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ARCHIVED - Canadian Adverse Reaction Newsletter - Volume 18 - Issue 3 July 2008

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Health Products and Food Branch
Marketed Health Products Directorate

Canadian Adverse Reaction Newsletter Editorial Team

In this Issue:
Fentanyl transdermal patch and fatal adverse reactions
Atomoxetine and suicidal behaviour: update
Twinject auto-injector and device malfunctions
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
Canada Vigilance Program
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.

Fentanyl transdermal patch and fatal adverse reactions

The fentanyl transdermal system is indicated for the management of moderate to severe chronic pain that cannot be managed by other means such as opioid combination products or immediate-release opioids.Footnote 1 The safety of this system is contingent on its use according to the conditions recommended in the Canadian product monograph.Footnote 1 The fentanyl transdermal system has been marketed in Canada under the brandname Duragesic since 1992. In July 2006, 2 generic products were introduced: Ratio-Fentanyl and Ran-Fentanyl transdermal systems.

Health Canada continues to monitor reports of serious adverse reactions (ARs) suspected of being associated with fentanyl transdermal patches. Fatal outcomes were previously described in this newsletter involving opioid-naive adolescents and adolescents who abused this medication.Footnote 2,Footnote 3 The Canadian product monograph for Duragesic was revised in 2005 to emphasize safety information following reports of death related to inappropriate use of this product. Related advisories were issued in September 2005.Footnote 4,Footnote 5 Numerous publications have highlighted safety issues related to the use of fentanyl patches.Footnote 6,Footnote 7,Footnote 8,Footnote 9

From Jan. 1, 1992, to Dec. 31, 2007, Health Canada received 105 reports of ARs suspected of being associated with fentanyl transdermal patches wherein a fatal outcome was reported. Twenty-seven of the reports were received after the last Health Canada risk communications.Footnote 4,Footnote 5 As part of the ongoing monitoring of AR reports, the data were analyzed to identify potentially preventable incidents and to increase awareness regarding the safe use of this product. In 33 of the 105 reports, the cause of death was reported to be unrelated to the fentanyl transdermal patches; in 20 cases, insufficient information was provided in the report for evaluation. The remaining 52 reports are summarized in Table 1.

Health care professionals are reminded to follow the directions in the product monographs for fentanyl transdermal patches.Footnote 1 Guidance on the safe use of this product is essential for patients, caregivers and their families, including the safe storage of fentanyl patches to prevent their accessibility for abuse and prevention of accidental overdose.

Marielle McMorran, BSc, BSc(Pharm); Maria Longo, BScPharm, Health Canada

Acknowledgement: Health Canada acknowledges the collaboration with Sylvia Hyland, RPh, BScPhm, MHSc (Bioethics), of the Institute for Safe Medication Practices Canada (ISMP Canada) and member of the Expert Advisory Committee on the Vigilance of Health Products, in the analysis of this data and preparation of this article.

Table 1: Summary of reports of 52 adverse reactions with a fatal outcome suspected of being associated with fentanyl transdermal patches submitted to Health Canada from Jan. 1, 1992, to Dec. 31, 2007
Factors related to adverse reaction (AR) No. of AR reports Additional information
  • 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.
  • The analysis is based on the information as reported in the cases.
Dose initiation and titration
6
Prescribed to opioid-naive patient (3 cases). Initiation dose high (1 case). Dose titration too quick (2 cases)
Concomitant use with other central nervous system (CNS) depressants
1
Death occurred within 24 hours after initiation of 100-µg/h fentanyl patch. Cause of death reported as probable central nervous system depression due to combination of fentanyl with other CNS depressants
Drug interaction between fentanyl and CYP3A4 inhibitor
1
Death occurred less than 4 days after initiation of lopinavirBritonavir (Kaletra), a CYP3A4 inhibitor, during fentanyl therapy
Application of patch by patient
6
Patient applied more patches than prescribed (4 cases). Patient left old patches on when applying new patch (1 case). Patient changed patch every day instead of every 3 days (1 case)
Application of patch by caregiver
3
Health care professional folded patch in half in attempt to reduce dose (1 case). Health care professional left old patches on when applying new patch (1 case). Caregiver damaged patch by pressing on it because it would not stick; fentanyl gel leaked and patient died of accidental overdose overnight (1 case)
Use of patch prescribed for another patient
1
To treat back pain, a 64-year-old man applied a 50-µg/h fentanyl patch that had been prescribed for his spouse. The patient was found unresponsive, having vomited and aspirated, and died 5 days later from pneumonia and renal failure
Accidental overdose or overdose effect
5
Patient was elderly and had lean body weight (1 case). Patient died of cardiac arrhythmia due to accidental overdose of fentanyl and elevated levels of antidepressant (1 case). Patient found dead with toxic level of fentanyl after second dose of 25-µg/h patch (1 case). Limited information provided in 2 cases
Intentional overdose or suicide 4  
Intentional drug abuse 25 Cases described abuse of fentanyl patches

Footnotes

Footnote 1

Duragesic (fentanyl transdermal system) [product monograph]. Toronto: Janssen-Ortho Inc; 2007.

