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Drugs and Health Products

Canadian Adverse Reaction Newsletter, Volume 23 - Issue 2 - April 2013

ISSN 1499-9447
Cat no H42-4/1-23-2E

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Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team

In this Issue:

Scope

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
Phone: 1-866-234-2345
Fax: 1-866-678-6789

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 Next link will take you to another Web site Official Languages Act. The material found there is therefore in the language(s) used by the sites in question.

Intraocular lenses and the development of glistenings

Key points

  • Health Canada received 69 reports of glistenings suspected of being associated with intraocular lenses (IOLs).
  • In 67 cases, the development of glistenings was associated with visual impairment.
  • Health care professionals are encouraged to report to Health Canada any adverse incidents suspected of being associated with IOLs and the development of glistenings.

An intraocular lens (IOL) is an artificial lens implanted in the eye to replace a cloudy crystalline lens in cataract patients.Footnote 1 It can also be used to correct different types of eye conditions such as myopia.Footnote 2 These class III medical devices (IV being the highest risk class) can be made of several types of material such as poly(methyl methacrylate) (PMMA), silicone and hydrophobic or hydrophilic acrylic.Footnote 1,Footnote 3 Different adverse incidents have been associated with IOLs including the development of glistenings.Footnote 3 Glistenings are fluid-filled microvacuoles that form when the IOL is in an aqueous environment.Footnote 4 They can range from 1 to 20 m in size. Glistenings are usually distributed throughout the thickness of the IOL and are visible by slitlamp due to the difference in refractive indices between the fluid and the IOL material. Light is refracted and scattered at the fluid-IOL material interface, leading to a sparkling or glistening-like appearance.

As of Mar. 19, 2013, Health Canada received 69 reports of glistenings suspected of being associated with IOLs. In 67 cases, the development of glistenings was reported to have affected the quality or amount of vision. In one case, a patient had a lens replaced due to decreased vision associated with the development of glistenings.

The incidence of glistenings in IOLs varies in the literature with results ranging from a relatively low incidence of glistenings to an incidence of 100%.Footnote 5 The development of glistenings has been observed with different IOL materials.Footnote 4 The current available literature often describes this phenomenon in association with hydrophobic acrylic IOLs. In a study comparing the degree of glistenings in three IOLs made of different materials (PMMA, silicone and hydrophobic acrylic), it was found that at approximately 12 years post-implantation there was a significantly higher degree of glistenings in patients with hydrophobic acrylic lenses compared to the two other lenses.Footnote 6

Several factors that may influence the development of glistenings in IOLs have been reported in the literature. These factors include, but are not limited to, the type of IOL material, manufacturing techniques, IOL packaging and changes in temperature.Footnote 6 Further investigation is required in order to confirm the root cause of the development of glistenings and factors influencing this phenomenon.

There is no clear consensus whether the development of glistenings in IOLs can impact visual function. Some studies found that some degree of visual impairment was associated with the development of glistenings. The impairment included decreased contrast sensitivity and decreased visual acuity.Footnote 7,Footnote 8,Footnote 9,Footnote 10 Other studies did not observe any impact of glistenings on vision.Footnote 11,Footnote 12,Footnote 13 These discrepancies may be attributed to the numerous differences in study designs and methods.

Health care professionals are encouraged to report to Health Canada any adverse incidents suspected of being associated with IOLs and the development of glistenings. Information including patient symptoms, clinical test results including visual acuity and contrast sensitivity, type of IOL and concomitant visual impairment is important to include when reporting adverse incidents.

