Canadian Adverse Reaction Newsletter, Volume 24 - Issue 4 - October 2014
Cat no H42-4/1-24-4E
Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team
In this Issue
This quarterly publication alerts health professionals to potential signals detected through the review of case reports submitted to Health Canada. It is a useful mechanism to stimulate adverse reaction reporting as well as to disseminate information on suspected adverse reactions to health products occurring in humans before comprehensive risk-benefit evaluations and regulatory decisions are undertaken. The continuous evaluation of health product safety profiles depends on the quality of your reports.
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.
Caveat: 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.
Incretin-based therapies and the risk of pancreatic cancer
- Incretin-based drug products are new therapies indicated for the management of type 2 diabetes mellitus.
- Scientific studies have suggested that incretin-based therapies could possibly be associated with an increased risk of developing pancreatic cancer. In addition, cases of pancreatic cancer with the use of incretin-based therapies have been reported in Canada and internationally.
- A causal relationship between incretin-based therapies and the development of pancreatic cancer has not been established and investigations are ongoing.
- Health care professionals are encouraged to document and report to Health Canada any adverse reactions suspected of being associated with incretin-based therapies.
Incretins (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), are hormones secreted from the gastrointestinal tract into the blood stream in response to food ingestion.Reference #r1b1 footnote #r1b1,Reference 1 footnote #r1b2 They participate in the physiologic regulation of glucose metabolism by enhancing insulin production and secretion from the pancreas, among other functions. Incretins are rapidly inactivated by the enzymatic action of dipeptidyl peptidase-4 (DPP-4).
Incretin-based therapies either prolong the half-life of endogenous circulating incretins through the inhibition of DPP-4 activity or function as a GLP-1 receptor agonist resistant to DPP-4 degradation.Reference #r1b1 footnote #r1b1,Reference 1 footnote #r1b2 In Canada, incretin-based therapies used for the management of type 2 diabetes mellitus (T2DM) include 4 DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin and sitagliptin) and 2 GLP-1 receptor agonists (exenatide and liraglutide). These drugs were introduced on the Canadian market between January 2008 and April 2014.
Non-clinical studies have suggested that incretin-based therapies can lead to increased pancreatic cell proliferation.Reference 1 footnote #r1b3,Reference 1 footnote #r1b4,Reference 1 footnote #r1b5 These findings, along with international reports of pancreatic cancer in patients using incretin-based therapies, raised concerns over the potential risk of developing pancreatic cancer with the use of these drugs.
Pancreatic cancer is the fourth leading cause of cancer death in Canada with a 5 year relative survival ratio of 8%.Reference 1 footnote #r1b6 Risk factors for pancreatic cancer include, but are not limited to, smoking, obesity, a family history of pancreatic cancer, chronic pancreatitis and diabetes.Reference 1 footnote #r1b7
In 2013, Health Canada informed health care professionals that cases of pancreatic cancer had been reported internationally with the use of exenatide; no Canadian cases were reported at the time.Reference 1 footnote #r1b8 As of July 31, 2014, Health Canada received 13 reports of pancreatic cancer suspected of being associated with all incretin-based therapies. Health Canada has not established a causal relationship between incretin-based therapies and the development of pancreatic cancer from the data currently available.
Presently, the potential risk of pancreatic cancer is labelled in the Canadian product monograph for 2 incretin-based therapies.Reference 1 footnote #r1b9,Reference 1 footnote #r1b10 Health Canada has initiated an epidemiological study through the Drug Safety and Effectiveness Network (DSEN) to assess the potential association between pancreatic cancer and incretin-based therapies and will continue its ongoing monitoring of this potential safety issue.
Other regulatory agencies have also reviewed the evidence regarding the pancreatic safety of incretin-based therapies and concluded that a causal association could not be established.Reference 1 footnote #r1b11 This potential safety issue continues to be investigated internationally.
Health care professionals are encouraged to document and report to Health Canada any adverse reactions (ARs) suspected of being associated with incretin-based therapies. Information such as treatment duration or exposure to incretin-based therapies, concomitant medications and date of onset of T2DM are important to include when reporting ARs. This information may help to further evaluate ARs suspected of being associated with incretin-based therapies.
