Canadian Adverse Reaction Newsletter, Volume 17, Issue 2, April 2007

Date: 2007-04-10

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

---

Contact
MHPD-DPSC

---

Volume 17 · Issue 2 · April 2007

Health Products and Food Branch
Marketed Health Products Directorate

In this Issue:
Quetiapine: pancreatitis and thrombocytopenia
Case presentation:
Telithromycin and toxic epidermal necrolysis
Bitter orange (synephrine): update on cardiovascular reactions
Adverse reaction reporting -- 2006
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.

Quetiapine: pancreatitis and thrombocytopenia

Quetiapine (Seroquel) is an atypical antipsychotic drug indicated for the management of the symptoms of schizophrenia and the acute management of manic episodes associated with bipolar disorder.¹ In Canada, quetiapine has been marketed since December 1997.

From Dec. 1, 1997, to Oct. 31, 2006, Health Canada received 615 domestic reports of adverse reactions (ARs) suspected of being associated with the use of quetiapine. Nine reports involved cases of pancreatitis and 11 involved cases of thrombocytopenia. Neither of these ARs is mentioned in the Canadian product monograph.¹

Pancreatitis

The 9 reported cases of pancreatitis involved patients aged 24-71 years (median 32 years). One patient experienced severe hemorrhagic pancreatitis, and another had necrotizing pancreatitis. In one case, the patient experienced pancreatitis on 2 occasions while taking quetiapine. In 5 cases, quetiapine was the only suspect drug; in the other 4 cases, reported co-suspect drugs included medications that, like quetiapine, have been associated with pancreatitis: clozapine, divalproex sodium, fenofibrate and minocycline.^2,3

Acute pancreatitis typically presents as an acute inflammation of the pancreas that may or may not involve the surrounding tissues.² Gallstones and heavy alcohol use are the most common causes.² Drug-induced pancreatitis is less common, with an incidence of 2%-5% of reported cases of acute pancreatitis in the general population.² Of the 9 cases reported to Health Canada, concomitant alcohol use was reported in 1 case. The severity of drug-induced pancreatitis is variable; the majority of patients recover without any long-term morbidity, but 5%-15% of patients experience life-threatening complications.⁴ People at risk of drug-induced pancreatitis include elderly patients taking multiple medications, patients who are HIV positive, patients who have cancer and patients receiving immunomodulatory agents.⁵

Thrombocytopenia

The 11 reported cases of thrombocytopenia involved patients aged 28-84 years (median 63.5 years). In 6 cases, quetiapine was the only suspect drug. In 1 of these 6 cases, the patient was rechallenged 1 month after the drug was stopped; the thrombocytopenia recurred 3 months after the quetiapine was reintroduced. In 5 cases, reported co-suspect drugs included medications that, like quetiapine, have been associated with thrombocytopenia: citalopram, clozapine, olanzapine, pantoprazole, rofecoxib and zuclopenthixol.^6-12

Thrombocytopenia is usually defined as a platelet count of less than 150 x 10⁹/L or a 50% decrease in the platelet count from baseline.⁶Some reports define drug-induced thrombocytopenia as a platelet count of less than 100 x 10⁹/L.⁶ Although relatively rare, drug-induced thrombocytopenia may be associated with risks of morbidity and mortality.⁶ Perhaps because of its low incidence and idiosyncratic nature, drug-induced thrombocytopenia has often gone unrecognized during early clinical trials of drugs and was first reported after marketing.⁶

Health Canada continues to monitor ARs suspected of being associated with quetiapine. Health professionals are encouraged to report any cases of pancreatitis or thrombocytopenia in patients receiving quetiapine.

