Contact MHPD-DPSC

This document is also available in PDF format [carn-bcei_v17n4-eng.pdf] Pages: 4, Size: 492 K, Date: 2007-10-09

Canadian Adverse Reaction Newsletter

Volume 17 • Issue 4

Health Products and Food Branch
Marketed Health Products Directorate

In this Issue:
Gadolinium-containing agents: update on nephrogenic systemic fibrosis
Sibutramine and cardiovascular adverse reactions
Swedish Adjustable Gastric Band and erosion
Summary of advisories

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 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
Contact Health Canada or a Regional AR Monitoring Office free of charge
Phone: 866-234-2345
Fax: 866-678-6789

Click here for the Adverse Reaction Reporting Form

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.

---

Gadolinium-containing contrast agents and nephrogenic systemic fibrosis: update

Gadolinium (Gd)-containing media are used to enhance the contrast of magnetic resonance images. Those authorized for sale in Canada include Magnevist, Omniscan, OptiMARK, Gadovist, ProHance, MultiHance and Vasovist.

Nephrogenic systemic fibrosis (NSF), also known as nephrogenic fibrosing dermopathy (NFD), is a systemic disorder whose most prominent and visible effects are on the skin.¹ It is associated with significant morbidity.^{2 3} The fibrosis can extend beyond the dermis and involve subcutaneous tissues, muscles and internal organs.^{2 3} The disease was first described in the medical literature in 2000,⁴ but the first case was reported in 1997.^{2 4} To date, NSF has been observed only in patients with kidney disease¹.

Internationally, cases of NSF have been observed with 5 different Gd-containing contrast agents,⁵ and a causal association has recently been suggested.⁶ In March 2007, Health Canada communicated this safety concern to the public and health professionals.^{2 3} As of June 27, 2007, 5 cases of NSF suspected of being associated with Gd-containing contrast agents have been reported in Canada. This recently discovered disease is currently not described in the Canadian product monographs for these agents.

The association between NSF and the use of Gd-containing contrast media needs to be characterized further. In particular, are other patient populations at risk for NSF (e.g., neonates)? Does the risk vary according to the nature of underlying renal disorder? What is the role of dialysis in the prevention and treatment of NSF?

Valuable information could be obtained from adverse reaction (AR) reports. Spontaneous reporting can be useful to identify the clinical spectrum of the drug-AR pair, the patient subtypes and medical circumstances associated with a suspected AR.⁷ It can also provide clues to the mechanism of action whereby a product can lead to an AR.⁷ The addition of clinical information in reports, such as the duration of kidney disease and its underlying cause, laboratory values (e.g., glomerular filtration rate), the type and dose of the contrast agents, and concomitant conditions and medications, is important to help characterize the risk factors of NSF. In summary, voluntary reporting to Health Canada remains an important postmarketing surveillance tool to further elucidate this disorder.

Tanja Kalajdzic, MSc, Health Canada

References

1. Conference announcement: First annual scientific symposium on NSF and MRI contrast. New Haven (CT): International Center for Nephrogenic Fibrosing Dermopathy Research; 2007 March 27. Available:  www.icnfdr.org (accessed 2007 July 11).
2. Association of nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy (NSF/NFD) with the use of gadolinium-containing contrast agents. Ottawa: Health Canada; 2007 March 9 & 13. Available: www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2007/gadolinium_nth-aah-eng.php and www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2007/2007_24-eng.php (accessed 2007 July 11).
3. Updated safety information on Omniscan and nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy (NSF/NFD). Ottawa: Health Canada; 2007 March 7 & 12. Available: www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2007/omniscan_hpc-cps2-eng.php and www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/_2007/omniscan_pc-cp-eng.php (accessed 2007 July 11).
4. Cowper SE, Robin HS, Steinberg SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000;356:1000-1. [ PubMed]
5. Gadolinium-based contrast agents for magnetic resonance imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance). Rockville (MD): US Food and Drug Administration; 2007 May 23. Available:  www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705HCP.pdf (accessed 2007 July 11).
6. Grobner T. Gadolinium -- A specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21(4):1104-8.  [ PubMed]
7. Clark JA, Klincewicz SL, Stang PE. Spontaneous adverse event signaling methods: classification and use with health care treatment products. Epidemiol Rev. 2001; 23(2):191-210.  [ PubMed]
   