Alain Beliveau, PhD, Health Canada
Intravenous methylprednisolone and liver injury
- Drug-induced liver injury such as acute hepatitis has been observed in association with intravenous methylprednisolone pulsed therapy.
- The time to onset of drug-induced liver injury, including acute hepatitis, can be several weeks or longer.
- Health care professionals are encouraged to report to Health Canada any cases of liver injury suspected of being associated with methylprednisolone.
Methylprednisolone is a potent anti-inflammatory steroid available in several dosage forms. Intravenous (IV) methylprednisolone (Solu-Medrol) is indicated in situations for which a rapid and intense hormonal effect is required.Reference 2 footnote #r2b1 These include, but are not limited to, hypersensitivity and anaphylactic reactions, dermatologic conditions, ulcerative colitis, shock, organ transplants, cerebral edema of non-traumatic origin and as adjunctive therapy in several other conditions.
Drug-induced liver injury has been defined as a liver injury induced by a drug leading to liver test abnormalities or liver dysfunction with reasonable exclusion of other etiologies.Reference #r2b2 footnote #r2b2 The Solu-Medrol Canadian product monograph lists the occurrence of hepatomegaly and an elevation of liver enzyme levels as potential adverse reactions (ARs).Reference 2 footnote #r2b1
As of June 30, 2014, Health Canada received 4 reports of liver injury during patient exposure to IV methylprednisolone. It was determined that one case could possibly be linked to IV methylprednisolone therapy.
Twenty-eight additional cases of drug-induced liver injury suspected of being associated with IV methylprednisolone have been identified in the literature.Reference #r2b2 footnote #r2b2,Reference 2 footnote #r2b3,Reference 2 footnote #r2b4,Reference 2 footnote #r2b5,Reference 2 footnote #r2b6,Reference 2 footnote #r2b7,Reference 2 footnote #r2b8,Reference 2 footnote #r2b9,Reference 2 footnote #r2b10,Reference 2 footnote #r2b11,Reference 2 footnote #r2b12,Reference 2 footnote #r2b13,Reference 2 footnote #r2b14,Reference 2 footnote #r2b15,Reference 2 footnote #r2b16,Reference 2 footnote #r2b17,Reference 2 footnote #r2b18,Reference 2 footnote #r2b19,Reference 2 footnote #r2b20,Reference 2 footnote #r2b21 Cases were published between 1997 and 2014. With the exception of one caseReference 2 footnote #r2b10 in which the patient developed a mild elevation in liver enzymes, ARs were reported using a variety of terms including acute and severe liver damage, hepatopathy, hepatitis, hepatic necrosis and liver failure.
A significant proportion of cases (n=10) reported transaminase (ALT and AST) levels reaching greater than 1000 U/L and some were accompanied by hyperbilirubinemia and jaundice. Death was reported in 4 cases. Three patients died from liver failureReference 2 footnote #r2b14,Reference 2 footnote #r2b16, while a fourth patient underwent liver transplantation and subsequently died from kidney complications.Reference 2 footnote #r2b16
Notably, 11 cases included a positive rechallenge (i.e., reappearance of the AR after reintroduction of IV methylprednisolone therapy), an observation which suggests a causal role for methylprednisolone. Many of these positive rechallenges were experienced several years after the last episode of liver injury.
Patients' age ranged from 11 to 71-years-old. The majority (n=17) were female. This may be related to the fact that treated conditions are more prevalent in women. Conditions included multiple sclerosis or closely related disorders such as demyelinating encephalopathy or retrobulbar optic neuritis (n=15) and thyroid-related ophthalmopathy (n=11). Other conditions included Crohn's disease and extensive alopecia areata. Additionally, the literature postulates that drug-induced liver injury is more common in women than men.Reference 2 footnote #r2b22
IV methylprednisolone was commonly administered as high dose pulse therapy in the cases. In at least 11 cases, patients received doses of IV methylprednisolone equivalent to 1000 mg per day. The variety of dosing regimens within these cases makes it challenging to calculate treatment duration and whether the risk is dose dependent. The time to onset of liver injury, including cases of acute hepatitis, varied from several days to several months since the beginning of therapy, a timeframe compatible with drug-induced liver injury.Reference #r2b2 footnote #r2b2
Prompt recognition of this AR may allow for more effective management of cases of liver injury.Reference 2 footnote #r2b20 Health care professionals are encouraged to report to Health Canada any cases of liver injury suspected of being associated with methylprednisolone.