Nadia Aziz, BScPharm; Gilbert Roy, BPharm, Health Canada

References

1. Seroquel (quetiapine fumarate tablets) [product monograph]. Mississauga (ON): AstraZeneca Canada Inc.; 2006.
2. Eltookhy A, Pearson NL. Drug-induced pancreatitis. Can Pharmacists J 2006;139(6):58-60.
3. Gropper D, Jackson CW. Pancreatitis associated with quetiapine use. J Clin Psychopharmacol 2004;24(3):343-5. [ PubMed]
4. Kale-Pradhan PB, Conroy JL. Pancreatitis. In: Tisdale JE, Miller DA, editors. Drug-induced diseases: prevention, detection, and management. Bethesda (MD): American Society of Health-System Pharmacists, Inc.; 2005. p. 537-47.
5. Adverse Drug Reactions Advisory Committee (ADRAC). Drug induced pancreatitis. Aust Adv Drug Reactions Bull 2006;25(6):22.
6. Skirvin JA. Thrombocytopenia. In: Tisdale JE, Miller DA, editors. Drug-induced diseases: prevention, detection, and management. Bethesda (MD): American Society of Health-System Pharmacists, Inc.; 2005. p. 649-59.
7. Kentos A, Robin V, Lambermont M, et al. Probable rofecoxib-induced thrombocytopenia. Rheumatology (Oxford) 2003;42(5):699-700. [ PubMed]
8. Hirshberg B, Gural A, Caraco Y. Zuclopenthixol-associated neutropenia and thrombocytopenia. Ann Pharmacother 2000;34(6):740-2. [ PubMed]
9. Huynh M, Chee K, Lau DH. Thrombotic thrombocytopenic purpura associated with quetiapine. Ann Pharmacother 2005;39(7-8):1346-8. [ PubMed]
10. Watson TD, Stark JE, Vesta KS. Pantoprazole-induced thrombocytopenia. Ann Pharmacother 2006;40(4):758-61. [ PubMed]
11. Celexa (citalopram hydrobromide tablets) [product monograph]. Montreal: Lundbeck Canada Inc.; 2006.
12. Clozaril (clozapine tablets) [product monograph]. Dorval (QC): Novartis Pharmaceuticals Canada Inc.; 2006.

 

Bitter orange or synephrine: update on cardiovascular adverse reactions

Synephrine is an α₁-adrenergic agonist found in bitter orange (Citrus aurantium). It is used in a variety of natural health products promoted for weight loss as an alternative to ephedrine. Such products are not authorized for sale in Canada. Safety issues identified with synephrine include effects on heart rate and blood pressure, which are significantly potentiated by caffeine.¹,² Health Canada has previously notified consumers and health professionals of these potential cardiovascular adverse reactions (ARs).^3,4

In the October 2004 issue of the Canadian Adverse Reaction Newsletter, it was reported that, from Jan. 1, 1998, to Feb. 28, 2004, Health Canada received 16 domestic reports of cardiovascular ARs suspected of being associated with bitter orange or synephrine.⁴ Health Canada continues to receive reports of ARs suspected of being associated with synephrine-containing natural health products. From Mar. 1, 2004, to Oct. 31, 2006, 21 additional domestic reports were received; 15 of these were of cardiovascular ARs, of which 10 were serious, including 1 case of myocardial infarction. Certain people may have an increased risk of ARs associated with the use of synephrine-containing products:

• People with heart conditions, diabetes, thyroid disease, central nervous system disorders, glaucoma, pheochromocytoma, hypertension, known risk factors for cardiovascular disease, or enlarged prostate.³
• Underweight people.⁵
• People taking thyroid hormones, monoamine oxidase inhibitors, medications to control heart rate or blood pressure, or caffeine-containing products.^1,4,6,7
  

Consumers should be aware of the potential serious ARs when using products containing bitter orange or synephrine and may wish to consult a health professional with regard to their use. Health professionals are encouraged to ask their patients about the natural health products they are taking and to report to Health Canada any suspected ARs associated with the use of these products. More information on the safe use of weight-loss products will be published in an It's Your Health article on this topic.

