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ARCHIVED - Canadian Adverse Reaction Newsletter
Volume 18 - Issue 4 - October 2008

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Health Products and Food Branch
Marketed Health Products Directorate

Canadian Adverse Reaction Newsletter Editorial Team

In this Issue:
Botulinum toxin type A and distant toxin spread
Case presentation: IVIG and transfusion-related acute lung injury
Cesium chloride and ventricular arrhythmias
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 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
Telephone: 866-234-2345
Fax: 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.


Botulinum toxin type A (Botox) and distant toxin spread

Botulinum toxin health products have recently been the subject of safety notices because of their suspected association with the potential spread of the toxin to sites in the body distant from the sites of administration (distant or systemic toxin spread).1,2 In Canada, botulinum toxin type A is marketed as Botox and Botox Cosmetic. Botox is indicated for the treatment of cervical dystonia, blepharospasm associated with dystonia, strabismus, dynamic equinus due to spasticity in pediatric cerebral palsy patients, hyperhidrosis of the axilla and focal spasticity.3 Botox Cosmetic is indicated for the treatment of facial wrinkling.4

Toxin spread may occur locally, when botulinum toxin disperses to surrounding tissues, as in the case of dysphagia reported with the use of botulinum toxin type A in patients with cervical dystonia.3 In addition, adverse reactions (ARs) suggestive of botulism were also reported and may occur as the result of systemic toxin spread beyond the site of injection.2 Symptoms of botulism can include muscle weakness or paralysis, dysarthria, dysphagia and dysphonia.5 Serious complications of botulism include respiratory depression and dysphagia, which may lead to aspiration pneumonia. These manifestations may be fatal if untreated.5,6

As of Mar. 28, 2008, Health Canada received 13 reports describing ARs suggestive of distant toxin spread suspected of being associated with Botox and Botox Cosmetic (Table 1). None was medically confirmed as distant toxin spread. Ten of the 13 cases were deemed to be serious owing to life-threatening reaction (1 case), hospitalization (3 cases), ongoing disability (1 case) or fatal outcome (5 cases). Reports involved 7 adults and 4 children (age not provided in 2 cases). All but 1 patient received Botox for a therapeutic rather than a cosmetic indication; 4 patients received Botox for an off-label indication.

Health care professionals and consumers are reminded that botulinum toxin health products should be administered only at the recommended doses and for authorized indications. Patients should contact their physician or pharmacist if they have questions about Botox or Botox Cosmetic, or if they experience an adverse reaction. Health professionals are also encouraged to report to Health Canada any adverse reactions suspected of being associated with Botox or Botox Cosmetic.