Mlanie Bousquet, PhD, Health Canada

References

Footnote 1

Ashwin PT, Shah S, Wolffsohn JS. Next link will take you to another Web site Advances in cataract surgery. Clin Exp Optom 2009;92(4):333-42. [PubMed]

Return to footnote 1 referrer

Footnote 2

Gell JL, Morral M, Kook D, et al. Next link will take you to another Web site Phakic intraocular lenses part 1: historical overview, current models, selection criteria, and surgical techniques. J Cataract Refract Surg 2010;36(11):1976-93. [PubMed]

Return to footnote 2 referrer

Footnote 3

Apple DJ, Escobar-Gomez M, Zaugg B, et al. Next link will take you to another Web site Modern cataract surgery: unfinished business and unanswered questions. Surv Ophthalmol 2011;56[Suppl 6]:S3-53. [PubMed]

Return to footnote 3 referrer

Footnote 4

Werner L. Next link will take you to another Web site Glistenings and surface light scattering in intraocular lenses. J Cataract Refract Surg 2010;36(8):1398-420. [PubMed]

Return to footnote 4 referrer

Footnote 5

Colin J, Praud D, Touboul D, et al. Next link will take you to another Web site Incidence of glistenings with the latest generation of yellow-tinted hydrophobic acrylic intraocular lenses. J Cataract Refract Surg 2012;38(7):1140-6. [PubMed]

Return to footnote 5 referrer

Footnote 6

Ronbeck M, Behndig A, Taube M, et al. Comparison of glistenings in intraocular lenses with three different materials: 12-year follow up. Acta Ophthalmol 2013;91(1):66-70. [PubMed]

Return to footnote 6 referrer

Footnote 7

Christiansen G, Durcan FJ, Olson RJ, et al. Next link will take you to another Web site Glistenings in the AcrySof intraocular lens: pilot study. J Cataract Refract Surg 2001;27(5):728-33. [PubMed]

Return to footnote 7 referrer

Footnote 8

Waite A, Faulkner N, Olson RJ. Next link will take you to another Web site Glistenings in the single-piece, hydrophobic, acrylic intraocular lenses. Am J Ophthalmol 2007;144(1):143-4. [PubMed]

Return to footnote 8 referrer

Footnote 9

Dhaliwal DK, Mamalis N, Olson RJ, et al. Next link will take you to another Web site Visual significance of glistenings seen in the AcrySof intraocular lens. J Cataract Refract Surg 1996;22(4):452-7. [PubMed]

Return to footnote 9 referrer

Footnote 10

Gunenc U, Oner FH, Tongal S, et al. Next link will take you to another Web site Effects on visual function of glistenings and folding marks in AcrySof intraocular lenses. J Cataract Refract Surg 2001;27(10):1611-4. [PubMed]

Return to footnote 10 referrer

Footnote 11

Colin J, Orignac I. Next link will take you to another Web site Glistenings on intraocular lenses in healthy eyes: effects and associations. J Refract Surg 2011;27(12):869-75. [PubMed]

Return to footnote 11 referrer

Footnote 12

Mnestam E, Behndig A. Next link will take you to another Web site Impact on visual function from light scattering and glistenings in intraocular lenses, a long-term study. Acta Ophthalmol 2011;89(8):724-8. [PubMed]

Return to footnote 12 referrer

Footnote 13

Moreno-Montañs J, Alvarez A, Rodrguez-Conde R, et al. Next link will take you to another Web site Clinical factors related to the frequency and intensity of glistenings in AcrySof intraocular lenses. J Cataract Refract Surg 2003;29(10):1980-4. [PubMed]

Return to footnote 13 referrer

Exenatide: international reports of pancreatic cancer

Key points

  • Glucagon-like peptide-1 (GLP-1) receptor agonists, such as exenatide, are new therapies for the management of type 2 diabetes mellitus.
  • Scientific literature raises concerns that exenatide may be associated with an increased risk of pancreatic cancer, but there is limited evidence to date.
  • Health care professionals are encouraged to report to Health Canada any adverse reactions suspected of being associated with the use of GLP-1 receptor agonists.

Exenatide (Byetta) is a synthetic peptide that mimics the biological properties of the incretin glucagon-like peptide-1 (GLP-1), a hormone that possesses several glucoregulatory functions.Footnote 1,Footnote 2,Footnote 3 Exenatide was marketed in Canada on May 31, 2011. It is indicated for the management of type 2 diabetes mellitus (T2DM) in combination with other antidiabetic therapies when these therapies, in addition to diet and exercise, do not provide adequate glycemic control.Footnote 1 Exenatide requires subcutaneous administration.

