Canadian Adverse Reaction Newsletter, Volume 18, Issue 1, January 2008

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Contact: MHPD-DPSC

Date: 2007-12-31

Volume 18 • Issue 1 • January 2008

Health Products and Food Branch
Marketed Health Products Directorate

In this Issue:
IVIG: myocardial infarction and cerebrovascular and thrombotic adverse reactions
Case presentation: NuvaRing and aortic thrombosis
Canada Vigilance Program
Evra: myocardial infarction and thromboembolic adverse reactions
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 Canada Vigilance Regional 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.

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Intravenous immune globulin: myocardial infarction and cerebrovascular and thrombotic adverse reactions

In Canada the use of intravenous immune globulin (IVIG) is reported to have increased by approximately 115% over the past 7-8 years, making Canada one of the highest per capita users of IVIG in the world.¹ In this context of increasing use, it is important that health professionals recognize some of the serious adverse reactions (ARs) suspected of being associated with the use of these products.

IVIG consists mostly of concentrated IgG manufactured from large pools of human plasma. Health Canada has authorized the use of a number of commercial brands for such indications as replacement therapy for primary or secondary immunodeficiency syndromes and treatment of idiopathic thrombocytopenic purpura. In addition, IVIG is often used off-label either as a passive immunizing agent or as an immunomodulator for the treatment of a growing number of conditions.²

From October 1997 to July 2007, Health Canada received 10 reports of stroke (reported as stroke, mini stroke, cerebral infarction or cerebrovascular accident), 6 reports of thrombosis (reported as thrombosis, thrombophlebitis or deep venous thrombosis), 4 reports of myocardial infarction (MI), 2 reports of pulmonary embolus and 1 report of transient ischemic attack (TIA) suspected of being associated with IVIG. Of the 21 patients involved, 2 had more than one AR. The median age was 61 (range 28-88, age not provided in 1 report).

The suspected products were reported as Gammagard S/D (stroke, MI, pulmonary embolism, thrombosis), Gamunex/IGIVnex (thrombosis, stroke, TIA) and Gamimune N (stroke, MI); the brand of IVIG was not specified in 3 reports (stroke, MI, thrombosis). The product monographs of all IVIG products marketed in Canada include information on the risk of thrombotic ARs.

Two patients received IVIG for common variable immune deficiency, and 17 were prescribed it off-label for polyneuropathy (4 reports), myositis (3), myasthenia gravis (2), dermatologic conditions (3) and other conditions (5). The indication for IVIG was not documented in 2 reports.

The number of days between the infusion of IVIG and the ARs varied depending on the type of reaction. Nine reported strokes occurred within a day after the IVIG administration, with most occurring during the infusion; the tenth stroke occurred 3 days after the last dose. Three MIs occurred during the infusion, and the fourth occurred 9 days later. The ARs occurred within 1 day of IVIG administration for TIA, within 11 days for pulmonary embolism and within 2 weeks for thrombosis.

Information on dose and infusion rate was often lacking or incomplete in the reports. Risk factors for the reported ARs were documented in all the reports of MI, pulmonary embolism and TIA, in 8 of the 10 reports of stroke and in 4 of the 6 reports of thrombosis. Strokes resulted in the most serious outcomes (1 death, 4 cases of persistent sequelae).

Serum viscosity has been shown to increase following IVIG administration.³ Although several possible mechanisms have been proposed,⁴ some authors have postulated that the change in serum viscosity during IVIG administration together with mild dehydration and other risk factors (e.g., age, atherosclerosis) contribute to the development of a "threshold" facilitating the production of thrombotic ARs.⁴ Five reports noted the concomitant use of diuretics, which may have contributed to a rise in serum viscosity.

Health care professionals are encouraged to report ARs suspected of being associated with the use of IVIG and to include any available information that could help characterize potential risk factors.

