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Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team
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.
Some of the hyperlinks provided are to sites of organizations or other entities that are not subject to the Official Languages Act. The material found there is therefore in the language(s) used by the sites in question.
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 1 footnote 1,Reference 1 footnote 2 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 1 footnote 1,Reference 1 footnote 2 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 3,Reference 1 footnote 4,Reference 1 footnote 5 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 6 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 7
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 8 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 9,Reference 1 footnote 10 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 11 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
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007;132(6):2131-57. [PubMed]
Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3(3):153-65. [PubMed]
Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013;62(7):2595-604. [PubMed]
Gier B, Matveyenko AV, Kirakossian D, et al. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes 2012;61(5):1250-62. [PubMed]
Matveyenko AV, Dry S, Cox HI, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interaction with metformin. Diabetes 2009;58(7):1604-15. [PubMed]
Canadian Cancer Society's Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto (ON): Canadian Cancer Society; 2014. (accessed 2014 Sept 18).
Risk factors for pancreatic cancer. Toronto (ON): Canadian Cancer Society; 2014. (accessed 2014 Sept 18).
Djelouah I, Al-Khalili E. Exenatide: international reports of pancreatic cancer. Can Advers Reaction Newsl 2013;23(2):2-3.
Onglyza (saxagliptin) [product monograph]. Mississauga (ON): AstraZeneca Canada Inc.; 2014.
Byetta (exenatide) [product monograph]. Mississauga (ON): AstraZeneca Canada Inc.; 2014.
Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment. N Engl J Med 2014;370(9):794-7. [PubMed]
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 1 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 2 footnote 2 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 1
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 2 footnote 2,Reference 2 footnote 3,Reference 2 footnote 4,Reference 2 footnote 5,Reference 2 footnote 6,Reference 2 footnote 7,Reference 2 footnote 8,Reference 2 footnote 9,Reference 2 footnote 10,Reference 2 footnote 11,Reference 2 footnote 12,Reference 2 footnote 13,Reference 2 footnote 14,Reference 2 footnote 15,Reference 2 footnote 16,Reference 2 footnote 17,Reference 2 footnote 18,Reference 2 footnote 19,Reference 2 footnote 20,Reference 2 footnote 21 Cases were published between 1997 and 2014. With the exception of one caseReference 2 footnote 10 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 14,Reference 2 footnote 16, while a fourth patient underwent liver transplantation and subsequently died from kidney complications.Reference 2 footnote 16
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 22
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 2 footnote 2
Prompt recognition of this AR may allow for more effective management of cases of liver injury.Reference 2 footnote 20 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
Solu-Medrol/Solu-Medrol Act-O-Vial (methylprednisolone sodium succinate for injection USP)[product monograph]. Kirkland (QC): Pfizer Canada Inc.; 2014.
Uppal R, Lau D, Tracy L, et al. Steroids may not be immune to causing hepatotoxicity. World Journal of Medicine 2012;7(4):301-6.
Carrier P, Godet B, Crepin S, et al. Acute liver toxicity due to methylprednisolone: consider this diagnosis in the context of autoimmunity. Clin Res Hepatol Gastroenterol 2013;37(1):100-4. [PubMed]
D'Agnolo HM, Drenth JP. High-dose methylprednisolone-induced hepatitis in a patient with multiple sclerosis: a case report and brief review of literature. Neth J Med 2013;71(4):199-202. [PubMed]
Das D, Graham I, Rose J. Recurrent acute hepatitis in patient receiving pulsed methylprednisolone for multiple sclerosis. Indian J Gastroenterol 2006;25(6):314-6. [PubMed]
Furutama D, Kimura F, Shinoda K, et al. Recurrent high-dose intravenous methylprednisolone succinate pulse therapy-induced hepatopathy in a patient with multiple sclerosis. Med Princ Pract 2011;20(3):291-3. [PubMed]
Gerolami R, Mambrini P, Barthet M, et al. Acute hepatitis caused by Solupred in a patient with Crohn disease. Gastroenterol Clin Biol 1997;21(3):236-7. [PubMed]
Gutkowski K, Chwist A, Hartleb M. Liver injury induced by high-dose methylprednisolone therapy: a case report and brief review of the literature. Hepat Mon 2011;11(8):656-61. [PubMed]
Hofstee HM, Nanayakkara PW, Stehouwer CD. Acute hepatitis related to prednisolone. Eur J Intern Med 2005;16(3):209-10. [PubMed]
