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Pub. no 140412
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Health Products and Food Branch
Marketed Health Products Directorate
Health Product InfoWatch Editorial Team
Pharmaceuticals and Biologics
Natural Health Products
This monthly publication is intended primarily for healthcare professionals and includes information on pharmaceuticals, biologics, medical devices and natural health products. It provides a summary of key health product safety information published in the previous month by Health Canada, as well as a selection of new health product safety information meant to raise awareness. New information contained in this issue is not comprehensive but rather represents a selection of clinically relevant items warranting enhanced dissemination.
Reporting Adverse Reactions
Canada Vigilance Program
For more information on how to report an adverse reaction, visit the Reporting Adverse Reactions to Drugs and Other Health Products page.
This in-depth safety review evaluated the risk of acetaminophen-related liver injury in Canada. Health Canada concluded that although acetaminophen remains a safe and effective medicine, there are risks of serious liver injury when it is not used as directed. Several options that may reduce the occurrence of acetaminophen-related liver injury, particularly in the context of unintentional overdoses, were proposed for consideration. Health Canada has worked collaboratively with stakeholders to develop an education approach to promote the safe use of acetaminophen, and continues to assess the feasibility and anticipated effectiveness of other risk minimization options. Health Canada has also communicated on the safe use of acetaminophen to Canadians.
This safety review evaluated the potential for decreased effectiveness of combined hormonal birth control products when used by obese women. Health Canada found no conclusive evidence showing a higher risk of pregnancy in obese women compared to non-obese women when using combined hormonal birth control products. Health Canada will continue to monitor this issue.
This safety review evaluated the potential for hypersensitivity reactions associated with the use of Feraheme (ferumoxytol). Health Canada concluded that although the Canadian prescribing information for Feraheme contained warnings about the serious risk of hypersensitivity reactions, an update to the prescribing information was necessary in light of the totality of the evidence. Health Canada has also communicated this information to Canadians.
These foreign health products have been found by regulators in other countries to contain undeclared drug ingredients. These products are not authorized for sale in Canada and have not been found in the Canadian marketplace but it is possible they may have been brought into the country by travellers or purchased over the Internet.
Co-administration of repaglinide and clopidogrel (a CYP2C8 inhibitor) may lead to a significant decrease in blood glucose levels due to a drug-drug interaction. The concomitant use of repaglinide and clopidogrel is now contraindicated.
Specific lots of NaturaLyte Sodium Bicarbonate Liquid Concentrate in 6.4 L volumes that may contain higher bacterial levels than acceptable have been recalled by Fresenius Medical Care.
Health Canada has advised consumers that it is introducing label changes for certain homeopathic products that fall under the Natural Health Product Regulations (NHPR). More particularly, to improve the safe use of these products, Health Canada is requesting the addition of statements on homeopathic nosode products to make it clear that they are not vaccines or alternatives to vaccines.
Health Canada is informing Canadians that five brands of unauthorized eye drops labelled to contain a prescription drug (neostigmine methylsulfate) have been seized from two retailers, Cube Inc. and Magic Queen Cosmetics in Richmond, B.C. These products may pose serious risks to the health of Canadians.
Health Canada advised Canadians that it has received a serious domestic adverse reaction report of abnormal heart rhythms associated with the ingestion of "Remogen" (containing ibogaine), an unauthorized natural health product in Canada that may pose serious health risks.
A typographical error was identified on one lot (lot BK112A14) of SteriMax Vancomycin Hydrochloride for Injection USP 1 g/vial. The error was only found on the French text of the secondary (outer) carton's reconstitution instructions of the product. The information found on the vial label and package insert correctly indicated the dosing information.
The following topics have been selected to raise awareness and, in some cases, to stimulate reporting of similar adverse reactions.
Rivaroxaban (Xarelto) is an oral anticoagulant. It acts by directly inhibiting factor Xa which occupies a central role in the blood coagulation cascade.Footnote 1 Like other direct-acting oral anticoagulants, rivaroxaban has a relatively rapid onset of action, a short half-life and is given as a fixed daily dose requiring no routine coagulation monitoring.Footnote 1,Footnote 2 It has been marketed in Canada since September 2008 and is indicated for the prevention and treatment of venous thrombotic events and the prevention of stroke and systemic embolism in select patients with atrial fibrillation.Footnote 1 Rivaroxaban is contraindicated in patients with liver disease associated with coagulopathy, and having clinically relevant bleeding risk.