---

Contraindicated use of sibutramine and cardiovascular adverse reactions

Sibutramine (Meridia), a serotonin and norepinephrine reuptake inhibitor, is an antiobesity agent marketed in Canada since February 2001. Sibutramine is indicated as adjunctive therapy within a weight management program for obese patients with an initial body mass index (BMI) of 30 kg/m² or higher, and for obese patients with an initial BMI of 27 kg/m² or higher in the presence of other risk factors (e.g., controlled hypertension, type 2 diabetes, dyslipidemia, visceral fat).¹

The Canadian product monograph of sibutramine includes several contraindications (Table 1). Noncompliance with contraindications could result in serious adverse reactions (ARs).*

Health Canada continues to receive reports of ARs in patients using sibutramine who have contraindications. From Jan. 1, 2001, to May 31, 2007, Health Canada received 65 reports of cardiovascular ARs suspected of being associated with sibutramine. Thirteen of these reports involved patients with at least 1 contraindicated condition. A brief description of these 13 cases follows.

Table 1: Contraindications for sibutramine therapy include:1

History of coronary artery disease, congestive heart failure, arrhythmias or cerebrovascular disease (stroke or transient ischemic attack) Inadequately controlled (> 145/90 mm Hg) or unstable hypertension Psychiatric illness Concomitant use of centrally acting drugs (e.g., antidepressants and antipsychotics) or herbal remedies (e.g., St John's Wort) for the treatment of psychiatric disorders; monoamine oxidase inhibitors; or other centrally acting weight-reducing agents History of, or presence of, a major eating disorder such as anorexia nervosa or bulimia nervosa Hypersensitivity to sibutramine or to any ingredient in the formulation or component of the container

A patient with a history of myocardial infarction (MI) who was taking fluoxetine experienced fatal ventricular fibrillation 2 days after starting sibutramine therapy. A patient with a history of MI experienced a non ST-segment elevation MI 21 days after starting sibutramine therapy. Three patients experienced serotonin syndrome, with cardiovascular ARs (e.g., hypertension, palpitation and tachycardia), from the concomitant use of a selective serotonin reuptake inhibitor (SSRI) and sibutramine. Five patients with a previous history of arrhythmia had arrhythmia while taking sibutramine. One patient took 10 capsules in 3 days and experienced tachycardia and confusion during concomitant use of sibutramine with other weight-reducing agents not currently authorized for sale in Canada. One patient, who experienced unstable hypertension after surgery, resumed her preoperative regimen of sibutramine 2 days after surgery and experienced worsening hypertension, headache and cerebral edema. In this case, meperidine was reported as a co-suspect drug. One patient experienced a vitreous hemorrhage approximately 10 days after starting sibutramine therapy. In this case, paroxetine and bupropion were stopped 1 day before sibutramine was started.

Sibutramine used at therapeutic doses has been reported to substantially increase blood pressure and heart rate in some patients.^{1 2} Such increases were observed within the first 4 months of therapy.¹ Regular monitoring of blood pressure and heart rate is required when prescribing sibutramine.¹ In the first 3 months of treatment, these parameters should be checked at least every 2 weeks and regularly every 1-3 months thereafter.¹

In 2002 and 2003, international regulatory actions were taken, including safety notices, concerning cardiovascular ARs associated with sibutramine.^{2 3 4} Health Canada and other foreign regulatory agencies reviewed the safety of sibutramine and concluded that the benefit-risk profile of sibutramine remained favourable.⁴ Contraindications to the use of sibutramine are well detailed in the Canadian product monograph. Health Canada continues to monitor ARs suspected of being associated with sibutramine.

Before starting treatment with sibutramine, health professionals are encouraged to review its labelled contraindications in the product monograph. Consumers are encouraged to consult the consumer information leaflet provided in the original packaging, particularly the section "When it should not be used".

Patrice Tremblay, MD, Health Canada

* A serious adverse reaction is one that requires in-patient hospitalization or prolongation of existing hospitalization, causes congenital malformation, results in persistent or significant disability or incapacity, is life-threatening or results in death. Adverse reactions that require significant medical intervention to prevent one of these outcomes are also considered to be serious.