Carole Légaré, MD, Health Canada

References

1. Hume HA, Anderson DR. Guidelines for the use of intravenous immune globulin for hematologic and neurologic conditions. Transfus Med Rev 2007;21:S1-2. [PubMed]
   
2. Constantine MM, Thomas W, Whitman L, et al. Intravenous immunoglobulin utilization in the Canadian Atlantic provinces: a report of the Atlantic Collaborative Intravenous Immune Globulin Utilization Working Group. Transfusion 2007;47(11):2072-80. [PubMed]
   
3. Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity and pseudohyponatremia. Am J Hematol 2003;73(2):97-100. [PubMed]
   
4. Alexandrescu DT, Dutcher JP, Hughes JT, et al. Strokes after intravenous gamma globulin: Thrombotic phenomenon in patients with risk factors or just coincidence? Am J Hematol 2005;78(3):216-20. [PubMed]

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CASE PRESENTATION Recent Canadian cases are selected based on their seriousness, frequency of occurrence or the fact that the reactions are unexpected. Case presentations are considered suspicions and are presented to stimulate reporting of similar suspected adverse reactions. Etonogestrel-ethinyl estradiol vaginal ring (NuvaRing) and aortic thrombosis A 21-year-old obese woman (body mass index 36.3 kg/m2) who smoked 10-20 cigarettes per day experienced an aortic thrombosis 15 months after she started using the etonogestrel-ethinyl estradiol slow-release vaginal ring (NuvaRing) for contraception. Following an aortic thrombectomy, an embolus was also removed from her left leg. Her contraceptive history included low-dose desogestrel-ethinyl estradiol pills (Marvelon) and medroxyprogesterone injection (Depo-Provera). The reporter indicated that the patient had an elevated fibrinogen level of 6.4 (normal 2-4) g/L but no known fibrinolytic system disorder. She had no known history of varicose veins, recent injection or infusion, long-distance travel, prolonged immobilization, surgery or trauma. Her personal and family history of venous thrombosis was also negative.

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Canada Vigilance: a new name and database for the Canadian Adverse Drug Reaction Monitoring Program

Health Canada is pleased to announce Canada Vigilance as the new name for the Canadian Adverse Drug Reaction Monitoring Program. The Program is also implementing a new database that will provide an enhanced capacity for the postmarketing surveillance of adverse reactions (ARs). The Canada Vigilance database will contribute to the ongoing assessment and communication of health product safety information. Health Canada, through the Canada Vigilance Program, is responsible for the collection and assessment of AR reports that have been submitted by health professionals or consumers, either directly or through Market Authorization Holders. Since 1965, Health Canada has been gathering information on suspected ARs to health products (pharmaceuticals, biologics [e.g., fractionated blood products, and therapeutic and diagnostic vaccines], natural health products and radiopharmaceuticals).

The new name also applies to our regional offices. The 7 Canada Vigilance Regional Offices (located in Vancouver, Edmonton, Saskatoon, Winnipeg, Toronto, Montréal and Halifax), in addition to the National Office (in Ottawa), will continue to collect AR reports. For more information on the Canada Vigilance Program and its database, and on other initiatives from the Marketed Health Products Directorate, visit the MedEffect Canada website.

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Transdermal norelgestromin-ethinyl estradiol (Evra): myocardial infarction and thromboembolic adverse reactions

Evra is a transdermal hormonal contraceptive system containing 6 mg of norelgestromin and 0.6 mg of ethinyl estradiol per patch. Since its introduction on the Canadian market in early 2004, 16 cases of thromboembolism and 1 of myocardial infarction suspected of being associated with the product have been reported to Health Canada (Table 1). Two of the 17 patients died.

Hormonal contraception is one of the known risk factors for venous thromboembolism (VTE). Others include prolonged immobility, major surgery, family history of VTE, increasing age, smoking and obesity (body mass index [BMI] ≥ 30 kg/m²).^1-5 The risks may be cumulative if more than one risk factor is present.¹ An association between overweight (BMI ≥ 25 < 30 kg/m²) and thrombosis has also been observed among women using oral contraceptives.⁶ The combined effect of obesity or overweight and oral contraceptive use was greater than the expected risks based on their individual effects.⁶ The risk of VTE is also reported to be higher during the first 3 postpartum months than during pregnancy.⁷ The product monograph states that women should be encouraged to use a nonhormonal form of contraception in the 3 months following delivery.⁵

Pascale Springuel, BPharm, RAC, Health Canada

References

1. Hirsh J. Guidelines for antithrombotic therapy. 5^th ed. Hamilton (ON): BC Decker Inc.; 2005. p. 64.
   
2. Grimes DA, Shields WC. Family planning for obese women: challenges and opportunities. Contraception 2005;72:1-4. [PubMed]
   