Return to footnote 1 referrer

Footnote 2

Raymond B, Morawiecka I. Transdermal fentanyl (Duragesic): respiratory arrest in adolescents. Can Advers Reaction News 2004;14(4):1-2.

Return to footnote 2 referrer

Footnote 3

Raymond B. Trandermal fentanyl (Duragesic): abuse in adolescents. Can Advers Reaction News 2005;15(3):1.

Return to footnote 3 referrer

Footnote 4

Duragesic (fentanyl transdermal system) safety information [Dear Health Care Professional letter]. Ottawa: Health Canada; 2005 Sept 13. (accessed 2008 Jun 3).

Return to footnote 4 referrer

Footnote 5

Duragesic (fentanyl transdermal system) safety information [public advisory]. Ottawa: Health Canada; 2005 Sept 16. (accessed 2008 Jun 3).

Return to footnote 5 referrer

Footnote 6

Transdermal fentanyl: a misunderstood dosage form. Next link will take you to another Web site ISMP Canada Safety Bull 2006;6(5).

Return to footnote 6 referrer

Footnote 7

Fentanyl patch linked to another death in Canada. Next link will take you to another Web site ISMP Canada Safety Bull 2007;7(5).

Return to footnote 7 referrer

Footnote 8

Ongoing, preventable fatal events with fentanyl transdermal patches are alarming! Horsham (PA): Institute for Safe Medication Practices; 2007 June 28.

Return to footnote 8 referrer

Footnote 9

Next link will take you to another Web site Fentanyl transdermal system (marketed as Duragesic and generics) information for Healthcare Professionals. Rockville (MD): US Food and Drug Administration; 2007 Dec 21. (accessed 2008 Jun 3).

Return to footnote 9 referrer

Atomoxetine and suicidal behaviour: update

Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention-deficit hyperactivity disorder (ADHD) in children 6 years of age and over, adolescents and adults.Footnote 1 In September 2005, following the marketing of the drug in February 2005, a Dear Health Care Professional letter was issued regarding the potential for behavioural and emotional changes, including the risk of self-harm,Footnote 2 with the use of atomoxetine. The Warnings and Precautions section of the Canadian product monograph was updated to include the following statement: "Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type of emotional and behavioural changes, and clinical worsening."Footnote 1,Footnote 2

As of Dec. 31, 2007, Health Canada received 189 reports of adverse reactions (ARs) suspected of being associated with the use of atomoxetine. Fifty-five ARs were classified as suicide attempt. According to the World Health Organization Adverse Reaction Terminology (WHOART), the term "suicide attempt" also encompasses "non-accidental overdose," "suicide," "suicidal tendency" and "thoughts of self-harm." Reports involved 41 children (aged 6 to 17 years) and 12 adults (aged 18 to 45); the age was not provided in 2 reports. Of the 55 patients, 29 recovered without sequelae, 3 had not yet recovered at the time of reporting, 1 patient died, and the outcome was not stated in 22 reports.

Treatment options for ADHD include the non-stimulant atomoxetine and stimulants such as methylphenidate and mixed amphetamines.Footnote 3 Suicide-related behaviours have been reported with stimulant-type treatments for ADHD.Footnote 4 Treatment is complex because patients with ADHD often have other psychiatric disorders.Footnote 5 Many studies have found that over 50% of individuals diagnosed with ADHD also meet the diagnostic criteria for one or more additional psychiatric disorders (e.g., mood, anxiety, learning or behaviour disorders).Footnote 6 When ADHD is comorbid with other psychiatric disorders, it is often the first disorder to develop, and children with severe symptoms of ADHD are at increased risk of developing other psychiatric disorders.Footnote 5 Health care professionals should remind patients, family members and caregivers to monitor moods, behaviours, thoughts and feelings when ADHD medications are used.