MÚlanie Derry, PhD; Kelly Robinson, MSc; Elaine Taylor, MD, FCFP, Health Canada

Table 1: Summary of reports of adverse reactions suggestive of distant toxin spread suspected of being associated with botulinum toxin type A submitted to Health Canada as of Mar. 28, 2008*
Case Patient age/sex Adverse reactionć
(time to onsetç)
Indication Dose Additional information Outcome§
1 69/F Dysphagia (day 2); asthenia (day 2); respiratory disorder (day 3) Cervical dystonia 100 U Parkinsonism with possible striatonigral degeneration; concomitant medications: levodopa-carbidopa, pergolide, temazepam Death
2 NA/M Gastrointestinal disorder; paresthesia; peripheral vascular disorder; asthenia (same day) Not specified Not Specified Previous Botox exposure with no adverse reactions Not recovered
3 54/F Respiratory arrest; aphonia; hoarseness (NA) Migraine and occipital cephalalgia
(off-label)
100 U Bupivacaine use (co-suspect for respiratory arrest); aphonia and hoarseness possibly attributable to intubation Recovered without sequelae
4 31/F Dysphagia; throat swelling nonspecific; headache; allergic reaction; facial palsy; fatigue (same day) Facial wrinkling 20 U Possible allergic reaction to Botox Cosmetic; patient was taking sleep aids, which suggested fatigue was pre-existing Not recovered (fatigue)
5 55/M Slurred speech; dysarthria; muscle weakness (same day) Torticollis 300 U Symptoms also suggestive of stroke Not specified
6 36-37/F Asthenia legs; dizziness; bladder control disorder
(same day)
Muscle spasms Not specified Muscle spasms in left leg due to multiple sclerosis Not recovered
7 60/F Aspiration pneumonia; dysphagia (1 month) Muscle spasms 500 U Muscle spasticity due to cerebral palsy; progressive choking disorder (6 months) Death
8 1/M Transverse myelitis
(9 days)
Talipes
(off-label)
94 U Possible misdiagnosis of toxin spread as transverse myelitis Not recovered
9 9/M Respiratory disorder (11 days) Drooling (off-label) 90 U Cerebral palsy; clonazepam use; history of seizures Death
10 11/F Respiratory infection (3 days) Drooling (off-label) 100 U Severe cerebral palsy; general anesthetic used; 3 episodes of respiratory infections occurred after Botox exposures on 3 different dates Recovered without sequelae
11 13/M Aspiration pneumonia (14 days) Muscle spasms 400 U Cerebral palsy; severe seizure disorder; recurrent respiratory infections, including aspiration pneumonia; severe reflux Death
12 67/F Aspiration pneumonia; apnea; asthenia; blepharoptosis; dyspnea; chest pain; muscular weakness (3 weeks) Cervical dystonia 220 U Myotonic dystrophy; atrial fibrillation; hypothyroidism; osteoarthritis Death
13 NA/M Migraine; weakness; fever; blurred vision (a few days) Hyperhidrosis 300 U Lorazepam Not recovered (weakness at injection site)
Note: NA = not available.
* 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.
ć Terms are listed according to the World Health Organization Adverse Reaction Terminology (WHOART).
ç Estimated from the beginning of the treatment.
§ At the time of reporting
¶ Patient received Botox Cosmetic.

References
1. Health Canada reviewing issue of distant toxin spread potentially associated with Botox and Botox Cosmetic. Ottawa: Health Canada; 2008 Feb 20. (accessed 2008 June 9).
2. Next link will take you to another website Early communication about an ongoing safety review - Botox and Botox Cosmetic (botulinum toxin type A) and Myobloc (botulinum toxin type B). Rockville (MD): US Food and Drug Administration; 2008 Feb 8. (accessed 2008 Apr 15).
3. Botox (botulinum toxin type A for injection) [product monograph]. Markham (ON): Allergan Inc.; 2007.
4. Botox Cosmetic (botulinum toxin type A for injection) [product monograph]. Markham (ON): Allergan Inc.; 2007.
5. Brook I. Botulism: the challenge of diagnosis and treatment. Rev Neurol Dis 2006;3(4):182-9. [Next link will take you to another website PubMed]
6. Palmer JL, Metheny NA. Preventing aspiration pneumonia in older adults with dysphagia. Am J Nurs 2008;108(2):40-8. [Next link will take you to another website PubMed]


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.

Intravenous immune globulin: suspected association with transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is a clinical syndrome that presents as acute hypoxemia and noncardiogenic pulmonary edema during or within 6 hours after blood transfusion.1,2 TRALI is an important cause of transfusion-associated death, even though it is probably still underdiagnosed and underreported.2 There have been few literature reports of TRALI in patients administered intravenous immune globulin (IVIG).3 The Canadian product monograph for Gamunex (human IVIG 10%) recommends that IVIG recipients be monitored for pulmonary adverse reactions.4

Health Canada received a report of a 38-year-old man who had received Gamunex for the treatment of streptococcal thoracic cellulitis, which had also required dÚbridement. Two hours and 50 minutes into the infusion, after receiving 57.5 g of Gamunex, the patient experienced hypotension and dyspnea. The infusion was stopped. The results of a chest radiograph were compatible with a diagnosis of TRALI. The patient was transferred to the intensive care unit, where he required intubation. The result of an anti-human leukocyte antigen test was pending at the time of reporting.