3. Sidney S, Petitti DB, Soff GA, et al. Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives. Contraception 2004;70:3-10. [PubMed]
   
4. Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med 2005;118:978-80. [PubMed]
   
5. Evra (ethynilestradiol, norelgestromin) [product monograph]. Toronto: Janssen-Ortho Inc; 2007.
   
6. Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost 2003;89:493-8. [PubMed]
   
7. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697-706. [PubMed]

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Table 1: Summary of reports submitted to Health Canada of myocardial infarction and thromboembolic disorders suspected of being associated with Evra, from date marketed in Canada to Aug. 27, 2007*
Case	Age, yr	Adverse reaction (AR)†	Time to onset‡	Outcome§	Risk factors and additional information
1	32-33	Myocardial infarction	"A few months"	Death	"Heavy patient"; smoker
2	35	Pulmonary embolism	3 months	Recovered without sequelae	Weight 57 kg; nonsmoker
3	NA	Pulmonary embolism	Unknown	Unknown	No information on risk factors available
4	37	Pulmonary embolism	7-8 days	Not recovered at time of reporting	Weight 87 kg; nonsmoker
5	23	Pulmonary embolism	3-4 months	Unknown	BMI 26.6 kg/m2; stopped smoking 6 weeks before pulmonary embolism
6	25	Pulmonary embolism	1.5 years	Unknown	BMI 22.5 kg/m2
7	16	Pulmonary embolism	1-2 months	Death	BMI 24 kg/m2; Evra therapy initiated 9 weeks after cesarean section ¶
8	NA	Deep venous thrombosis	Unknown	Unknown	No information on risk factors available
9	29	Deep venous thrombosis	14 months, but Evra use stopped 5-6 weeks before AR	Unknown	Weight 62 kg; quit smoking 1 year earlier
10	30	Deep venous thrombosis	Unknown	Unknown	No information on risk factors available
11	NA	Deep venous thrombosis	4 months	Unknown	No information on risk factors available
12	27	Arm thrombophlebitis	6 months	Not recovered at time of reporting	BMI 24.7 kg/m2; nonsmoker
13	NA	Thrombosis/ embolism-blood clot	Unknown	Unknown	No information on risk factors available
14	28	Thrombophlebitis/ embolism-blood clot	2-3 years**	Unknown	No information on risk factors available
15	25	Thromboembolism	Unknown	Unknown	No information on risk factors available
16	15	Deep leg thrombophlebitis	5 weeks	Unknown	Smoker; family history of deep vein thrombosis
17	34	Deep leg thrombophlebitis	2-4 months	Unknown	Overweight (exact weight not provided); nonsmoker

Note: NA = not available, BMI = body mass index.
*These data cannot be used to determine the incidence of adverse reactions (ARs) because ARs are underreported and neither patient exposure nor the amount of time the drug was on the market has been taken into consideration.
†Terms are listed according to the World Health Organization Adverse Reaction Terminology (WHOART).
‡Estimated from the beginning of the treatment.
§At the time of reporting, as indicated by the reporter.
¶Conflicting data: one source reported that therapy was initiated immediately after cesarean section.
**Conflicting data: report stated that therapy with Evra was initiated in 2002; however, Evra has been marketed in Canada only since January 2004.

