Drug Injury Watch

Gadolinium Toxicity Risks Higher For Children, Pregnant Women, And People Receiving Multiple Doses

Gadolinium Deposition Disease And Neurological Adverse Reactions Associated With The Use Of Gadolinium-Based Contrast Agents

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In May 2018 Health Canada announced the results of its second safety review of Magnevist, MultiHance, Omniscan, and Optimark, as well as other radiology contrast agents containing gadolinium.

From "Summary Safety Review - Gadolinium based contrast agents - Assessing the risk of gadolinium build-up in the brain and potential brain and nervous system (neurological) side effects" we get the following points, which are found in the Key Messages section:

• In 2016, Health Canada reviewed the risk of gadolinium build-up in the brain and the unknown potential neurological side effects because some published studies showed that gadolinium may stay in the brain when [gadolinium based contrast agents (GBCAs)] are given repeatedly. Health Canada’s review concluded that the risk of gadolinium build-up in the brain is higher with repeated doses of both types of GBCAs, and with the use of linear GBCAs compared to macrocyclic GBCAs....
• Health Canada carried out a second review in 2017 because new information was emerging, including: a review from the European Medicines Agency; reports from the manufacturers; and scientific publications. Health Canada’s second review concluded that children and pregnant women may be at greater risk of gadolinium build-up in the brain.

In more detail, as set forth in the Safety Review Findings part of that same May 2018 Health Canada document:

• This safety review looked at published and unpublished studies (57 in humans and 12 in animals) and 7 international case reports of gadolinium build-up in the brain linked to the use of GBCAs. The human studies and case reports found evidence of gadolinium build-up in the brain, in most cases this occurred many months after the use of GBCAs. Similar findings were seen in the animal studies.
• Evidence from these studies suggests that the risk of gadolinium build-up in the brain is higher with repeated use of GBCAs and with linear GBCAs. However, gadolinium build-ups were seen with both types of GBCAs.
• The review did not find any neurological side effects linked to gadolinium build-up in the brain based on the information available at the time. However, it is difficult to identify potential effects because they could take some time to appear and some patients may have similar symptoms because of their condition.
• Factors that may increase the risk of gadolinium build-up in the brain following the use of GBCAs are not yet completely understood. However, patients who may need repeated GBCA use and vulnerable populations (e.g. children, pregnant women) may be more at risk of gadolinium build-up in the brain.

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Gadolinium-Containing Contrast Agents

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__________________________________________________________________

 

In conclusion, Health Canada -- similar to what the FDA has said here in the US -- stated that it will continue to monitor drug safely information involving GBCAs and, in particular, the link between repeated gadolinium contrast agents administration or injection and the risk of gadolinium build-up in the brain, i.e.,  Gadolinium Deposition Disease (GDD).

Our law firm is investigating possible products liability lawsuits against the pharmaceutical companies responsible for the linear gadolinium-based contrast agents, or contrast dyes, which are shown below:

Magnevist -- Bayer HealthCare Pharmaceuticals Inc.

Eovist -- Bayer HealthCare Pharmaceuticals Inc.

MultiHance -- Bracco Diagnostics Inc.

Omniscan -- GE Healthcare

OptiMARK -- Liebel-Flarsheim Company LLC

Ablavar -- Lantheus Medical Imaging, Inc.

If we can be of assistance to you or a loved one as regards a possible gadolinium contrast agents case, please do not hesitate to contact us.

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

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Tasigna Side Effects Include Ischemic Cerebrovascular Events, Ischemic Heart Disease, And Peripheral Arterial Occlusive Disease

Less Warning About These Atherosclerosis-Related Diseases By Novartis In The US, It Seems, Compared To What Has Been Done By The Drug Company In Canada

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Tasigna (nilotinib) was approved by the FDA in 2007 for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML).

In April 2013 a so-called "Dear Doctor" letter was sent out in Canada by the responsible drug company warning about some serious side effects associated with Tasigna and a drug label change with new information concerning those Tasigna side effects, or adverse events. Relevant parts of this April 9, 2013 letter from Novartis Pharmaceuticals Canada Inc. are set forth below:

Dear Healthcare Professional:

Subject: Updated information regarding the possible risk of developing atherosclerosis-related diseases with the use of TASIGNA* (nilotinib)

Novartis Pharmaceuticals Canada Inc. (“Novartis”), in collaboration with Health Canada, would like to inform you of important information regarding reports of atherosclerosis-related diseases in patients treated with TASIGNA* (nilotinib).