References
1. Kleinman S, Caulfield T, Chan P et al. Toward an understanding of transfusion-related acute lung injury: statement of a consensus panel. Transfusion 2004;44(12):1774-89. [Next link will take you to another website PubMed]
2. Toy P, Popovsky MA, Abraham E et al. Transfusion-related acute lung injury: definition and review. Crit Care Med 2005;33(4):721-6. [Next link will take you to another website PubMed]
3. Rizk A, Gorson KC, Kenney L, et al. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41(2):264-8. [Next link will take you to another website PubMed]
4. Gamunex (immune globulin intravenous human 10%) [product monograph]. Toronto: Bayer Inc; 2005.


Cesium chloride and ventricular arrhythmias

Nonradioactive cesium chloride (CsCl) is used orally as a natural health product. Although not authorized for therapeutic use in Canada, unauthorized cesium products are accessible for purchase (e.g., on the Internet) and are used for the self-treatment of cancer. As of May 28, 2008, Health Canada received 3 reports of prolonged QT interval and ventricular tachyarrhythmia suspected of being associated with the oral use of CsCl.

One case involved an 84-year-old woman who took CsCl (reagent-grade powder, 1 g orally 3 times daily) to self-treat renal cell carcinoma. One month later, she was admitted to hospital with decreased level of consciousness and ventricular tachycardia with prolonged QT interval. She received Prussian blue and isoproterenol to maintain her heart rhythm. The patient had not yet recovered at the time of reporting.

The other 2 cases described similar symptoms and were published in the literature. In one case, a 52-year-old woman took CsCl (3 g orally daily) to treat colon cancer with liver metastasis;1 in the second case, a 62-year-old man took CsCl (1 g orally 3 times daily) for prostate cancer.2 The latter patient had also received prior naturopathic treatment with 2 g of intravenous CsCl 4 times a day for 2 weeks. In these 2 cases, other reported adverse reactions included ventricular extrasystoles, syncope and hypokalemia. In the second case, torsades de pointes was also reported, and the tachyarrhythmia with prolonged QT interval persisted after the serum potassium level returned to normal. Both patients recovered after they stopped taking CsCl.

CsCl's effects on cardiac rhythm have been demonstrated in animal studies, where it has been used to experimentally induce ventricular arrhythmias.3 Although the mechanism is not fully understood, CsCl is known to block a variety of potassium channels, including many of those involved in the cardiac action potential. 4,5

Health care professionals should be aware that cancer patients may use unauthorized alternative therapies. They are encouraged to discuss such use with their patients. Adverse reactions involving CsCl should be reported to Health Canada's Canada Vigilance Program.

Danika Painter, PhD; Elliot Berman, MD; Karen Pilon, RN, Health Canada

References
1. Lyon AW, Mayhew WJ. Cesium toxicity: a case of self-treatment by alternative therapy gone awry. Ther Drug Monit 2003;25(1):114-6. [Next link will take you to another website PubMed]
2. Pinter A, Dorian P, Newman D. Cesium-induced torsades de pointes. N Engl J Med 2002;346(5):383-4. [Next link will take you to another website PubMed]
3. Jones DL, Petrie JP, Li HG. Spontaneous, electrically, and cesium chloride induced arrhythmia and afterdepolarizations in the rapidly paced dog heart. Pacing Clin Electrophysiol 2001;24(4 pt 1):474-85. [Next link will take you to another website PubMed]
4. Vyas H, Johnson K, Houlihan R, et al. Acquired long QT syndrome secondary to cesium chloride supplement. J Altern Complement Med 2006;12(10):1011-4. [Next link will take you to another website PubMed]
5. Zhang S. Isolation and characterization of IKr in cardiac myocytes by Cs+ permeation. Am J Physiol Heart Circ Physiol 2006;290(3):H1038-49. [Next link will take you to another website PubMed]

