Side Effects Blog

In more detail, according to the April 2018 CNN Investigates story:

Even some committee members who voted in favor of the drug expressed reservations, according to the hearing transcript. “I guess I’m hoping that the risks are going to be small, and I think the benefits for some of these people who are very sick and whose families are affected by this, I think they’re probably willing to take that risk,” one physician stated. Another committee member said she wouldn’t have voted for the drug’s approval if there had been a safe and effective alternative on the market. A third made a “plea” to the FDA to “consider a large observational study so we can ensure that, once it goes into real-world use, that the benefits will outweigh the risks.”

Nuplazid was thereafter approved by the FDA in April 2016, and became available to US patients in June 2016.

Returning to the April 2018 CNN news story about Nuplazid:

In November, an analysis released by a nonprofit health care organization, the Institute for Safe Medication Practices, warned that 244 deaths had been reported to the FDA between the drug’s launch and March 2017. The organization also noted that hundreds of reports suggested the drug was “not providing the expected benefit” or potentially worsening the condition….

Since the institute released its analysis, FDA data shows that the number of reported deaths has risen to more than 700. As of last June, Nuplazid was the only medication listed as “suspect” in at least 500 of the death reports.

We will continue to watch developments concerning the safety profile of the Parkinsons drug Nuplazid, including possible regulatory action by the FDA.

“Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study”:

Use of dipeptidyl peptidase-4 inhibitors was associated with an overall 75% increase in risk of inflammatory bowel disease. In secondary analyses, the association was particularly elevated between three and four years of use and between two and four years after the start of dipeptidyl peptidase-4 inhibitor treatment. This gradual increase in the risk is consistent with the hypothesis of a possible delayed effect of the use of dipeptidyl peptidase-4 inhibitors on the incidence of inflammatory bowel disease.

The following relative new medicines are classified as DPP-4 inihibitor diabetes drugs:

Januvia (sitagliptin)
Janumet (sitagliptin / metformin HCl)
Janumet XR (sitagliptin / metformin HCl)
Tradjenta (linagliptin)
Jentadueto (linagliptin / metformin HCl)
Glyxambi (empagliflozin / linagliptin)
Onglyza (saxagliptin)
Kombiglyze XR (saxagliptin and metformin)
Qtern (dapagliflozin and saxagliptin)
Nesina (alogliptin)
Kazano (alogliptin and metformin)
Oseni (alogliptin and pioglitazone)

We will continue to monitor the safety profile of these DPP-4 inhibitor diabetes drugs.

From the “Conclusions” part of the Abstract for that NEJM article:

In patients with gout and major cardiovascular coexisting conditions, [Uloric (febuxostat)] was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with [Uloric (febuxostat)] than with allopurinol.

Allopurinol, approved by the FDA in 1966, and Uloric, approved in 2009, are two commonly prescribed medicines for gout. Takeda Pharmaceuticals is the drug company responsible for Uloric.

One expects the FDA will be looking closely at these new CARES findings about all-cause and cardiovascular deaths associated with Uloric over the next several months.

Similarly, it is presumed that safety analyses by those medical researchers involved with the CARES trial are ongoing to evaluate the unexpected higher mortality rates in patients using Uloric in comparison to allopurinol.

Of course, we will be watching for significant developments regarding the safety profile of Uloric.

That earlier article, by TD Kim and several others, was titled “Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or Imatinib.” In summary, it reported the prevalence of PAOD in tyrosine kinase inhibitor (TKI)-treated patients with chronic myeloid leukemia (CML).

Dr. Tefferi started his Letter by setting the stage, so to speak, in this manner:

Atherosclerosis is the leading cause of death and morbidity in developed countries and is the culprit behind coronary artery disease (CAD), cerebral vascular disease (CVD) and peripheral artery occlusive disease (PAOD). Atherosclerosis leads to segmental narrowing and occlusion of arteries….

Later, Dr. Tefferi makes this relatively strong statement, which probably gave rise to the caption attributed to this April 2013 Leukemia Letter to the Editor by Tefferi:

Taken together, the above observations strongly implicate [Tasigna (nilotinib)] therapy as being proatherogenic. Regardless of what the underlying mechanisms for this might be, the question is whether or not it is necessary or appropriate to subject newly diagnosed patients with CP-CML to this risk [of atherosclerosis associated with Tasigna (nilotinib)], considering the remarkable efficacy and safety of imatinib therapy.

In closing this article, I will point out that in the US there still has not been any “Dear Doctor” letter sent nor any Tasigna drug label change made by Novartis Pharmaceuticals Corporation regarding atherosclerosis, despite the actions taken by its Canadian counterpart during April 2013.