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Summary of health professional and consumer advisories posted by Health Canada from Aug. 17 to Nov. 10, 2007
Date Product Subject and type Nov 6 & 1 Rosiglitazone New restrictions on the use of rosiglitazone products due to cardiac safety concerns (Avandia, Avandamet, Avandaryl) -- consumer information and health professional communication -- GlaxoSmithKline Inc. Nov 5 Trasylol Manufacturer temporarily suspends marketing of Trasylol in Canada -- consumer information Nov & Oct 15 Sprint Fidelis Lead Urgent Medical Device Information on Medtronic Sprint Fidelis Lead Recall and Patient Management Recommendations -- consumer information and health professional communication -- Medtronic of Canada Ltd. Oct 25 Foreign Product Foreign Product Alert - Xie Gan Wan -- consumer information Oct 25 Foreign Product Foreign Product Alert - Red Yeast Rice, Red Yeast Rice/Policosonal Complex and Cholestrix -- consumer information Oct 18 Definity Important safety information on Definity (Perflutren Injectable Suspension) -- health professional communication -- Bristol-Myers Squibb Canada Oct 11 Cough and cold products Recommendations for the Appropriate Use of Cough and Cold Products in Children -- consumer information Oct 5 Colleague Pumps Important Safety Information on Colleague Volumetric Infusion Pumps -- health professional communication -- Baxter Corporation Oct 5 Complete All-in-One Update on recall of Complete All-in-One Contact Lens Care Solution -- consumer information Oct 4 & 3 Prexige Withdrawal of Market Authorization for Prexige (lumiracoxib) -- health professional communication -- Novartis Pharmaceuticals Canada Inc. -- consumer information Oct 2 Calabash Chalk Calabash Chalk May Pose Health Risk for Pregnant and Breastfeeding Women -- consumer information Oct 1 Foreign Products Foreign Product Alert - Gu Ci Dan and Xu Log Bou -- consumer information Oct 1 Foreign Products Foreign Product Alert - Zhen Feng Da Brand Xi Tong Wan (lot# 060908) and Wellring Brand Yin Qiao Jie Du (lot# 51005) -- consumer information Sept 28 Foreign Product Foreign Product Alert - Asam Urat Flu Tulang, PJ Dewandaru -- consumer information Sept 28 Foreign Product Foreign Product Alert - Khun-Phra -- consumer information Sept 24 Vitamin D Information Update - Vitamin D and Health -- consumer information Sept 21 Foreign Product Foreign Product Alert - Top Gun for Men Herbal Extracts -- consumer information Sept 21 Foreign Product Foreign Product Alert - Oyster Plus -- consumer information Sept 21 Foreign Product Foreign Product Alert - Deguozhanjiang -- consumer information Sept 21 Foreign Products Foreign Product Alert - Chongcaoliubian Jiaonang and Santi Scalper Penis Erection Capsule -- consumer information Sept 19 Sodium Phosphates Injection Important Safety Information on Sodium Phosphates Injection -- notice to hospitals -- Pharmaceutical Partners of Canada Sept 17 Foreign Products Foreign Product Alert - Jacaranda, Queenmer Fat Loss, Li Da Dai Dai Hua Jiao Nang, J-minus and Jelimel Slimming Capsules -- consumer information Sept 17 Foreign Products Foreign Product Alert - Junyu Jiaonanyihao -- consumer information Sept 13 Foreign Product Foreign Product Alert - Satis 60 Hours Ever Lasting Formula -- consumer information Sept 13 Foreign Product Foreign Product Alert - Qiangli Zhuanggutongbiling -- consumer information Sept 13 Foreign Product Foreign Product Alert - Heng Tong Jiangtangning Jiaonang -- consumer information Sept 13 Foreign Product Foreign Product Alert - Endopile Capsules -- consumer information Sept 13 Foreign Product Foreign Product Alert - BuXie PaiDu XiaoDou Su -- consumer information Sept 13 Foreign Product Foreign Product Alert - True Man and Energy Max -- consumer information Sept 12 Precision Xtra Important Safety Information on Abbott Diabetes Care Precision Xtra -- consumer information and health professional communication -- Abbott Diabetes Care Sept 10 Viracept Important Safety Information on Viracept (nelfinavir mesylate) --consumer information and health professional communication -- Pfizer Canada Inc Sept 10 Colloidal Silver Water Product Unauthorized Colloidal Silver Water Product May Pose Health Risk -- consumer information Sept 4 Iressa Important Safety Information on Iressa (gefitinib) -- health professional communication -- AstraZeneca Canada Inc. Sept 5 & Aug 30 Ketek Important Safety Information on Ketek (telithromycin) --consumer information and health professional communication -- Sanofi-aventis Canada Inc. Aug 24 Toothpaste Neem Active Toothpaste with Calcium found to pose additional health risks -- consumer information Aug 17 Metaboslim capsules Recall of Metaboslim capsules due to potential health risks -- consumer information Aug 17 Foreign Products Foreign Product Alert - Excite for women and Ultimates for men -- consumer information July 23 IV Administration Sets Safety Alert Notification for IV Administration Sets -- health professional communication -- Cardinal Health July 9 Thelin Important Safety Information on Thelin (sitaxsentan sodium) -- health professional communication -- Encysive Canada, Inc.
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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

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Copyright
Her Majesty the Queen in Right of Canada, 2008. 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.

ISSN 1499-9447; Cat no H42-4/1-18-1E

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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.