Stephanie Jack, MSc; Thérèse Desjarlais-Renaud, MD, CCFP; Karen Pilon, RN, Health Canada

References

1. Haller CA, Benowitz NL, Jacob P. Hemodynamic effects of ephedra-free weight-loss supplements in humans. Am J Med 2005;118(9):998-1003. [ PubMed]
2. Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate effects following a single dose of bitter orange. Ann Pharmacother 2006;40(1):53-7. [ PubMed]
3. Health Canada warns consumers not to use "Thermonex". Ottawa: Health Canada; 2004 May 28. (accessed 2007 Jan 12).
4. Jordan S, Murty M, Pilon K. Products containing bitter orange or synephrine: suspected cardiovascular adverse reactions. Can Adverse Reaction Newsl 2004;14(4):3. [ PubMed]
5. Gray S, Woolf AD. Citrus aurantium used for weight loss by an adolescent with anorexia nervosa. J Adolesc Health 2005;37(5):415-6. [ PubMed]
6. Firenzuoli F, Gori L, Galapai C. Adverse reaction to an adrenergic herbal extract (Citrus aurantium). Phytomedicine 2005;12(3):247-8.
7. Gen-levothyroxine (levothyroxine) [product monograph]. Toronto: Genpharm Inc.; 2005.

Adverse reaction reporting -- 2006

In 2006, Health Canada received reports of 10 518 new domestic cases of suspected adverse reactions (ARs) to health products (pharmaceuticals, biologics [e.g., fractionated blood products, and therapeutic and diagnostic vaccines], natural health products and radiopharmaceuticals), which were derived from 14 549 reports. The initial report and all subsequent information received as follow-up reports are combined and considered to be one case. Domestic cases were reported for the most part by health professionals, either directly to Health Canada or indirectly through another source (Table 1). A further analysis of the total number of cases by reporter type (originator) is outlined in Table 2. In Canada, Market Authorization Holders (MAHs) of health products are required to submit to Health Canada all reports of serious domestic ARs within 15 days of receipt. In addition, MAHs are required to send within 15 days all reports of serious unexpected ARs that have occurred outside Canada (foreign ARs) for the products they sell in other countries as well as in Canada. Of the domestic cases received, 7000 (67 %) were classified as serious.*

The reporting of domestic ARs in Canada has increased steadily over the last several years, with 108 more cases in 2006 than in 2005 (Fig. 1).

Health Canada also received 252 493 reports of foreign ARs in 2006, a 43% increase since 2005 (Fig. 2). Because of this volume and the capacity of the Canadian Adverse Drug Reaction Monitoring Program (CADRMP) database, foreign reports are not included in the domestic AR database.

Health Canada would like to thank all who have contributed to the program and encourages the continued support of postmarketing surveillance through AR reporting. To report an AR:

• complete and submit a report online at Health Canada's MedEffectwebsite, or
• download and print a paper copy of the reporting form and submit it by toll-free fax (866 678-6789) or by mail to one of the Regional AR Monitoring Offices (addresses are on page 2 of the form).

You can also report an AR by toll-free phone (866 234-2345); calls will automatically be directed to the appropriate Regional AR Monitoring Office. Incidents involving medical devices are not collected in the CADRMP database and should be reported toll free through the Inspectorate Hot Line (800 267-9675).

Jennifer Lo, BSc, BA, Health Canada

* In the Food and Drugs Act and Regulations, a serious AR is defined as "a noxious and unintended response to a drug that occurs at any dose and 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." A serious unexpected AR is defined as "a serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out on the label of the drug."

Table 1: Source of domestic cases^* of adverse reactions (ARs) received by Health Canada in 2005 and 2006

Source	No. (%) of cases received
	2005		2006
Manufacturer	6 482	(62.3)	6 937	(66)
Regional AR Monitoring Office	3 470	(33.3)	3 370	(32)
Other†	458	(4.4)	211	(2)
Total	10 410	(100.0)	10 518	(100.0)

* Cases result from the merge of initial, follow-up and duplicate reports.
† Includes, but not limited to, professional associations, nursing homes, hospitals, physicians, pharmacists, Health Canada regional inspectors, coroners, dentists and patients.