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.

Here are the four serious side effects, or adverse events, linked to Tasigna by this 2015 Journal of Clinical Oncology article:

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

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

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.

1)  IN RE: Incretin-Based Therapies Products Liability Litigation

Number of lawsuits pending in MDL-2452: 936

Primary side effect for these cases:
Pancreatic Cancer / Pancreas Cancer

2)  IN RE: Invokana (Canagliflozin) Products Liability Litigation  

Number of lawsuits pending in MDL-2750: 985

Primary side effects for these cases:
Diabetic Ketoacidosis (DKA)
Leg Amputation / Foot or Toe(s) Amputation

3)  IN RE: Farxiga (Dapagliflozin) Products Liability Litigation

Number of lawsuits pending in MDL-2776: 51

Primary side effect for these cases:
Diabetic Ketoacidosis (DKA)

4)  IN RE: Onglyza (Saxagliptin) and Kombiglyze XR (Saxagliptin and Metformin) Products Liability Litigation

Number of lawsuits pending in MDL-2809: 84

Primary side effect for these cases:
Heart Failure

We will continue to monitor the number of pending lawsuits in these four distinct diabetes drugs MDL cases and watch for significant developments in each of these federal court MDL litigations.

According to that JPML Transfer Order the Defendants — AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Co., and McKesson Corp. — opposed centralization of approximately 80 Onglyza and Kombiglyze lawsuits into this new MDL:

Defendants oppose transfer by arguing that plaintiffs’ allegations are supported by a single study (the SAVOR study), which itself supports only claims regarding heart failure – not the various other injuries (congestive heart failure, acute hypoxic respiratory failure, coronary artery disease and cardiovascular injury) plaintiffs allege….

Defendants concede that most cases involve allegations of heart failure, which is squarely in line with the results of the SAVOR study and the subsequent label change for Onglyza and Kombiglyze XR in April 2016.

As indicated above, MDL No. 2809 involves only Onglyza and Kombiglyze lawsuits filed in the federal court system. However, at the present time we are investigating heart failure cases for patients who used Onglyza or Kombiglyze as well as patients who used Nesina, Kazano, Oseni, or Qtern.

In September 2017, Intercept Pharmaceuticals 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.

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.

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

Four years earlier, the FDA approved another liraglutide-containing medicine, Victoza, which is a popular Type-2 diabetes drug.

Like Victoza, Saxenda has been associated with an increased risk of pancreatic cancer, or pancreas cancer, in patients using this still relatively new obesity, or weight-loss, drug.

However, the alarming difference between Saxenda and Victoza is that the standard dose of Saxenda for obesity contains 3.0 mg of liraglutide, while the standard doses of Victoza for diabetes are 1.2 mg or 1.8 mg of liraglutide. So the patient using Saxenda is getting about two-times more liraglutide than the patient using Victoza.

We are currently investigating pancreatic cancer cases involving Saxenda — as well as Victoza and other incretin mimetic diabetes drugs such as Byetta, Bydureon, Januvia, and Janumet — as drug injury lawsuits filed against the responsible pharmaceutical company based on this failure to warn about the increased risk of pancreatic cancer.

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 (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.

We will continue monitor the medical literature and the drug safety regulators for further developments regarding this drug-induced liver injury issue for OLEV.

There is currently no evidence that gadolinium deposition in the brain has caused adverse neurological effects in patients; however, licences for gadodiamide (Omniscan) and intravenous gadopentetic acid (also known as gadopentetate dimegulumine; Magnevist) will be suspended from 1 February 2018 and these products will be recalled.

Further, this MHRA document points out that “One linear agent, gadoversetamide (OptiMARK), has been withdrawn by the Marketing Authorisation Holder and is not available in the UK.”

In comparison, at the present time FDA is only requiring that there be certain changes made to the Prescribing Information, or drug label, of all gadolinium-based contrast agents (GBCAs)

From the December 2017 “FDA Drug Safety Communication: FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings”:

… A causal association between these adverse events and gadolinium retention could not be established.

We are continuing to assess the health effects of gadolinium retention in the body and will update the public when new information becomes available….

Accordingly, we will be watching for any future label changes or regulatory actions for gadolinium-based contrast agents, especially Magnevist, Omniscan, and OptiMARK, here in the US.

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.

Primus Pharmaceuticals, Inc. is the company responsible for Limbrel.

From the “FDA Limbrel Alert” page of the Limbrel.com website (accessed 12/8/17) presented by Primus:

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.

Returning the FDA Safety Alerts & Advisories page, under the section, “What is the Problem and What is Being Done About It?”, there is 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.

Be assured we will continue to follow this developing drug safety issue.