TASIGNA* belongs to the pharmacological class of protein-tyrosine kinase inhibitors....

• Cases of atherosclerosis-related diseases have been reported during clinical trials and post marketing experience with the use of TASIGNA*.
• Patients should be monitored for signs of atherosclerosis-related diseases during treatment with TASIGNA* Monitoring of lipid and glucose profiles should also be performed before and frequently during treatment with TASIGNA* and as clinically indicated.
• Updated information regarding Tasigna safety profile has been added to the product monograph under the Warnings and Precautions, common clinical adverse drug reactions and post-marketing adverse reactions sections.

In a Phase III study (A2303) in newly diagnosed Ph+ CML patients, atherosclerosis-related diseases such as peripheral arterial occlusive disease, femoral artery stenosis, coronary artery stenosis, carotid artery stenosis, and cerebrovascular accident were reported in patients taking TASIGNA* (5.0% for TASIGNA* 300 mg BID and 6.1% for TASIGNA* 400 mg BID). A review of the Novartis global safety database search (between January 1st, 2005 and January 31, 2013) identified a total of 277 cases of atherosclerosis, of which 14 were Canadian cases. The cumulative patient exposure since the first launch of TASIGNA* in 2007 is estimated to be approximately 39,299 patient-years.... 

*TASIGNA is a registered trademark.

We point out that there was no similar "Dear Doctor" letter sent in the US by Novartis Pharmaceuticals Corporation in 2013, nor was any similar Tasigna drug label change made by Novartis in the US back then.

__________________________________________________________________

Tasigna

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More recently, a December 2015 medical journal article, "Tyrosine Kinase Inhibitor–Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia", presented more findings about the atherosclerosis-related diseases addressed in the April 2013 "Dear Doctor" letter and label change up in Canada. From this medical article published by the Journal of Clinical Oncology:

Several recent studies have reported vascular toxicity with [Tasigna (nilotinib)] (Table 1). In a retrospective multicenter analysis of 179 patients, 11 patients (6.2%) developed peripheral arterial disease (PAD) involving lower limbs. Most striking was the severity of PAD; eight patients required invasive therapy (angioplasty and stent placement), and four patients required amputation. A single-center study of 24 patients reported PAD in three patients, all requiring angioplasty or surgery. A number of other retrospective studies from single institutions have confirmed a higher than expected incidence of peripheral or cardiac ischemic events in patients treated with [Tasigna (nilotinib)] (Table 1). The finding that cardiovascular risk factors were common in patients with vascular [adverse events (AEs)], combined with the elevations in glucose and cholesterol, suggested that [Tasigna (nilotinib)] may aggravate a pre-existing arteriosclerotic condition. In a meta-analysis of the [International Randomized Interferon Versus STI571 (IRIS)], Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS), and [Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd)] studies, peripheral arterial occlusive disease (PAOD) was reported in seven (1.3%) of 556 patients treated with [Tasigna (nilotinib)], three (0.6%) of 533 patients treated with no [tyrosine kinase inhibitor (TKI)], and two (0.2%) of 1,301 patients treated with imatinib. A 3-year follow-up of the ENESTnd trial suggests a higher incidence of vascular events in patients treated with [Tasigna (nilotinib)] compared with imatinib; eight (1.4%) of 556 and 11 (2.0%) of 556 [Tasigna (nilotinib)]-treated patients had PAOD and ischemic heart disease, respectively, whereas these occurred in none (0%) and one (0.4%) of 280 patients in the imatinib group, respectively. These data are more striking at 6-year follow-up. Twenty-eight (10%) of 279 patients treated with [Tasigna (nilotinib)] 300 mg twice per day, 44 (15.9%) of 277 patients treated with [Tasigna (nilotinib)] 400 mg twice per day, and seven (2.5%) of 280 patients treated with imatinib 400 once per day had cardiovascular events. Cardiovascular events included ischemic heart disease, ischemic cerebrovascular disease, and peripheral artery disease, suggesting that the [Tasigna (nilotinib)]-associated toxicity occurs in all arterial beds. Few venous events were seen in each arm. Importantly, the dose-dependent increased risk of events in the [Tasigna (nilotinib)] arms implicates a drug-dependent process.  [Footnotes omitted.]