Loraschi A, Banfi P, Mauri M, et al. Hepatotoxicity after high-dose methylprednisolone for demyelinating disease. Clin Neuropharmacol 2010;33(1):52-4. [PubMed]
Marin˛ M, Morabito E, Altea MA, et al. Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves' ophthalmopathy treated successfully with glucocorticoids themselves. J Endocrinol Invest 2005;28(3):280-4. [PubMed]
Rivero Fernßndez M, Riesco JM, Moreira VF et al. Recurrent acute liver toxicity from intravenous methylprednisolone. Rev Esp Enferm Dig 2008;100(11):720-3. [PubMed]
Salvi M, Vannucchi G, Sbrozzi F, et al. Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid-associated ophthalmopathy in a patient with Hashimoto's thyroiditis: case report. Thyroid 2004;14(8):631-4. [PubMed]
Weissel M, Hauff W. Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe thyroid eye disease. Thyroid 2000;10(6):521. [PubMed]
Takahashi A, Kanno Y, Takahashi Y, et al. Development of autoimmune hepatitis type 1 after pulsed methylprednisolone therapy for multiple sclerosis: a case report. World J Gastroenterol 2008;14(35):5474-7. [PubMed]
Marin˛ M, Morabito E, Brunetto MR, et al. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves' ophthalmopathy. Thyroid 2004;14(5):403-6. [PubMed]
Ghozlane L, Aouinti I, Kastalli S, et al. Cytolitic hepatitis following methylprednisolone bolus. Fundamental and Clinical Pharmacology 2012;26 (Suppl.1):109.
Koenig D, Baldin B, Rocher F, et al. Severe hepatitis observed after a bolus administration of methylprednisolone. Fundamental and Clinical Pharmacology 2012;26 (Suppl.1):24.
Lee HM, Ditelberg JS, Kaplan MM. Pericentral liver cell necrosis associated with the use of high-dose intravenous methylprednisolone. Dig Dis Sci 2007;52(6):1533-4. [PubMed]
Melamud B, Lurie Y, Goldin E, et al. Methylprednisolone-induced liver injury: a diagnostic challenge. Isr Med Assoc J 2014;16(3):180-1. [PubMed]
Reub R, Retzlaff K, Vogel S, et al. Autoimmune hepatitis after high-dose intravenous methylprednisolone pulse in RR-MS. CEJMed 2007;2(3);356-9.
Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003;349(5):474-85. [PubMed]
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 1 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 2 ONJ is characterized by the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks.Reference 3 footnote 2,Reference 3 footnote 3,Reference 3 footnote 4 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 2
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 4 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 5,Reference 3 footnote 6 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 * 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 4,Reference 3 footnote 7 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 2,Reference 3 footnote 8 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 2,Reference 3 footnote 4
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.
World Health Organization (WHO) adverse reaction information provided by: The WHO Collaborating Centre for International Drug Monitoring. This information is not homogeneous with respect to the sources of the information or the likelihood that the health product caused the suspected adverse reaction. Also, this information does not represent the opinion of the WHO.
Nexavar (sorafenib) [product monograph]. Toronto (ON): Bayer Inc.; 2014.
van Rhee F, Anaissie E, Angtuaco E, et al. Chapter 109. Myeloma. In: Kaushansky K, Lichtman M, Beutler E, et al., editors. Williams Hematology. 8th ed. New York (NY): McGraw-Hill; 2010.
ONJ Task Force. Morrison A. UPDATE Osteonecrosis of the jaw: etiology, incidence, diagnosis and management and the establishment of a Canadian registry. Ottawa (ON): Canadian Association of Oral & Maxillofacial Surgeons; Jan 2012.
Special Committee on Medication-Related Osteonecrosis of the Jaws. Ruggiero SL, Dodson TB, Fantasia J, et al. Medication-related osteonecrosis of the jaw - 2014 update. Rosemont (IL): American Association of Oral and Maxillofacial Surgeons; 2014.
Nexavar (sorafenib) [prescribing information]. Whippany (NJ): Bayer HeatlhCare Pharmaceuticals Inc.; 2013.
Nexavar (sorafenib) - Detailed view: safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER). Silver Spring (MD): US Food and Drug Administration; October 2013. (accessed 2014 Sept. 5).
Khan AA, Sßndor GKB, Dore E, et al. Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 2009;36(3):478-90. [PubMed]
Khan AA, Sßndor GKB, Dore E, et al. Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 2008;35(7):1391-7. [PubMed]
|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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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
ę 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.
Due to time constraints relating to the production of this publication, information published may not reflect the most current information.