 

Table 2: Number of domestic AR cases^* by type of reporter (originator) in 2005 and 2006

Reporter	No. (%) of cases
	2005		2006
Physician	2 970	(28.5)	3 077	(29.2)
Pharmacist	2 592	(24.9)	2 396	(22.8)
Nurse	926	(8.9)	806	(7.7)
Health professional†	1 267	(12.2)	1 281	(12.2)
Consumer/patient	2 304	(22.1)	2 544	(24.2)
Other	351	(3.4)	414	(3.9)
Total	10 410	(100.0)	10 518	(100.0)

*Cases result from the merge of initial, follow-up and duplicate reports.
†Type not specified in report.

Fig. 1: Number of domestic reports and cases of adverse reactions (ARs) received by Health Canada from 2000 to 2006. (Reports include follow-up, duplicate and unenterable reports. Cases result from the merge of initial, follow-up and duplicate reports.)

Fig. 2: Number of foreign AR reports received by Health Canada from 2000 to 2006. (Reports include follow-up, duplicate and unenterable reports.)

Summary of health professional and consumer advisories posted from November 15, 2006 to February 14, 2007

Date	Product	Subject and type
Feb 9	Bone Cements	Important Safety Information on Bone Cements Used in Vertebroplasty and Kyphoplasty Procedures -- notice to hospitals
Feb 6	CPAP Masks and Connectors	Important Safety information concerning the recall of Fisher & Paykel Healthcare Continuous Positive Airway Pressure (CPAP) Masks and Connectors -- consumer information -- Fisher & Paykel Healthcare
Feb 1	Unauthorized products for erectile dysfunction	Foreign Product Alert - Power 58; Platinum Power 58; Ehanix; Jolex; Onyo; Deguozonghengtianxia --consumer information
Jan 5	Kang Da	Foreign Product Alert - Kang Da -- consumer information
Jan 5	Qing Zhi	Foreign Product Alert - Qing Zhi -- consumer information
Dec 21	Xigris	Increased mortality and risk of serious adverse events when prophylactic heparin is abruptly discontinued in patients to be started on Xigris [drotrecogin alfa (activated)] for severe sepsis -- notice to hospitals -- Eli Lilly Canada Inc.
Dec 13	Herbal sleep supplement	Health Canada advises consumers not to use herbal sleep supplement containing habit-forming drug -- consumer information
Dec 11	Detox Peptide	Foreign Product Alert - Detox Peptide -- consumer information
Dec 11	Slim	Foreign Product Alert - Slim -- consumer information
Dec 8	Patient Lifts	Important Safety Information on Attachment Handles for Portable Patient Lifts -- notice to hospitals
Dec 7	Robaxacet	Health Canada advises consumers of the lack of a child-resistant cap on certain Robaxacet Caplets bottles -- consumer information
Dec 1	Iressa	Important Safety Information on Iressa (gefitinib) -- health professional communication -- AstraZeneca Canada Inc.
Nov 29	Tamiflu	New information regarding Tamiflu -- consumer information
Nov 29	Xylocaine Jelly 2%	Important Safety Information on Xylocaine (lidocaine HCI) Jelly 2% Single Use Plastic Syringe (10 mL) -- notice to hospitals -- AstraZeneca Canada Inc.
Nov 24 & 23	Benzocaine Sprays	Association of Benzocaine Sprays with Methemoglobinemia -- consumer information and notice to hospitals
Nov 22	Embrun de mer	Health Canada warns consumers not to use the product Embrun de mer due to the risk of serious bacterial infection -- consumer information
Nov 21	Evra	New safety information about Evra (norelgestromin and ethinyl estradiol) Transdermal System -- consumer information and health professional communication -- Janssen-Ortho Inc.
Nov 17	Air-Shields Isolette Infant Incubator	Safety information and corrective action on Air-Shields Isolette C2000/C2000e Infant Incubator -- notice to hospitals -- Draeger Medical Canada Inc.

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
Christianne Scott, BPharm, MBA

Acknowledgements
Expert Advisory Committee on Pharmacovigilance, Regional AR Monitoring Offices and Health Canada staff.

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.

ISSN 1499-9447; Cat no H42-4/1-17-2E

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.