Heather Morrison, BSc, MLIS, Health Canada

Footnotes

Footnote 1

Strattera (atomoxetine capsules) [product monograph]. Toronto: Eli Lilly Canada Inc; 2007.

Return to footnote 1 referrer

Footnote 2

Warning for atomoxetine regarding the potential for behavioural and emotional changes, including risk of self-harm [Dear Health Care Professional letter]. Ottawa: Health Canada; 2005 Sept 28. (accessed 2008 Jun 3).

Return to footnote 2 referrer

Footnote 3

Eiland LS, Guest AL. Atomoxetine treatment of attention-deficit/hyperactivity disorder. Ann Pharmacother 2004;38(1):86-90. [Next link will take you to another Web site PubMed]

Return to footnote 3 referrer

Footnote 4

Strandell J, Star K. Reports of suicide related behaviour with methylphenidate and atomoxetine in children and adolescents [poster presentation P.080]. Drug Saf 2007;30(10):919-90.

Return to footnote 4 referrer

Footnote 5

Kunwar A, Dewan M, Faraone SV. Treating common psychiatric disorders associated with attention-deficit/hyperactivity disorder. Expert Opin Pharmacother 2007;8(5):555-62. [Next link will take you to another Web site PubMed]

Return to footnote 5 referrer

Footnote 6

Brown TE. Attention-deficit disorders and comorbidities in children, adolescents and adults. Washington (DC): American Psychiatric Press; 2000.

Return to footnote 6 referrer

Twinject auto-injector and device malfunctions

Twinject, a prefilled auto-injector device containing epinephrine, is indicated for emergency treatment of severe allergic reactions, including anaphylaxis.Footnote 1 In Canada, Twinject has been marketed since August 2005 in both 0.3-mg and 0.15-mg formats. The auto-injector unit is designed to be compact and easy to carry and is able to provide a second dose of epinephrine to individuals who need it.Footnote 1 Since this product is used for life-threatening allergic reactions, it is essential for patients, caregivers and health care professionals to receive proper training regarding its use.Footnote 1,Footnote 2

As of Dec. 31, 2007, Health Canada received 25 reports of serious adverse reactions (ARs) suspected of being associated with the use of Twinject. All reports described device malfunctions in which the epinephrine could not be administered from the first dose, the second dose or in some cases both doses. Reports involved 9 children (aged 3 to 17 years) and 14 adults (aged 18 to 52); the age was not provided in 2 reports. Twenty-one patients had life-threatening conditions requiring interventions such as emergency department visits and hospital admission. Twenty-four patients were treated and recovered without sequelae; one patient received treatment, but the outcome was unknown.

Three main types of malfunction were reported: the needle did not fire when the first dose was attempted (15 patients); the plunger did not depress when the second dose was attempted (4 patients); and the needle was either bent or cracked (3 patients). In 3 of these cases, the device had a combination of these defects and did not deliver any dose of epinephrine. In 14 cases the individual who administered Twinject had received training on the use of the device, including viewing the training videoFootnote 3 or reading the instructions or both. Seven of the 25 individuals had previously used the product.

Health Canada is continuing to monitor ARs suspected of being associated with Twinject and encourages health care professionals to report similar cases to the Canada Vigilance Program and to subscribe to MedEffect e-Notice to be aware of other potential risk communications. Health Canada is assessing the issue and will work with the manufacturer to mitigate the potential risks in relation to device malfunction.

Sophie Bourbonnais, BScPht; Marielle McMorran, BSc, BSc(Pharm); Ying Wang, MSc(Biological Science), MSc(Engineering), Health Canada

Footnotes

Footnote 1

Twinject (0.3mg and 0.15mg Auto-Injector, epinephrine injection) [prescribing product information]. San Diego (CA): Verus Pharmaceutical Inc. Distributed in Canada by Paladin Labs Inc., MontrÚal (QC); 2006.

Return to footnote 1 referrer

Footnote 2

Barnett CW. Need for community pharmacist-provided food-allergy education and auto-injectable epinephrine training. J Am Pharm Assoc 2005;45(4):479-85. [Next link will take you to another Web site PubMed]

Return to footnote 2 referrer

Footnote 3

Next link will take you to another Web site How to use twinject? [video]. (accessed 2008 Feb 13).