Patrice Tremblay, MD, Health Canada
Sorafenib and osteonecrosis of the jaw
- Osteonecrosis of the jaw (ONJ), a severe bone disease of the jaw, has been reported in patients taking sorafenib. To date, no Canadian reports have been received by Health Canada.
- To decrease the risk of ONJ, patients should maintain good oral hygiene. A dental examination and appropriate preventive dental measures should be considered prior to starting treatment with drugs reported to be associated with ONJ.
- Health care professionals are encouraged to report all cases of ONJ suspected of being associated with the use of sorafenib to Health Canada.
Sorafenib (Nexavar), marketed in Canada since July 2006, is an oral multi-kinase inhibitor that targets tumour cell proliferation and tumour angiogenesis.Reference 3 footnote #r3b1 It is indicated for the treatment of patients with unresectable hepatocellular carcinoma, locally advanced or metastatic renal cell (clear cell) carcinoma and locally advanced or metastatic, progressive differentiated thyroid carcinoma.
Osteonecrosis of the jaw (ONJ) is a severe bone disease that affects the jaws and typically presents as infection with necrotic bone in the mandible or maxilla.Reference 3 footnote #r3b2 ONJ is characterized by the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks.Reference 3 footnote #r3b2,Reference #r3b3 footnote #r3b3,Reference 3 footnote #r3b4 Although asymptomatic at times, ONJ usually presents as pain and/or numbness in the affected area, soft-tissue swelling, drainage, and tooth mobility.Reference 3 footnote #r3b2
Osteonecrosis is classically considered an interruption in vascular supply and therefore, the inhibition of angiogenesis is a leading hypothesis in ONJ pathophysiology.Reference 3 footnote #r3b4 There is a growing body of literature linking osteonecrosis of the jaw and other bones with novel antiangiogenic drugs (tyrosine kinase inhibitors and monoclonal antibodies targeting vascular endothelial growth factor). Sorafenib has been listed as one of the antiangiogenic agents that have been suspected of being associated with ONJ.
The product information available in the United States for Nexavar (sorafenib) indicates that ONJ has been reported with the post-market use of sorafenib.Reference 3 footnote #r3b5,Reference 3 footnote #r3b6 As of August 29, 2014, the World Health Organization (WHO) Global Individual Case Safety Reports Database System (VigiBase) contained 8 reports of ONJ suspected of being associated with sorafenib.Reference 3 footnote #r3b0 As of July 31, 2014, Health Canada had not received any reports of ONJ suspected of being associated with the use of sorafenib.
Risk factors for ONJ include: radiotherapy, dentoalveolar surgery, including tooth extraction and implant placement, denture use, periodontal disease, and other co-morbid conditions such as cancer, anemia and diabetes.Reference 3 footnote #r3b4,Reference 3 footnote #r3b7 Medications that have been reported as risk factors for ONJ include antiresorptive medications, such as bisphosphonates and denosumab, corticosteroids, chemotherapy, as well as antiangiogenic agents.
To help decrease the risk of ONJ, it is recommended that patients maintain good oral hygiene.Reference 3 footnote #r3b2,Reference 3 footnote #r3b8 A complete dental examination and appropriate preventive dental measures prior to treatment initiation may be effective in reducing the risks of medication-related ONJ.Reference 3 footnote #r3b2,Reference 3 footnote #r3b4
In order to improve the understanding of the potential risk of ONJ in patients taking sorafenib, health care professionals are encouraged to report this adverse reaction to Health Canada.