In normal glucose homeostasis, GLP-1 is released from endocrine cells in the small intestine in response to food ingestion, activating insulin secretion among other actions.Footnote 2,Footnote 4 However, in patients with T2DM or in patients with impaired glucose tolerance, plasma levels of GLP-1 are reduced.Footnote 3 Exenatide has been shown to bind to and activate the human GLP-1 receptor in vitro.Footnote 1 This stimulates in vivo secretion of insulin from pancreatic β-cells, enhancing glucose-dependent insulin secretion and restoring first-phase insulin secretion. It also suppresses glucagon secretion during periods of hyperglycemia in patients with T2DM. These actions work together to reduce fasting and postprandial glucose concentrations by modulating both glucose release and glucose disposal.

Additional adverse reaction (AR) information is emerging subsequent to the marketing of exenatide. One study examined the US Food and Drug Administration Adverse Event Reporting System database for reported adverse events associated with the use of exenatide from 2004 to 2009.Footnote 5 The reported event rate for pancreatic cancer was found to be 2.9 times higher for exenatide compared with control therapies. However, the study was subject to various limitations and potential confounding factors. In line with these findings, an analysis of spontaneous reports from Germany found an unusual frequency of reports of pancreatic cancer associated with exenatide compared with other antidiabetic therapies.Footnote 6 The scientific literature discusses various mechanisms of action that may be involved in mediating the potential association between exenatide and pancreatic cancer.Footnote 5,Footnote 7 However, due to limited evidence, there is a need for additional long-term prospective studies and continued monitoring.

There are also several known risk factors associated with pancreatic cancer. Although the relationship between diabetes and pancreatic cancer is complex, T2DM has been associated with an increased risk of pancreatic cancer.Footnote 8

The current Canadian product monograph for exenatide includes the following AR terms in the Post-Market Adverse Drug Reactions section: adenocarcinoma pancreas, pancreatic carcinoma, pancreatic carcinoma metastatic, pancreatic carcinoma non-resectable, pancreatic carcinoma recurrent and pancreatic carcinoma stage II.Footnote 1

As of Oct. 31, 2012, Health Canada received 6 reports of ARs suspected of being associated with exenatide. None of the reports involved pancreatic cancer. Another GLP-1 receptor agonist, liraglutide (Victoza), was marketed in Canada on May 27, 2010.Footnote 9 As of Oct. 31, 2012, there were no reports of pancreatic cancer suspected of being associated with liraglutide in Canada.

Health care professionals are encouraged to report to Health Canada any ARs suspected of being associated with exenatide or liraglutide. Information such as treatment duration or exposure to exenatide or liraglutide, 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 exenatide or liraglutide.

Ilhemme Djelouah, RPh, BScPhm, DIS Medical Biology (University of Paris V); Emir Al-Khalili, RPh, BScPhm, MSc, Health Canada

References

Footnote 14

Byetta (exenatide) [product monograph]. Toronto (ON): Eli Lilly Canada Inc.; 2012.

Return to footnote 1 referrer

Footnote 15

Ross SA, Eko JM. Next link will take you to another Web site Incretin agents in type 2 diabetes. Can Fam Physician 2010;56(7):639-48. [PubMed]

Return to footnote 2 referrer

Footnote 16

Gautier JF, Choukem SP, Girard J. Next link will take you to another Web site Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes Metab 2008;34[Suppl 2]:S65-72. [PubMed]

Return to footnote 3 referrer

Footnote 17

Baggio LL, Drucker DJ. Next link will take you to another Web site Biology of incretins: GLP-1 and GIP. Gastroenterology 2007;132(6):2131-57. [PubMed]

Return to footnote 4 referrer

Footnote 18

Elashoff M, Matveyenko AV, Gier B, et al. Next link will take you to another Web site Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011;141(1):150-6. [PubMed]

