis added]

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To put this development into context, we turn to journalist Tracy Staton's September 22, 2017 report, "FDA flags 19 deaths in Ocaliva patients, putting Intercept's NASH bid in doubt".  From her piece we get this looking-forward information:

The deaths and injuries could lead to a black-box warning, the FDA’s most severe, and that would likely affect Ocaliva’s current sales. That possibility “bears close watching, given the deleterious impact this could have on Intercept revenues now and in the future,” Leerink analyst Joseph Schwartz said in a note Thursday afternoon, adding, “This could significantly constrain the market opportunity for Ocaliva in PBC.”

But the bigger hit would come from a denied approval in NASH—nonalcoholic steatohepatitis—which is also known as fatty liver disease. A hit worth up to $7 billion, in fact. Analysts have predicted up to $8.6 billion in Ocaliva sales if it moves into the NASH market, and predictions run to $1.6 billion with just PBC on the label.

The dosing issue could raise a red flag with the FDA when that approval decision rolls around, because higher doses of Ocaliva would be on tap for NASH treatment. Also, PBC is an orphan indication. NASH isn’t, and myriad other drugs are moving toward an approval in that disease, though some have reported setbacks of their own....

In their Ocaliva Drug Safety Communication the FDA said patient should contact their doctors if they develop any of the following symptoms that may be signs of liver injury:

New or worsening fatigue
Diarrhea
Weight loss
Abdominal pain
Decreased appetite
Nausea and vomiting
Change in behavior or confusion
Vague symptoms such as anxiety or unease
Abdominal swelling
Yellow eyes or skin
Bloody stools

We will continue to monitor the safety profile of Ocaliva and watch for any drug label revisions, such as a black-box warning, which may be mandated by the FDA.

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

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Health Canada: There Is No Apparent Link Between Sovaldi Or Harvoni With Liver Cancer Recurrence As Of April 2017

Drug Regulatory Agency Has Requested Additional Safety Information From Some Manufacturers Of Direct-Acting Antivirals (DAAs)

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

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 Key Messages part of this drug safety report concerning Sovaldi, Harvoni, and other Direct-Acting Antivirals (DAAs), we get these three main points:

• Direct-acting antivirals (DAAs) are prescription drugs authorized for sale in Canada to treat chronic hepatitis C virus (HCV) infection in adult patients, which is a serious condition that can result in decreased liver function, serious scarring of the liver (cirrhosis) or liver cancer.
• Health Canada reviewed the potential risk of liver cancer coming back (recurrence) with the use of DAAs, following the publication of a study suggesting this potential risk.
• Health Canada’s review concluded that there was not enough information to establish a link between DAAs and liver cancer recurrence. Health Canada has requested additional safety information from some manufacturers of DAAs.

In more detail, from the Safety Review Findings part of same report we get this additional 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.

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This recent report from Health Canada serves to update our April 2017 article, "Harvoni / Sovaldi: Spring 2017 Update On Issue Of Liver Cancer Recurrence After Using Direct-Acting Antiviral 'Hep-C' Drugs".

We will continue to monitor the safety profile of Harvoni, Sovaldi, and Viekira Pak. These newer hepatitis C medicines and several others 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, besides the possibility of liver cancer recurrence.

To learn more, you can go to the Harvoni / Sovaldi / Viekira Pak / Technivie / Olysio / Daklinza / Epclusa / Zepatier page on our Drug Injury Law website.

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

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February 2017 Label Changes For Sovaldi, Harvoni, And Other DAA Hepatitis C Drugs Are Made So As To Add A "Black-Box" Warning

Drug Safety Regulators Flag An Increased Risk Of Hepatitis B Virus Reactivation Which Can Result In Cases Of Fulminant Hepatitis, Liver Failure, And Death

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

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.

You can view the Prescribing Information for Sovaldi (accessed 2/16/17) to see how this new black-box, or bolded, warning appears on the drug label.

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. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.

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.

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Here is some background about this new drug safety development:

• 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"; and,
• In October 2016 we posted this article, "Harvoni, Sovaldi, Viekira Pak, And Other Direct-Acting Antivirals Get Black-Box Warning: Risk Of Hepatitis B Virus Reactivation".

More recently, on December 1, 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 information:

Key Messages

• Direct-­acting antivirals (DAAs) are drugs authorized for sale in Canada to treat chronic hepatitis C virus (HCV) infection, a serious condition that can result in decreased liver function, serious scarring of the liver (cirrhosis) and liver cancer.
• 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).

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Multiple Sclerosis Drug Tecfidera: FDA Mandates January 2017 Label Change Which Adds Warnings About Liver Injury Cases

Besides Hepatotoxicity, Progressive Multifocal Leukoencephalopathy, Renal Toxicity, And Other Safety Issues Have Surfaced Since Clinical Trials

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Tecfidera (dimethyl fumarate) was approved by the FDA in 2013 as a treatment of patients with relapsing forms of multiple sclerosis (MS).

In February 2016 a rare but potentially fatal neurological disorder, progressive multifocal leukoencephalopathy (PML), was added to the Warnings and Precautions part of the Prescribing Information document, or drug label, for Tecfidera.

A more recent major change came in January 2017, with this one adding liver injury to the Warnings and Precautions part, as seen in the current Tecfidera drug label (accessed 2/7/17):

5.4      Liver Injury
Clinically significant cases of liver injury have been reported in patients treated with TECFIDERA in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment with TECFIDERA. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients....

From this January 25, 2017 article published by Reuters, "Possible liver injury added to label of Biogen MS drug", we get the news report about this new drug safety issue for Tecfidera:

The prescribing label for Biogen Inc's big-selling oral multiple sclerosis drug Tecfidera has been updated to include a warning of potential liver injury that could require hospitalization, the company said on Wednesday.

However, the updated label says signs of liver injury resolved when those patients stopped taking the medicine.

Tecfidera, the world's top-selling oral MS treatment, accounts for about a third of Biogen revenue. It had sales of $1.03 billion in the third quarter....

A Biogen spokeswoman said there have been 14 cases of liver injury reported out of some 230,000 patients treated with Tecfidera.

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We get additional 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.

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