Quarterly Summary of health professional and consumer advisories
|DateTable 1 footnote *||Product||Subject|
Table 1 footnotes
|Sept 30||Products from 3 sites in India||Health Canada takes action to stop import of products from these sites|
|Sept 28||Biomedic Acetaminophen with Codeine||Recall: missing child-resistant packaging|
|Sept 26||Ceftriaxone for injection 10g/vial||Recall of 7 lots: presence of particulate matter|
|Sept 26||Cefixime||Recommended management of gonococcal infections during cefixime shortage|
|Sept 24||Apotex products manufactured at the Apotex Research Private Limited facility in Bangalore, India||Quarantine requested by Health Canada|
|Sept 21 & 22||Mylan-Nitro Sublingual Spray 0.4 mg/metered dose||Additional information on the recall|
|Sept 20 & 22||Baxter Calcium-45, 24 EA/CA||Recall of one lot: missing bottle labels|
|Sept 20||Mylan-Nitro Sublingual Spray 0.4 mg/metered dose||Recall: defective pump|
|Sept 19||Baxter Acid Concentrate 45X||Urgent product recall for 2 lots: presence of particulate matter|
|Sept 17||Products from IPCA Laboratories in India||Quarantine requested by Health Canada following falsification and manipulation of data issues|
|Sept 9||Dacarbazine for injection 600 mg/vial, BP||Discoloration after reconstitution of vials|
|Aug 29||AMSA PD Inj 50 mg/mL (amsacrine injection)||Potential low risk of microbial contamination|
|Aug 18||Controlled-release opioid pain medicines||Label changes to encourage more targeted prescribing and safer use|
|Aug 15 & 16||Apo-Mycophenolic Acid 360 mg||Recall of one lot: French labelling error|
|Aug 15||White Widow marijuana for medical purposes||Recall of one lot: presence of mould|
|Aug 6||Arzerra (ofatumumab)||Fatal infusion reaction reported in a patient with chronic lymphocytic leukemia|
|Aug 1||Pre-Attached LTA Kit 4% Lidocaine Hydrochloride Topical Solution USP||Recall: cannula breakage|
|July 30||Nuvaring (etonogestrel / ethinyl estradiol slow release vaginal ring)||New usage restrictions|
|July 30||Cytarabine Injection 2g/20mL||Missing or partially detached label|
|July 28||Duragesic MAT (fentanyl transdermal system)||Introduction of a single ink colour (dark green) on all strengths of patches|
|July 25||Topical antiseptics||Risk of contamination|
|July 15||Testosterone products||Possible cardiovascular problems|
|July 11||Feraheme (ferumoxytol)||New usage restrictions due to serious allergic reactions|
|June 23||Cellfood||Recall of unauthorized health product: false and misleading labelling|
|June 12||Intravenous Zofran (ondansetron)||New dosing and administration recommendations in elderly patients|
|June 9||Terazol 7 Vaginal Cream and Terazol 3 Dual-Pak Vaginal Cream / Vaginal Ovules (terconazole)||Risk of anaphylaxis and toxic epidermal necrolysis|
|June 9||Drug products from CanadaDrugs.com LP||Wholesale no longer permitted: establishment license suspension due to significant concerns with Good Manufacturing Practices|
|May 29||Clinimix 5% Travasol Amino Acid Injection||Expanded recall to include 4 additional products/lots: presence of particulate matter|
|May 27||Vectibix (panitumumab)||Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis|
|May 27 to
|Foreign products||26 Foreign Product Alerts (FPAs) were posted during this period|
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Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
Address Locator 0701D
Ottawa ON K1A 0K9
Patricia Carruthers-Czyzewski, BScPhm, MSc (Editor-in-Chief)
Christianne Scott, BPharm, MBA
Jared Cousins, BSP
Hoa Ly, BSc
Emir Al-Khalili, RPh, BScPhm, MSc
Nicoleta Hosszu Ungureanu, MSc
We thank Sally Pepper, RPh, BScPhm for her participation in the production of the newsletter.
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Reporting Adverse Reactions
Canada Vigilance Program
© 2014 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.
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