Return to footnote 3 referrer


Quarterly Summary of health professionaland consumer advisories (posted on Health Canada's Web site: Feb. 15 - May 1)
Date Product Subject and type
May 15 Trophic Kelp & Glutamic Acid HCl Health Canada Warns Consumers Not to Use Trophic Kelp & Glutamic Acid HCl Due to Health Risk
- consumer information
May 14 Trasylol Health Canada Comments on Trasylol and the Publication of the BART Study
- consumer information
May 12 Prezista Association of Prezista (darunavir) with hepatotoxicity
- consumer information and health professional communication
May 8 Ayurvedic products Health Canada Reminds Consumers That Some Ayurvedic Medicinal Products Contain High Levels of Heavy Metals
- consumer information
May 5 Foreign product Foreign Product Alert: vpxl N01 Dietary Supplement for Men
- consumer information
Apr 30 Foreign product Foreign Product Alert: Tian Sheng Yi Bao
- consumer information
Apr 30 Foreign products Foreign Product Alert: Qili Brand Tongbianling Jiaonang, Sincere Brand ChuanXinLian Jiaonang, Xiangyao Brand Xiangyao Weian Jiaonang, Biflora Brand Fufang Danshen Pian (film-coated), Biflora Brand 306 Xiaoyan Jiedu capsules and Xiang Sha Liu Jun Wan
- consumer information
Apr 29 Foreign product Foreign Product Alert: Xian Zhi Wei II
- consumer information
Apr 29 Foreign product Foreign Product Alert: Tian Li
- consumer information
Apr 25 Vigoureux Health Canada Warns Consumers Not to Use Vigoureux or Any Unauthorized Products Promoted for Erectile Dysfunction
- consumer information
Apr 17 Foreign products Foreign Product Alert: Aspire 36 and AspireLite
- consumer information
Apr 11 Foreign product Foreign Product Alert: Baby Balm"Eucalyptus and Scotch Pine"
- consumer information
Apr 11 Foreign product Foreign Product Alert: Power 1 Walnut
- consumer information
Apr 3 Foreign products Foreign Product Alert: Tetrasil, Genisil, Aviralex, OXi-MED, Beta-mannan Micronutrient, Qina and SlicPlus
- consumer information
Mar 27 Heparin Details on Recall of Contaminated Heparin
- consumer information
- notice to hospitals
Mar 21 PediaCol Health Canada Warns Consumers not to use a Certain Lot of PediaCol Due to Health Risk
- consumer information
Mar 20 Heparin B. Braun Recalls Contaminated Heparin Productsin Canada
- consumer information
Mar 20 Libidus Health Canada Warns Consumers not to use Libidus or any Unauthorized Products Promoted for Erectile Dysfunction
- consumer information
Mar 20 Carbamazepine Patients of Asian ancestry using epilepsy drug carbamazepine may be at increased risk of serious skin reactions
- consumer information
Mar 17 Tegretol New Safety Information for the anti-epileptic drug Tegretol (carbamazepine)
- health professional communication
- Novartis Pharmaceuticals Canada Inc.
Mar 12 & 7 Sebivo Risk of peripheral neuropathy in patients treated with telbivudine (Sebivo) and interferon
- consumer information and health professional communication
- Novartis Pharmaceuticals Canada Inc.
Mar 11 Ephedra & Ephedrine Health Canada Reminds Canadians not to use Ephedra/Ephedrine Products
- consumer information
Mar 10 ADAM Health Canada Warns Consumers not to use ADAMor any Unauthorized Erectile Dysfunction Products
- consumer information
Mar 7 Daylight Saving Time change Health Canada reminds Canadians to check medical device clocks for Daylight Saving Time change
- consumer information
Mar 7 & 4 Exjade Reports of Hepatic Failure with Exjade (deferasirox)
- consumer information and health professional communication
- Novartis Pharmaceuticals Canada Inc.
Mar 6 Icy Hot Heat Therapy Urgent Voluntary Recall of Icy Hot Heat Therapy Products
- consumer information
- Chattem Canada
Mar 3 Vaccine Review Determines Measles, Mumps and Rubella Vaccine Lots Can be Released for Use
- consumer information
Feb 27 Losec and Nexium Health Canada Completes Safety Review of Losec (omeprazole) and Nexium (esomeprazole)
- consumer information
Feb 20 Botox and Botox Cosmetic Health Canada reviewing issue of distant toxin spread potentially associated with Botox and Botox Cosmetic
- consumer information

To receive the Newsletter and health product Advisories free byemail, join Health Canada's MedEffect e-Notice.

Canadian Adverse Reaction Newsletter

Health Canada
Marketed Health Products Directorate
AL 0701C
Ottawa ON K1A 0K9
Tel 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)

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

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

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 H42-4/1-18-3E

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

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.