To break down that dense paragraph a bit, here is a list of the four serious side effects, or adverse events, linked to Tasigna by this 2015 medical journal article:

• peripheral arterial disease (PAD) involving lower limbs;
• peripheral arterial occlusive disease (PAOD);
• ischemic heart disease; and
• ischemic cerebrovascular disease.

To date there has still not been any "Dear Doctor" letter sent in the US by Novartis about these four Tasigna side effects.

The current Full Prescribing Information document for TASIGNA® (accessed 2/26/18), or drug label, does have some mention about these four adverse events, but is it sufficient?

In the "WARNINGS AND PRECAUTIONS" part of the Tasigna drug label, there is this information:

5.4 Cardiac and Arterial Vascular Occlusive Events

Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in newly diagnosed CML patients and observed in the postmarketing reports of patients receiving nilotinib therapy. With a median time on therapy of 60 months in the clinical trial, cardiovascular events, including arterial vascular occlusive events, occurred in 9.3% and 15.2% of patients in the Tasigna 300 and 400 mg twice daily arms, respectively, and in 3.2% in the imatinib arm. These included cases of cardiovascular events including ischemic heart disease-related cardiac events (5.0% and 9.4% in the Tasigna 300 mg and 400 mg twice daily arms respectively, and 2.5% in the imatinib arm), peripheral arterial occlusive disease (3.6% and 2.9% in the Tasigna 300 mg and 400 mg twice daily arms respectively, and 0% in the imatinib arm), and ischemic cerebrovascular events (1.4% and 3.2% in the Tasigna 300 mg and 400 mg twice daily arms respectively, and 0.7% in the imatinib arm). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively.

And in the "PATIENT COUNSELING INFORMATION", there is some additional guidance for doctors who are prescribing Tasigna:

Cardiac and Arterial Vascular Occlusive Events

Advise patients that cardiovascular events (including ischemic heart disease, peripheral arterial occlusive disease, and ischemic cerebrovascular events) have been reported. Advise patients to seek immediate medical attention if any symptoms suggestive of a cardiovascular event occur, such as chest or leg pain, numbness or weakness, or problems walking or speaking occur suddenly [see Warnings and Precautions (5.4)].

Going back to the Tasigna situation in Canada, the current Product Monograph for TASIGNA® [PDF download file] (accessed 2/26/18) warns about these particular side effects (and some others, also) in the WARNINGS AND PRECAUTIONS section.  And that warning is highlighted, if seems, by placing the following text within a box captioned "Serious Warnings and Precautions":

• Ischemic heart disease, ischemic cerebrovascular events and peripheral arterial occlusive disease (PAOD), (in some rare cases, fatal) (see Warnings and Precautions and Monitoring and Laboratory Tests)

Why the different treatment of this Tasigna drug safety issue by Novartis in Canada, i.e., apparent stronger warnings, as opposed to in the US?

For whatever reason, it seems Novartis has issued stronger warnings about the ischemic heart disease, ischemic cerebrovascular events, and peripheral arterial occlusive disease side effects associated with Tasigna in Canada compared with what the drug company has done, or not done, in the US.

If you have some insight about this divergent Tasigna warnings situation, please share it by leaving a Comment below.

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."

__________________________________________________________________

OFEV

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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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A "Dear Doctor" Letter For Invokana Amputations Side Effect Was Sent September 2017 By Janssen In Canada

In US There Was A "Black-Box Warning" Added On Revised Drug Label Issued In July 2017 But Without Any Such Letter, It Seems

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

The "FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR)" document which was issued in May 2017 previewed a drug label change with increased warnings about the risk of these lower limb amputations.

In an article published here earlier, "Invokana - Amputation Side Effect Gets 'Black-Box Warning' On Revised Drug Label Issued In July 2017", we reported on that revised label for Invokana (canagliflozin) and Invokamet (canagliflozin and metformin).

Up in Canada, it was back in October 2016 that the Product Monographs for Invokana and Invokamet were updated to include a warning about the risk of toes, foot, and leg amputations. This action was based on interim results of the Canagliflozin Cardiovascular Assessment Study (CANVAS) study.