Return to footnote 5 referrer

Footnote 19

Spranger J, Gundert-Remy U, Stammschulte T. Next link will take you to another Web site GLP-1-based therapies: the dilemma of uncertainty. Gastroenterology 2011;141(1):20-3. [PubMed]

Return to footnote 6 referrer

Footnote 20

Goggins M. Next link will take you to another Web site GLP-1 receptor agonist effects on normal and neoplastic pancreata. Diabetes 2012;61(5):989-90. [PubMed]

Return to footnote 7 referrer

Footnote 21

Klein AP. Next link will take you to another Web site Identifying people at a high risk of developing pancreatic cancer. Nat Rev Cancer 2013;13(1):66-74. [PubMed]

Return to footnote 8 referrer

Footnote 22

Victoza (liraglutide) [product monograph]. Mississauga (ON): Novo Nordisk Canada Inc.; 2011.

Return to footnote 9 referrer

Quarterly Summary of health professional and consumer advisories

Health professional and consumer advisories posted on the Healthy Canadians Web site: November 19, 2012 - February 17, 2013
Date Product Subject
Date of issuance. This date may differ from the posting date on the Healthy Canadians Web site.
Feb 8 IND Diagnostic Medical device licences suspended
Jan 31 Diane-35 (cyproterone acetate and ethinyl estradiol) Safety being reviewed by Health Canada
Jan 31 Cough and cold products Recall: faulty child resistant bottle cap mechanism
Jan 30 RE9 Advanced for Men Facial Moisturizer SPF 20 Sunscreen Recall: microbial contamination
Jan 24 Infant's Little Remedies for Fevers Recall: one lot may contain less than the claimed amount of acetaminophen
Jan 24 Statins Labelling update regarding the risk of increased blood sugar levels and diabetes
Jan 21 Botulinum toxin products New labelling information
Jan 3 Weight-loss health products Important safety reminder
Jan 1 ExtenZe products Unauthorized health products removed from sale
Dec 21 Pradaxa (dabigatran, previously called Pradax) Contraindication in patients with artificial heart valves
Dec 21 EV Princess Express Peeling, EV Princess Extra Whitening Night Cream and Ling Zhi BB Whitening Cream Unauthorized health products containing high levels of mercury
Dec 4 Chemi Pharmaceutical Inc. Suspension of establishment licence due to falsified testing results
Nov 30 & Dec 20 Unauthorized health products Removed from sale at Richmond store due to possible serious health risks
Nov 30 Man Up Now, Black Ant and Triple Power Zen Gold 1200 mg Recall: presence of undeclared ingredients
Nov 28 Thermography machines Unauthorized for breast cancer screening in Canada
Nov 26 Banana Boat sun care products Additional products recalled due to fire risk
Nov 21 Prolia (denosumab) New safety information on the risk of atypical femoral fractures
Nov 19 to Feb 17 Foreign products 6 Foreign Product Alerts (FPAs) were posted on the Healthy Canadians Web site during this period

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Canadian Adverse Reaction Newsletter

Health Canada
Marketed Health Products Directorate
Address Locator 0701D
Ottawa ON K1A 0K9
Telephone: 613-954-6522
Fax: 613-952-7738

Editorial Team
Patricia Carruthers-Czyzewski, BScPhm, MSc (Editor-in-Chief)
Jared Cousins, BSP
Hoa Ly, BSc
Emir Al-Khalili, RPh, BScPhm, MSc
Aleksandar Brezar, BSc
Sophie Bourbonnais, BScPht
Nicoleta Hosszu Ungureanu, MSc

Acknowledgement
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 Kristina Klinovski, BSc, and Rachel Mailhot, students in Occupational Therapy and Biomedical Sciences, respectively, and Sally Pepper, RPh, BScPhm, for their participation in the production of the newsletter.

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Reporting Adverse Reactions
Canada Vigilance Program
Telephone: 1-866-234-2345
Fax: 1-866-678-6789

Copyright
2013 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.