Drug-induced liver injury (DILI) is a relatively rare adverse drug reaction.Footnote 3 It refers to any injury to the liver by a drug manifesting as a spectrum from asymptomatic liver test elevations to acute liver failure.Footnote 4 Given the wide range of clinical presentations and potential causative factors, and a lack of an objective diagnostic test, diagnosing DILI generally relies on the systematic exclusion of alternate causes.Footnote 5 DILI is often classified as intrinsic (predictable) or idiosyncratic (unpredictable).Footnote 4,Footnote 5 Intrinsic DILI (e.g., acetaminophen toxicity) has a short latency, is dose-dependent and is the most common form of DILI. Idiosyncratic DILI is less common, has a less consistent relationship to dose and has a longer latency (usually within the first 6 months after starting a new medication). DILI may also be categorized according to varying pathological patterns of liver injury including cholestatic, hepatocellular or mixed types. Distinguishing between these patterns can be accomplished by using liver biochemical parameters, primarily the ratio of the alanine aminotransferase (ALT) to alkaline phosphatase (ALP) relative to their respective upper limits of normal. The pattern of liver injury can be used to guide the diagnostic approach.Footnote 5
Health Canada's review of rivaroxaban and liver injury identified 16 published cases of liver injury suspected of being associated with rivaroxaban use.Footnote 6,Footnote 7 Patients were 41 to 91 years of age and received daily doses of rivaroxaban between 10 to 20 mg. Most patients were being treated for knee or leg surgery. Latency time from exposure to the first signs or symptoms of liver injury ranged from 3 days to 2 months. In addition, varying degrees of transaminase elevations suggest the occurrence of cholestatic, hepatocellular and mixed patterns of liver injury. Given the varied dose, latency period and pattern of liver injury, these cases may be idiosyncratic. All but one patient recovered.
In contrast, a systematic review and meta-analysis of phase III randomized controlled trials examining the risk of DILI among new oral anticoagulants (NOACs), including rivaroxaban, determined that NOACs were not associated with an increased risk of DILI compared to respective comparators.Footnote 8
A variety of patient and medication-specific risk factors for DILI have been cited in the literature. The evidence supporting the role of patient-related risk factors (e.g., gender, age and concomitant disease) is limited.Footnote 4,Footnote 5,Footnote 9 For specific drugs, genetic predisposition may be influential. Progress has been made in identifying medication-specific risk factors. These include drug dose, drug lipophilicity and the degree of hepatic metabolism.Footnote 4,Footnote 9 The current scientific literature indicates that rivaroxaban exhibits moderate lipophilicity and approximately two-thirds of the administered dose is metabolized by the liver via cytochrome P450 (CYP) enzymes and CYP-independent mechanisms.Footnote 1,Footnote 10
As of Sept. 30, 2014, Health Canada received 61 reportsFootnote * of liver-related adverse reactions (ARs) involving rivaroxaban. However, the majority of reports lacked important information such as dosing information, duration of exposure, liver biochemistries, comorbidities and concomitant medications. In particular, most reports did not contain sufficient detail to permit the exclusion of alternate causes of liver injury (e.g., viral or autoimmune hepatitis, hepatic ischemia, etc.Footnote 5). In several cases (including cases reported in the literatureFootnote 6), the recent or concomitant use of acetaminophen represents a potential contributory factor for liver injury. Consequently, a causal relationship between rivaroxaban and liver injury could not be established in most Canadian cases.
Healthcare professionals are encouraged to report any suspected cases to Health Canada. When reporting liver-related ARs, the following information is important to include:
The inclusion of such information will help in evaluating the causal relationship between rivaroxaban and liver injury. Health Canada continues to monitor the potential risk of liver injury with rivaroxaban use.
The sum of all reports may differ from the total number of individual patient cases, as one case may be reported from more than one source.
Xarelto (rivaroxaban) [product monograph]. Mississauga (ON): Bayer Inc.; 2015.
Bauer KA. Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and factor Xa. J Thromb Haemost 2011;9 Suppl 1:12-9. [PubMed]
Björnsson ES. Incidence and outcomes of DILI in western patients. Clin Liver Dis 2014;4(1):9-11.
Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc 2014; 89(1):95-106. [PubMed]
Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014;109(7):950-66. [PubMed]
Russmann S, Niedrig DF, Budmiger M, et al. Rivaroxaban postmarketing risk of liver injury. J Hepatol 2014;61(2):293-300. [PubMed]
Liakoni E, Rätz Bravo AE, Terracciano L, et al. Symptomatic hepatocellular liver injury with hyperbilirubinemia in two patients treated with rivaroxaban. JAMA Intern Med 2014;174(10):1683-6. [PubMed]
Caldeira D, Barra M, Santos AT, et al. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. Heart 2014;100(7):550-6. [PubMed]
Lammert C, Bjornsson E, Niklasson A, et al. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology 2010;51(2):615-20. [PubMed]
Mueck W, Stampfuss J, Kubitza D, et al. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014;53(1):1-16. [PubMed]
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Marketed Health Products Directorate
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© 2015 Her Majesty the Queen in Right of Canada. This publication may be reproduced without permission provided the source is fully acknowledged. The use of this publication for advertising purposes is prohibited. Health Canada does not assume liability for the accuracy or authenticity of the information submitted in case reports.
Adverse reactions (ARs) to health products are considered to be suspicions, as a definite causal association often cannot be determined. Spontaneous reports of ARs cannot be used to estimate the incidence of ARs because ARs remain underreported and patient exposure is unknown.
Due to time constraints relating to the production of this publication, information published may not reflect the most current information.