Canadian Adverse Reaction Newsletter, Volume 24 - Issue 1 - January 2014
Cat no H42-4/1-24-1E
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.
Vascular endothelial growth factor receptor inhibitors and thrombotic microangiopathy
- Scientific literature suggests a potential association between vascular endothelial growth factor (VEGF) receptor inhibition and thrombotic microangiopathy (TMA).
- In certain cases, clinical manifestations of TMA resolved or improved upon treatment discontinuation.
- Health care professionals are reminded that strict monitoring and early recognition of signs and symptoms of TMA are important when treating patients with anti-VEGF agents.
Vascular endothelial growth factor (VEGF) and its receptors play a central role in tumour angiogenesis.Reference 1 Blockade of this pathway is considered to be a therapeutic strategy to inhibit tumour growth. Anti-VEGF agents block the VEGF pathway by generally one of 2 mechanisms - by preventing the interaction of VEGF with its receptor (i.e., VEGF antagonists, which include anti-VEGF monoclonal antibodies such as bevacizumab) or by targeting surface receptor function (i.e., VEGF receptor inhibitors, the focus of this article).
Six marketed VEGF receptor inhibitors are available in Canada (Table 1). The risk of thrombotic microangiopathy (TMA) is currently labelled in the Post-Marketing Experience section of the sunitinib (Sutent) Canadian product monograph (CPM) and in the Warnings and Precautions, Adverse Reactions and Post-Market Adverse Drug Reactions sections of the pazopanib (Votrient) CPM.Reference 2,Reference 3
|VEGF receptor inhibitor (Trade name)||Date of initial marketing|
TMAs are a group of disorders characterized by occlusive microvascular thrombosis, thrombocytopenia and end-organ damage.Reference 4 Two main subtypes of TMA are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Clinical symptoms of TTP typically include thrombocytopenia, microangiopathic hemolytic anemia (MAHA), neurological abnormalities, renal failure and fever. HUS can present with similar signs and symptoms, however HUS is usually diagnosed in cases in which renal failure is the most prominent sign. A diagnosis of TTP is generally designated for cases in which neurologic abnormalities such as seizure and vision loss predominate.
Several cases of TMA involving sunitinib have been published in the literature.Reference 5,Reference 6,Reference 7,Reference 8,Reference 9,Reference 10 In some of these cases, clinical manifestations of TMA resolved or improved upon discontinuation of sunitinib (along with management therapy).Reference 5,Reference 6,Reference 8,Reference 10 In one case, renal function remained normal, and laboratory investigations did not indicate any signs of TMA, however a renal biopsy later revealed features typical of TMA.Reference 7 This case highlights the possible discrepancy between mild clinical manifestations and severe TMA features on renal biopsy. Although most cases of anti-VEGF agent-induced TMA appear to be localized to the kidneys, systemic organ dysfunction can occur.Reference 11 For example, 5 cases of systemic TMA involving MAHA were reported in patients receiving a combination of sunitinib and bevacizumab.Reference 12
While VEGF receptor inhibitors are suspected of being associated with TMA, the exact mechanism of this association is unclear. A compromised renal endothelium is the proposed mechanism underlying TMA-related adverse reactions.Reference 13 This association does not exclude the possibility of other contributing factors or pathways.Reference 7,Reference 8 Although not the focus of the current article, published cases of TMA or suspected TMA have also been reported with VEGF antagonists.Reference 13,Reference 14 Considering that TMA has been observed with the use of multiple anti-VEGF agents, it has been suggested that this risk may represent a class effect.Reference 4,Reference 7
As of June 30, 2013, Health Canada has not received any reports of TMA such as TTP or HUS suspected of being associated with any of the 6 VEGF receptor inhibitors marketed in Canada.
Health care professionals are reminded that this adverse reaction may be underdiagnosed and underreported. Management of TMA should focus on strict monitoring and early recognition of signs and symptoms in patients treated with anti-VEGF agents.Reference 4 Health care professionals are encouraged to report to Health Canada any cases of TMA such as TTP or HUS suspected of being associated with anti-VEGF agents.