References

1. Meridia (sibutramine hydrochloride monohydrate) [product monograph]. Saint-Laurent (QC): Abbott Laboratories Ltd; 2005.
2. Nisoli E, Carruba MO. A benefit-risk assessment of sibutramine in the management of obesity. Drug Saf 2003;26(14):1027-48. [ PubMed]
3. Health Canada investigates safety of Meridia (sibutramine). Ottawa: Health Canada; 2002 Mar 27. Available: www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2002/2002_21-eng.php (accessed 2007 July 10).
4. Health Canada reports back to public on safety profile of Meridia (sibutramine). Ottawa: Health Canada; 2003 Feb 28. Available: www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2003/2003_07-eng.php (accessed 2007 July 10).

---

Swedish Adjustable Gastric Band: erosion and other reported incidents leading to explantation

The Swedish Adjustable Gastric Band (SAGB) is an implantable, adjustable gastric band indicated for use in the treatment of morbid obesity in adults.¹ It consists of a reinforced silicone gastric band fitted around the stomach and an injection port placed under the skin and connected to the band by tubing. The SAGB is designed to reduce food intake and can be inflated or deflated as needed after implantation to meet weight-loss requirements without the need for further surgery. The SAGB was originally licensed for sale in Canada in November 2002. A modified version of the device, the SAGB Quick Close (SAGB-QC), was added to the licence as part of a device licence amendment in August 2004.²

Although band erosion is listed among the possible adverse events in the device labelling for physicians,² the device labelling for patients states that the overall rate of reoperation following placement of the SAGB is low and that extensive use of the SAGB has led to a method where failure is uncommon.³ By definition, band erosion is "a situation where a part of the band has eroded through the full-thickness gastric wall and migrated into the lumen."⁴ This represents a total failure of the gastric banding procedure.⁵

From Nov. 1, 2002, to June 15, 2007, Health Canada received 19 reports of incidents suspected of being associated with the SAGB and 17 with the SAGB-QC. Thirteen of the 36 reports described cases of band erosion necessitating removal of the band. Other reports described incidents such as band slippage, band leakage, abscess, dysphagia and regurgitation. In 35 of the 36 reports, band explantation was reported as an outcome.

Although reported rates of band erosion vary across published studies, evidence in the medical literature suggests that the frequency of band erosion is approximately linear over time following surgery, with erosions still being diagnosed 5 or more years after implantation.^{4 5} Since band erosion is often asymptomatic or only mildly symptomatic initially and since the condition is best diagnosed by gastroscopy, which may not be included in the follow-up of asymptomatic patients, the true incidence of band erosion is underestimated in the literature and its diagnosis can be markedly delayed.^{4 5} Moreover, band erosion is associated with dense scarring and distortion of tissues, which can complicate revision procedures.⁵

The complication rates and outcomes associated with SAGB and reported in the literature are variable. Although the authors of some studies have concluded that use of the SAGB demonstrates acceptable levels of safety and effectiveness,^{6 7} others have reported high long-term complication and failure rates and poor long-term outcomes.^{4 5} The medical literature suggests that, until reliable selection criteria for patients at low risk for long-term complications are determined, alternative treatment options should be considered and gastric banding should be performed only in carefully selected and fully informed patients.⁵

Andrew Gaffen, BSc, DDS; Gina Coleman, MD; Health Canada

References

1. Swedish Adjustable Gastric Band [Canadian instructions for use]. Baar (SWI): Obtech Medical AG; 2000.
2. Swedish Adjustable Gastric Band Quick Close [Canadian instructions for use]. Zug (SWI): Ethicon Endo-Surgery in cooperation with Obtech Medical AG; 2003.
3. Swedish Adjustable Gastric Band Quick Close [Canadian patient manual]. Zug (SWI): Ethicon Endo-Surgery in cooperation with Obtech Medical AG; 2003.
4. Gustavsson S, Westling A. Laparoscopic adjustable gastric banding: complications and side effects responsible for the poor long-term outcome. Semin Laparosc Surg 2002;9(2):115-24. [ PubMed]
5. Suter M, Calmes JM, Paroz A, et al. A 10-year experience with laparoscopic gastric banding for morbid obesity: high long-term complication and failure rates. Obes Surg 2006;16(7):829-35. [ PubMed]
6. Steffen R, Biertho L, Ricklin T, et al. Laparoscopic Swedish adjustable gastric banding: a five-year prospective study. Obes Surg 2003;13(3):404-11. [ PubMed]
7. Zehetner J, Holzinger F, Tiraca H, et al. A 6-year experience with the Swedish adjustable gastric band. Prospective long-term audit of laparoscopic gastric banding. Surg Endosc 2005;19(1):21-8. [ PubMed]