Now, in September 2017 it seems that Health Canada is moving more aggressively than the FDA by requiring Janssen, the drug company responsible for Invokana and Invokamet, to send a Dear Healthcare Professional Letter -- commonly referred to as a "Dear Doctor" letter -- about the lower limb amputations side effect.

From this September 2017 "Dear Doctor" from Janssen about Invokana and Invokamet we get the following information:

Canagliflozin is a member of a class of drugs called sodium glucose co-transporter type 2 (SGLT2) inhibitors indicated as oral antihyperglycemic agents for the treatment of patients with type 2 diabetes.

The increase in the incidence rate of lower limb amputation (mostly affecting the toe and midfoot, but also of the leg) occurred as early as the first 26 weeks of therapy during long-term clinical studies, CANVAS and CANVAS-R, in patients taking INVOKANA. Patients in the CANVAS and CANVAS-R studies were followed for an average of 5.7 and 2.1 years, respectively.

This increased risk was independent of predisposing risk factors, although the absolute risk was higher in patients with previous amputations, existing peripheral vascular disease or neuropathy. No dose response was observed.

Lower limb infections, diabetic foot ulcers, peripheral arterial disease, and gangrene were the most common medical events associated with the need for an amputation in both treatment groups.

____________________________________________

Invokana / Farxiga / Jardiance

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____________________________________________

 

And here are some of the points presented in this September 2017 Janssen letter to Canadian healthcare professionals:

• Carefully monitor patients with risk factors for amputation events, e.g., patients with previous amputations, existing peripheral vascular disease or neuropathy.
• Advise patients to notify their healthcare provider if they develop sores, ulceration, discoloration, infection, new lower extremity pain or tenderness.
• Initiate early treatment for foot problems for, but not limited to, ulceration, infection, new pain or tenderness.
• Discontinue canagliflozin treatment in patients who develop a significant complication, such as a lower-extremity skin ulcer, infection, osteomyelitis or gangrene.

To our knowledge, no such "Dear Doctor" letter has been sent out in the US, yet. If you know otherwise, however, you can let us know by submitting a Comment below or sending an email to me.

We will continue to monitor this risk of lower limb amputations for Invokana and Invokamet as well as watch to whether this adverse reaction also involves other diabetes medicines in this SGLT2 class of drugs, such as Farxiga and Jardiance.

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.

__________________________________________________________________

Harvoni / Sovaldi / Technivie / Viekira Pak

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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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May 2017 "Dear Doctor" Letter About Aranesp Cases Of Stevens-Johnson Syndrome (SJS) And Toxic Epidermal Necrolysis (TEN)

Current U.S. Version Of Full Prescribing Information Document For Aranesp Mentions Skin Rash Among Other Serious Allergic Reactions

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Aranesp (darbepoetin alfa) products for subcutaneous and intravenous use are approved by the FDA for two indications: (1) anemia due to chronic kidney disease; and, (2) anemia due to chemotherapy in patients with cancer.

From the Warnings and Precautions section of the current Full Prescribing Information document for ARANESP® (darbepoetin alfa) injection (accessed 5/18/17):

5.7   Serious Allergic Reactions
Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp. Immediately and permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs. [emphasis added]

However, it seems that Health Canada wants a more clear or stronger warning about skin-related adverse reactions associated with Aranesp use.

__________________________________________________________________

Aranesp

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__________________________________________________________________

 

On May 5. 2017 the Canadian drug regulatory agency issued this Dear Healthcare Professional Letter: "ARANESP - Risk of Severe Skin Reactions: Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis".  From this recent Health Canada Aranesp alert we get this updated drug safety information:

• In some patients, ARANESP has been associated with severe skin reactions, including life-threatening reactions called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS/TEN are serious life-threatening conditions that often begin with flu-like symptoms including fever, tiredness, muscle and joint pain which are followed by a widespread rash with reddening and blistering of the skin and moist lining of the mouth, eyes, nose, throat, or genital area. This often leads to peeling and shedding of the affected skin which looks like a severe burn. Patients should discuss any skin reaction with their doctor, and seek immediate medical attention if they experience any of the SJS/TEN symptoms.
• As of October 31, 2016, cumulative exposure to ARANESP was estimated to be over 6 million patient-years in the post-marketing setting. The potential risk of SJS/TEN with ARANESP use was evaluated using the global safety databases. As of April 5, 2017, 11 cases of SJS and 4 cases of TEN have been reported internationally in patients treated with ARANESP. To date no Canadian cases of SJS/TEN related to ARANESP treatment have been identified.