Rania Mouchantaf, PhD, Health Canada
- Footnote 1
Moreira IS, Fernandes PA, Ramos MJ. Vascular endothelial growth factor (VEGF) inhibition - a critical review. Anticancer Agents Med Chem 2007;7(2):223-45. [PubMed]
- Footnote 2
Sutent (sunitinib) [product monograph]. Kirkland (QC): Pfizer Canada Inc.; 2013.
- Footnote 3
Votrient (pazopanib) [product monograph]. Mississauga (ON): GlaxoSmithKline Inc.; 2013.
- Footnote 4
Blake-Haskins JA, Lechleider RJ, Kreitman RJ. Thrombotic microangiopathy with targeted cancer agents. Clin Cancer Res 2011;17(18):5858-66. [PubMed]
- Footnote 5
Levey SA, Bajwa RS, Picken MM, et al. Thrombotic microangiopathy associated with sunitinib, a VEGF inhibitor, in a patient with factor V Leiden mutation. NDT Plus 2008;1(3):154-6.
- Footnote 6
Kapiteijn E, Brand A, Kroep J, et al. Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome. Ann Oncol 2007;18(10):1745-7. [PubMed]
- Footnote 7
Bollée G, Patey N, Cazajous G, et al. Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant 2009;24(2):682-5. [PubMed]
- Footnote 8
Frangié C, Lefaucheur C, Medioni J, et al. Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol 2007;8(2):177-8. [PubMed]
- Footnote 9
Talebi TN, Stefanovic A, Merchan J, et al. Sunitinib-induced microangiopathic hemolytic anemia with fatal outcome. Am J Ther 2012;19(4):143-5. [PubMed]
- Footnote 10
Choi MK, Hong JY, Jang JH, et al. TTP-HUS associated with sunitinib. Cancer Res Treat 2008;40(4):211-3. [PubMed]
- Footnote 11
Hayman SR, Leung N, Grande JP, et al. VEGF inhibition, hypertension, and renal toxicity. Curr Oncol Rep 2012;14(4):285-94. [PubMed]
- Footnote 12
Feldman DR, Baum MS, Ginsberg MS, et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27(9):1432-9. [PubMed]
- Footnote 13
Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358(11):1129-36. [PubMed]
- Footnote 14
Pellé G, Shweke N, Duong Van Huyen JP, et al. Systemic and kidney toxicity of intraocular administration of vascular endothelial growth factor inhibitors. Am J Kidney Dis 2011;57(5):756-9. [PubMed]
Incidents involving the combined use of Durepair Dura Regeneration Matrix with ancillary wound closure products
- There is some evidence to suggest a possible increased risk of complications when ancillary wound closure products are used in combination with collagen duraplasty grafts, including Durepair.
- As of October 15, 2013, Health Canada received 5 reports of incidents suspected of involving Durepair. In some of these cases, it was reported that Durepair was implanted in conjunction with Tisseel fibrin sealant.
- Physicians are encouraged to consult the product labelling of ancillary products when considering their concomitant use with Durepair.
Durepair Dura Regeneration Matrix is a collagen implant used to repair dura mater defects during neurosurgery. It is a dural graft substitute derived from fetal bovine dermis.Reference 1 During implantation, Durepair may either be sutured into place or applied as an onlay graft.Reference 2 The porous structure of Durepair allows for fibroblast infiltration and vascularization of the implant, and eventual remodelling of the site with native collagenReference 1.