Quarterly Summary of health professional and consumer advisories
(posted on Health Canada's Web site: [May 16 to Aug. 1, 2008)
Date Product Subject and type
July 31 Ceftriaxone Fatal interactions ceftriaxone-calcium - notice to hospitals
July 24 Foreign products Foreign Product Alert: Therma Power (red and blue varieties) and Grenade Fat Burner - consumer information
July 24 Foreign product Foreign Product Alert: Viril-Ity-Power (VIP) Tabs - consumer information
July 24 Foreign product Foreign Product Alert: Wodibo - consumer information
July 22 Jin Bu Huan Health Canada Warns Consumers Not to Use Jin Bu Huan Anodyne Tablets Due to Potential Health Risk - consumer information
July 22 Wild Vineyard Unauthorized Wild Vineyard Products Pose a Risk to Health - consumer information
July 18 Ratio-Metformin Important Safety Information on ratio-Metformin 500mg lot 638812 - health professional communication - ratiopharm inc.
July 18 Toothbrushes Toothbrushes Pulled From Shelves Due to Potential Choking Risk - consumer information
July 18 Sandoz Timolol Recall of Sandoz Timolol Ophthalmic Solution 0.25% and Sandoz Timolol Ophthalmic Solution 0.5% due to potential health risk - consumer information
July 17 Sandoz Timolol Recall of All Lots of Sandoz Timolol Ophthalmic Solution (Timolol Maleate Ophtalmic Solution USP) 0.25% and 0.5% - health professional communication -- Sandoz Canada
July 15 DDAVP DDAVP Spray (desmopressin acetate nasal spray) and DDAVP Rhinyle (desmopressin acetate nasal solution) have been associated with an increased risk of hyponatremia - health professional communication - Ferring Pharmaceuticals
July 15 DDAVP DDAVP Spray (desmopressin acetate nasal spray) and DDAVP Rhinyle (desmopressin acetate nasal solution) have been associated with an increased risk of hyponatremia - consumer information - Ferring Pharmaceuticals
July 11 Twinject Reported Malfunctions with Twinject Auto-Injector Pose Potential Health Risks - consumer information
July 11 Avastin Association of Microangiopathic anemia with the combined use of AVASTIN (bevacizumab) and sunitinib malate in metastatic renal cell carcinoma notice to hospitals - Hoffmann-La Roche Limited
July 11 Avastin Association of Microangiopathic anemia with the combined use of AVASTIN (bevacizumab) and sunitinib malate in metastatic renal cell carcinoma - consumer information - Hoffmann-La Roche Limited
July 10 Purepillz Health Canada Advises Consumers Not to Use Purepillz Unauthorized Products - consumer information
July 9 Ratio-Morphine Ratio-Morphine Tablets Recalled in Canada due to Risk of Accidental Overdose - consumer information>
July 8 Ratio-Morphine Ratio-Morphine Tablets Recalled in Canada due to Risk of Accidental Overdose - health professional communication - ratiopharm inc.
July 7 Foreign products Foreign Product Alert:  Super Shangai, Strong Testis, Shangai Ultra, Shangai Ultra X, Lady Shangai, Shangai Regular (also known as Shangai Chaojimengnan), Actra-Sx, An unknown product containing the plant Lycium barbarum L., Adam Free, NaturalUp, Erextra, Yilishen, Blue Steel, Hero, NaturalŰ Super Plus - consumer information
July 3 Acid Concentrates Recall of Hemodialysis Acid Concentrates - notice to hospitals - Baxter Corporation
June 30 Foreign product Foreign Product Alert: Mommy's Bliss Nipple Cream - consumer information
June 30 Foreign product Foreign Product Alert: 3rd Generation In Homoeopathy Arthrit Indica Tablet - consumer information
June 25 Tensor Heat Therapy Safety information concerning Tensor Heat Therapy - consumer information - BD Canada
June 24 Foreign product Foreign Product Alert: Zhong Hua Niu Bian - consumer information