This so-called "Dear Doctor" letter about Aranesp also informed that Health Canada is currently working with the manufacturer, Amgen Canada Inc., to include this safety information in the Canadian Product Monograph for Aranesp.

We will be watching to see whether the FDA takes any similar regulatory action regarding the possible Aranesp side effects of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

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.

__________________________________________________________________

Harvoni / Sovaldi / Technivie / Viekira Pak

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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).

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)

 

---

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.

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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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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.

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The Essure Birth Control Product: Safety, Regulatory, And Legal Developments Over The Past Several Months

Increasing Number Of Women Who Have Allegedly Been Harmed By The Essure Inserts Have Filed Lawsuits Against Bayer

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Bayer's Essure® product is a permanent birth control system that a woman can get with a non-surgical procedure to help her stop worrying about an unplanned pregnancy.

But while that may sound all good, the Essure birth control insert product has been surrounded with controversy having to do with its safety and some past clinical trials. Not surprisingly, these issues have resulted in lawsuits filed by women who allege being harmed by the Essure inserts.

Starting with the Essure safety issues, we get the following from a May 31, 2016 "Dear Healthcare Professional Letter" issued by Health Canada with the title "ESSURE (permanent birth control system) - Risk of Serious Complications":

Complications have been reported in some patients with the use of ESSURE (permanent birth control system) including changes in menstrual bleeding, unintended pregnancy, chronic pain, perforation and migration of device, allergy and various non-specific symptoms suggestive of sensitivity or immune-type reactions. Some complications may be considered serious. In some cases, the extent of the symptoms led to the removal of ESSURE. The removal of ESSURE requires surgery and may include hysterectomy.

Post-marketing information suggests that some patients may not always be fully informed of the various possible device and procedure-related complications before they choose whether to proceed with ESSURE.

That same Health Canada document went on to state: "The product labelling for ESSURE will be updated including a new Boxed Warning section to reflect this safety information."

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Shifting from current safety concerns to earlier clinical trials for the Essure product, and from Canada to the US, we get this excerpt from a September 6, 2016 news report, "FDA: No evidence of data manipulation in clinical trials for Bayer’s Essure", published on the MassDevice website:

The [FDA] set out to review the allegations, which accused Bayer of clinical trial misconduct, “notably that clinical trial participants’ medical records were altered to reflect more favorable data about participants’ experiences, and that the sponsor violated the terms of the PMA approval order and violated laws that relate to the manufacturing and marketing of Essure,” according to an FDA release....

After analyzing the forms, the [FDA] said it found “less than 1% of case report form data pertaining to pain, bleeding, device placement/movement and pregnancy were changed during the clinical trials.”

“Although modifications to the case report forms were identified, our analysis did not find evidence the sponsor purposefully modified patient responses to reflect more favorable data for Essure,” the FDA wrote in a report.

The FDA noted that the analysis had “several limitations,” most notably being that the investigation was conducted more than 13 years after the initial premarket approval was granted for the product.

That recent MassDevice article concluded with this rather ominous note:

The FDA said last year that in the 13 years since Essure’s approval, it had received 5,093 complaints, including for pain or menstrual irregularities after using the device, and complaints of the device breaking. In addition to 5 fetal deaths, there were 4 reports of adult deaths for reasons such as infection and uterine perforation, the FDA said.

Which brings us to the legal realm and the numerous lawsuits against Bayer filed by women who experienced various complications allegedly caused by their Essure birth control inserts.

Hundreds of such legal cases have been filed around the country, with the most attention going to Essure lawsuits pending in the Superior Court of California in Alameda County. In early August 2016 Winifred Y. Smith, of that California state court, ruled against the defendant Bayer, which sought to have some of those cases thrown out on three different legal grounds. Judge Smith's rulings in favor of the plaintiffs in those cases mean that Bayer could possibly be held liable for the harm alleged in current Essure lawsuits filed in California. In addition, those legal rulings might also establish the groundwork for future lawsuits against Bayer involving the Essure birth control product.

Be assured that we will continue to monitor safety, regulatory, and legal developments concerning the Essure contraceptive insert from Bayer.

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