As of October 15, 2013, Health Canada received 5 reports of medical device incidents suspected of involving Durepair. In one incident, it was reported that a Durepair graft implanted in a patient in conjunction with Tisseel fibrin sealant was later removed and had a texture similar to toothpaste. The other 4 cases described patients developing chemical (or aseptic) meningitis after implantation with Durepair. In one of these 4 cases, the Durepair was implanted in conjunction with Tisseel fibrin sealant and revision surgery was required. In the other 3 of these 4 cases, it was unknown whether ancillary wound closure products (e.g., sealants, hemostatics) were used in conjunction with Durepair. The Tisseel product monograph states that its safety and effectiveness in neurosurgical procedures has not been evaluated.Reference 3
Known complications associated with the use of dural grafts are often hydrodynamic in nature, and include cerebrospinal fluid (CSF) leakage, pseudomeningocele, chemical (or aseptic) meningitis, and delayed hydrocephalus.Reference 4 However, nonrandomized studies have shown results suggesting a possible increased risk of complications when ancillary wound closure products are used in combination with collagen duraplasty grafts,Reference 5,Reference 6 including Durepair.Reference 7 One study found that 5 out of 9 patients receiving Durepair in combination with DuraSeal dural sealant (a polyethylene glycol hydrogel) experienced hydrodynamic complications and that 3 out of 9 patients required reoperation. All 5 complications presented 16 days after surgery or later and the authors suggested that the use of ancillary sealant may have inhibited cell migration in the area of the graft, hence delaying postsurgical inflammation and healing.Reference 7
Other researchers have also postulated that the use of ancillary sealants may reduce the efficacy of a collagen dural graft over time, possibly by impairing conductivity, leading to graft decay without native tissue repair.Reference 6 However, increases in complications may be related to the tendency to use multiple products in cases with higher perceived risk of CSF leak (or other hydrodynamic complications) at the outset.Reference 6 There are no published randomized clinical trials specifically investigating this issue. However, the Durepair Instructions for Use state "Animal study results suggest that the foreign body response associated with the use of sealants and hemostatic agents in conjunction with Durepair may be more pronounced than use of Durepair alone. This response may increase the incident rates of known risks of dura substitutes".Reference 2 Physicians are encouraged to consult the product labelling of ancillary products when considering their concomitant use with Durepair.
Andrew Gaffen, DDS, MSc, Health Canada
- Footnote 1
Zerris VA, James KS, Roberts JB, et al. Repair of the dura mater with processed collagen devices. J Biomed Mater Res B Appl Biomater 2007;83B(2):580-8. [PubMed]
- Footnote 2
Durepair Dura Regeneration Matrix [instructions for use]. Minneapolis (MN): Medtronic; 2011.
- Footnote 3
Tisseel (Fibrin Sealant (Human), Vapor Heated, Solvent/Detergent Treated) [product monograph]. Mississauga (ON): Baxter Corporation; 2013.
- Footnote 4
Moskowitz SI, Liu J, Krishnaney AA. Postoperative complications associated with dural substitutes in suboccipital craniotomies. Neurosurgery 2009;64(3 Suppl):28-33. [PubMed]
- Footnote 5
Litvack ZN, Anderson VC, Delashaw JB. Neurosurgical applications for a PEG based hydrogel (DuraSeal): effectiveness and safety across the spectrum of neurosurgical procedures [poster presentation]. Congress of Neurological Surgeons 56th Annual Meeting; 2006.
- Footnote 6
Litvack ZN, West GA, Delashaw JB, et al. Dural augmentation: Part I - Evaluation of collagen matrix allografts for dural defect after craniotomy. Neurosurgery 2009;65(5):890-7. [PubMed]
- Footnote 7
Parker SR, Harris P, Cummings TJ, et al. Complications following decompression of Chiari malformation Type I in children: dural graft or sealant? J Neurosurg Pediatrics 2011;8(2):177-83. [PubMed]
Looking for old issues of CARN?
CARN issues from January 2000 to present are available in the Index of Published Canadian Adverse Reaction Newsletters on the Health Canada Web site.
- Those published prior to April 2011 have been marked as archived as part of the Government of Canada Web Standards initiative.
- What does this mean? When accessing the file in PDF format, the CARN is reproduced in its entirety; however archived issues now begin on the second page. The publication itself has not been altered or updated.
CARN issues from October 1996 to present are also available online in the Electronic Collection of Library and Archives Canada in original format.