June 24 Foreign products Foreign Product Alert: Nangen Zengzhangsu (may also be known as Nangen or Nangeng), Sanbianwan, Jiu Bian Wang, Tian Huang Gu Shen Dan, Zui Xian Dan Gong Shi Zi, and Power Up - consumer information
June 23 Abacavir Association of abacavir-containing medicinal products (ZIAGEN, KIVEXA and TRIZIVIR) with a potential increased risk of myocardial infarction - consumer information - GlaxoSmithKline
June 18 Abacavir Association of abacavir-containing medicinal products (ZIAGEN, KIVEXA and TRIZIVIR) with a potential increased risk of myocardial infarction - health professional communication - GlaxoSmithKline
June 18 Dietary supplements Health Canada Warns Consumers not to use the Dietary Supplements 6-OXO and 1-AD due to Potential Serious Health Risks - consumer information
June 13 Champix New safety information regarding Champix (varenicline tartrate) - health professional communication - Pfizer Canada Inc.
June 13 Champix New safety information regarding Champix (varenicline tartrate) - consumer information - Pfizer Canada Inc.
June 11 Heparin Important Safety Information on Contaminated Heparin Coated Medical Devices - notice to hospitals
June 5 Desire Additional Lot of Product Desire Found to Contain an Unlabelled Ingredient - consumer information
June 2 Somavert Increased risk of marked hepatic enzyme elevations in patients taking SOMAVERT (pegvisomant) in combination with a somatostatin analogue - health professional communication - Pfizer Canada Inc.
June 2 Somavert Increased risk of marked hepatic enzyme elevations in patients taking SOMAVERT (pegvisomant) in combination with a somatostatin analogue - consumer information - Pfizer Canada Inc.
June 2 Tysabri New Safety Information Regarding Liver Injury and Hypersensitivity Associated with TYSABRI (natalizumab) - health professional communication - Biogen Idec Canada Inc.
June 2 Tysabri New Safety Information Regarding Liver Injury and Hypersensitivity Associated with TYSABRI (natalizumab) - consumer information - Biogen Idec Canada Inc.
May 30 Foreign products Foreign Product Alert: Total Body Formula (Tropical Orange flavour and Peach Nectar flavour) & Total Body Mega Formula (Orange/Tangerine flavour) - consumer information
May 28 Foreign toothpaste Update on Foreign Toothpaste Containing Diethylene Glycol (DEG) - consumer information
May 23 Definity Association of Definity with Serious Adverse Cardiopulmonary Reactions - health professional communication - Bristol-Myers Squibb Medical Imaging
May 22 Desire Health Canada Warns Consumers Not to Use Desire or Any Unauthorized Products Promoted to Enhance Sexual Performance - consumer information
May 7 Trillium Coating Important Safety information concerning Medtronic Cardiopulmonary Bypass Devices Coated with Trillium Process using Contaminated Heparin - notice to hospitals - Medtronic of Canada Ltd.
May 7 Carmeda Coating Important Safety Information Concerning the Recall of Medtronic Cardiopulmonary Bypass Devices Coated with Carmeda Process using Contaminated Heparin - notice to hospitals - Medtronic of Canada Ltd.
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Canadian Adverse Reaction Newsletter

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

Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Ilhemme Djelouah, BScPhm, DIS, AFSA, Medical Biology (University of Paris V)
Gilbert Roy, BPharm
Jared Cousins, BSP
Christianne Scott, BPharm, MBA
Marielle McMorran, BSc, BSc(Pharm)

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

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

Copyright
© 2008 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.

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

Aussi disponible en franšais.

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.