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.
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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.
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