Quarterly Summary of health professional and consumer advisories
|Nov 20||Phosphate injectable products||Potential for particulate matter in some vials|
|Nov 19 & several earlier datesFootnote †||"Poppers" (products containing alkyl nitrites)||Updated list of retail locations selling "poppers"|
|Nov 15||OxyElite Pro weight loss products||Reports of serious liver injury|
|Nov 14||Gadolinium-based contrast agents||Update on nephrogenic systemic fibrosis / nephrogenic fibrosing dermopathy|
|Nov 14||Risperidone- or paliperidone-containing products||Risk of intraoperative floppy iris syndrome (IFIS)|
|Nov 6||Vega One Nutritional Shakes and Sports Performance Drinks||Recall: possible contamination with chloramphenicol|
|Nov 1||Vega One Vanilla Chai and Vega Sport Performance Chocolate||Contamination with chloramphenicol|
|Nov 1||Imitrex (sumatriptan succinate) Injection||Recall: needle may no longer be sterile|
|Oct 24||Bodico Hand Sanitizer||Found to contain undeclared methanol (associated with two deaths)|
|Oct 23||Dextran 40 in Dextrose injection and Dextran 40 in Sodium Chloride injection||Potential for crystallization|
|Oct 18||A number of natural health products||Recall: possible contamination with chloramphenicol|
|Oct 18||Natural health products sold by Lion King Health Enterprises Group Ltd.||Seized products found to contain hidden ingredients and unauthorized substances similar to sildenafil|
|Oct 17||Kamizym-U and Kamizym+||Recall: possible contamination with chloramphenicol|
|Oct 17||Acetylsalicylic Acid (ASA) products||Updated labelling standard|
|Oct 17 & several earlier datesFootnote †||Vita Health over-the-counter products||Labelling errors: updated list of recalled products|
|Oct 15||Sensipar (cinacalcet)||New warnings: risk of abnormal heart rhythm associated with low blood calcium|
|Oct 11||Nitroglycerin 100 mg in 5% Dextrose Solution||Recall: particulate matter found in solution|
|Oct 11||Spectrazyme||Recall: possible contamination with chloramphenicol|
|Oct 11||Fentanyl patches||Reminder about safe use and disposal to prevent accidental exposure|
|Oct 10||Flora Essentials||Recall: possible contamination with chloramphenicol|
|Oct 9||Kadcyla (trastuzumab emtansine) and Herceptin (trastuzumab)||Risk of medication error due to similarity in the non-proprietary names|
|Sept 26||Designer drugs||Reminder that these drugs are dangerous and illegal|
|Sept 26||Badger Baby and Badger Kids SPF 30 Sunscreen Lotion||Recall: microbial contamination|
|Sept 6||Sutent (sunitinib malate)||Cases of severe skin reactions|
|Sept 6||Vita Health over-the-counter products||Recall: labelling errors|
|Sept 5||Esme-28 (levonorgestrel and ethinyl estradiol)||Recall: possibility of a placebo pill being in place of an active pill|
|Sept 3||BiCNU (carmustine for injection U.S.P.) lyophilized powder||Shortage of Canadian-labelled BiCNU; replacement with U.S. labelled stock|
|Aug 30||Life, Exact, Rexall and Tanta Extra Strength Allergy Sinus Medication||Recall: labelling error|
|Aug 29||282 MEP (meprobamate-containing medicine)||Market withdrawal|
|Aug 27||Freya-28 (desogestrel and ethinyl estradiol)||Recall: placebo pill was found in place of an active pill|
|Aug 23||Prema G||Contains an undeclared ingredient (hydroxyhomosildenafil thione)|
|Aug 23||OM Fusion Distributors LLC products||Unauthorized health products|
|Aug 23||Personnelle Cold and Flu-in-One Extra Strength and Personnelle Flu Relief||Recall: labelling error|
|Aug 20||Zelboraf (vemurafenib)||Risk of progression of certain types of cancer and risk of serious rash|
|August 19 to November 21||Foreign products||9 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 the following members of the Expert Advisory Committee on the Vigilance of Health Products for their review of material for this issue: Colleen J. Metge, BSc(Pharm), PhD; Yola Moride, PhD, FISPE; Rishma Walji, ND, PhD; and Darrel Forsythe, RN, BN, ACCN. We also thank Sally Pepper, RPh, BScPhm; Sylvie Martin, MD; and Mélanie Bousquet, PhD, as well as Alexandre Pratt; Kristina Klinovski, BSc; and Rachel Mailhot, students in Biomedical Sciences, Occupational Therapy and Biomedical Sciences, respectively, for their participation in the production of the newsletter.
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Reporting Adverse Reactions
Canada Vigilance Program
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