---

Canada Vigilance Health Canada is pleased to announce Canada Vigilance as the new name for the Canadian Adverse Drug Reaction Monitoring Program. The Canada Vigilance Program is also implementing a new information system that will provide an enhanced capacity for the postmarketing surveillance of adverse reactions. For more information, visit the MedEffect Canada Web site.

---

Expert Advisory Committee on the Vigilance of Health Products Health Canada's Marketed Health Products Directorate, Health Products and Food Branch, is establishing the Expert Advisory Committee on the Vigilance of Health Products. To obtain more information on this committee, visit the MedEffect Canada Web site.

---

Summary of health professional and consumer advisories posted by Health Canada from May 15 to August 16, 2007
Date Product Subject and type Aug 16 Prexige New safety information regarding Prexige (lumiracoxib) -- consumer information Aug 16 & 10 Permax Cease sale of Permax (pergolide mesylate) in Canada as of August 30, 2007 -- consumer information and health professional information -- Eli Lilly Canada Inc. Aug 15 Drugs online Health Canada reminds consumers about the risk of buying drugs online -- consumer information Aug 9 Losec & Nexium Health Canada reviewing new safety information on cardiac events in patients taking Losec (omeprazole) or Nexium (esomeprazole) -- consumer information Aug 8 Rituxan Important Safety Information on Rituxan (rituximab) -- consumer information and health professional information -- Hoffmann-La Roche Limited Aug 1 Lancing devices Reminder to use lancing devices for blood sampling as directed -- consumer information July 27 Resolve Unauthorized smoking cessation product Resolve may pose health risk -- consumer information July 26, 6, 5, June 29 & 21 Toothpaste Neem Active Toothpaste with Calcium in Canada found to contain diethylene glycol -- consumer information Update on counterfeit toothpaste -- consumer information Additional serious harmful bacteria potentially found in counterfeit toothpaste -- consumer information Health Canada updates list of toothpastes from China found to contain diethylene glycol -- consumer information Chinese toothpaste in Canada found to contain diethylene glycol -- consumer information Counterfeit toothpaste falsely labelled as Colgate found to contain harmful bacteria -- consumer information Health Canada's investigation into toothpaste containing diethylene glycol (DEG) -- consumer information July 23 Liviro3 Health Canada advises consumers not to use Liviro3 dietary supplement due to potential health risks -- consumer information July 20 Xylocaine Jelly 2% Safety information on Xylocaine (lidocaine HCl) Jelly 2% Single Use Plastic Syringe (10mL): Update -- notice to hospitals -- AstraZeneca Canada Inc. July 20 Zencore Tabs Health Canada warns consumers not to use Zencore Tabs due to potential health risks -- consumer information July 18 & June 14 Sleep supplement Sleep supplement found to contain habit-forming drug -- consumer information July 16 Unauthorized foreign products Foreign Product Alert - Kui Hua Chut Lee San Bird's Nest & Pearl - Batch #WA00030 -- consumer information Foreign Product Alert - Dai Dai Hua Jiao Nang, Darling Capsules, Dali Capsules, Spanish Fly Capsules, an unnamed product -- consumer information Foreign Product Alert - Jie Jie Pills and Chuan Xiong Cha Tiao Wan -- consumer information July 9 MdMt Health Canada warns consumers not to use the dietary supplement MdMt due to potentially serious health risks -- consumer information June 25 Encore Tabs for Men Health Canada warns consumers not to use Encore Tabs for Men due to potential health risks -- consumer information June 21 Fluotic Voluntary Recall of One Lot of Fluotic (sodium fluoride) 20 mg tablets and Notice of product discontinuation -- health professional communication -- sanofi-aventis Canada Inc. June 19 Sensipar Product Update: New information about Sensipar (cinacalcet hydrochloride) -- consumer information and health professional communication -- Amgen Canada Inc. June 18 CADD Medication Cassette Reservoirs Urgent: Product safety and recall notification -- health professional communication -- Smiths Medical Canada Ltd. June 15 Vitamin D Vitamin D and Health -- consumer information June 13 & 5 Fraxiparine Voluntary recall of Fraxiparine graduated syringes, 0.6 mL and Fraxiparine Forte graduated syringes, 0.8 mL -- consumer information and health professional communication -- GlaxoSmithKline Inc. June 12 Ventolin Safety information on Ventolin I.M. injection and Ventolin I.V. infusion solution for pregnant women & labour and delivery -- notice to hospitals -- GlaxoSmithKline Inc. June 6 Colleague Pumps Important product information on the Colleague Volumetric Infusion Pumps -- health professional communication -- Baxter Corporation June Avastin Association of Avastin (bevacizumab) with tracheo-esophageal fistula -- consumer information and health professional communication -- Hoffman-La Roche Ltd. June 1 & May 30 Avandia Cardiac safety of Avandia (rosiglitazone maleate) -- consumer information and health professional communication -- GlaxoSmithKline Inc. May 30 Unauthorized products for erectile dysfunction Foreign Product Alert - Power 58 Extra, Platinum Power 58 Extra, Enhanix New Extra Men's Formula, Valentino, King Power Oral Solution, and Stretch Up Capsules -- consumer information May 30 Complete All-In-One Recall of Complete All-In-One Contact Lens Care Solution -- consumer information May 30 HS Joy of Love Foreign Product Alert - HS Joy of Love -- consumer information May 30 Bone Cements Safety Information on Bone Cements used in vertebroplasty and kyphoplasty procedures -- notice to hospitals May 17 S8 flow generator devices Medical Device Recall - Models Affected: S8 Compact, S8 Escape, S8 Elite and S8 AutoSet Vantage -- consumer information -- ResMed Corp. May 16 Xiaokeshuping Jiangtangning Jiaonang Foreign Product Alert - Xiaokeshuping Jiangtangning Jiaonang -- consumer information May 14 & 11 Depakene Voluntary Type 1 Recall of Depakene (valproic acid) 500-mg Enteric-Coated Capsules in Canada -- consumer information and health professional communication -- Abbott Laboratories, Limited May 11 Insulin Pump Important safety information on Medtronic MiniMed Paradigm insulin infusion pump -- consumer information and health professional communication -- Medtronic of Canada Ltd. May 11 Ratio-Valproic Urgent: Voluntary Type 1 Recall of ratio-Valproic (valproic acid) 500-mg Enteric-Coated Capsules in Canada -- health professional communication -- ratiopharm inc May 3 Myozyme Recent reports of black particles after reconstitution of Myozyme -- health professional communication -- Genzyme Canada Inc. May & Apr 30 OneTouch Ultra Test Strips Safety information concerning OneTouch Ultra Test Strips -- consumer information and health professional communication -- LifeScan Canada Ltd.
To receive the Newsletter and health product Advisories free by email, join Health Canada's MedEffect e-Notice.

---

Canadian Adverse Reaction Newsletter

Marketed Health Products Directorate
AL 0701C
Ottawa ON K1A 0K9
Tel 613-954-6522
Fax 613-952-7738

Health professionals/consumers report toll free:
Tel 866-234-2345
Fax 866-678-6789

Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Ilhemme Djelouah, BScPhm, DIS, AFSA, Medical Biology (University of Paris V)
Gilbert Roy, BPharm
Michel Trottier, BScPhm, RPEBC, RPh
Jared Cousins, BSP

Suggestions?
Your comments are important to us. Let us know what you think.

Copyright
Her Majesty the Queen in Right of Canada, 2007. 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.

IISSN 1499-9447; Cat no H42-4/1-17-4E

USPS periodical postage paid at Champlain, NY, and additional locations.

Aussi disponible en français.

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.