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ARCHIVED - Canadian Adverse Reaction Newsletter, Volume 19 - Issue 3 July 2009

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Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team

In this Issue:

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
Phone: 1-866-234-2345
Fax: 1-866-678-6789

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.

Some of the hyperlinks provided are to sites of organizations or other entities that are not subject to the Next link will take you to another Web site Official Languages Act. The material found there is therefore in the language(s) used by the sites in question.

Montelukast (Singulair): suicidality and other psychiatric adverse reactions

Montelukast sodium (Singulair), a leukotriene-receptor antagonist, is indicated for the prophylaxis and chronic treatment of asthma in patients 2 years of age and older.Footnote 1 It is also indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years of age and older when other treatments are not effective or not tolerated. Montelukast has been marketed in Canada since 1997.

Between September 2007 and July 2008, updates were made to the "Adverse drug reactions" section of the Canadian product monograph for montelukast to include depression, suicidality and anxiousness.Footnote 1 The American product monograph was similarly updated.Footnote 2 In March 2008, the US Food and Drug Administration (FDA) issued an "Early communication" stating that it was investigating further the suspected association between montelukast and suicidality.Footnote 3 Following the FDA's early communication, there was a 7-fold increase in the number of montelukast-related cases reported to the Adverse Event Reporting System database in the United States.Footnote 4

From the date of marketing to Jan. 31, 2009, Health Canada received 13 adverse reaction (AR) reports related to suicidality or self-injury suspected of being associated with the use of montelukast (Table 1). Eight reports stated that the reaction abated after the dose was reduced or the drug was stopped. The reaction reappeared after the reintroduction of montelukast in 1 case. All but 1 of the reports were received by Health Canada after the FDA's early communication.

From the date of marketing to Jan. 31, 2009, Health Canada received 29 other AR reports relating to depression, hostility or psychosis suspected of being associated with the use of montelukast (Table 1). In 19 cases, the reaction abated after montelukast was stopped or the dose was reduced. The reaction reappeared after the reintroduction of montelukast in 4 cases. Thirteen of the 29 reports were received by Health Canada after the FDA's early communication.

Table 1: Summary of reports relating to suicidality and other psychiatric adverse reactions (ARs) suspected of being associated with montelukast received by Health Canada from date marketed in Canada (1997) to Jan. 31, 2009
Reaction No. of reports Serious AR Positive dechallenge Positive rechallenge
NA = Not applicable
  • Terms are listed according to the Medical Dictionary for Regulatory Activities (MedDRA).
  • 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."
  • No. of reports that described abatement of reaction after montelukast was stopped or the dose was reduced.
  • No. of reports that described reappearance of reaction after reintroduction of montelukast.
Suicide attempt 2 2 NA NA
Suicidal or self-injury ideation 11 11 8 1
Other (relating to depression, hostility or psychosis) 29 14 19 4
Total 42 27 27 5

No deaths were reported in any of the cases discussed above. Twenty-six of the 42 reports involved patients under 18 years of age (age was not indicated in 5 reports).

The consumer information section of the Canadian product monograph warns patients that, if suicidal thoughts and actions occur, montelukast should be discontinued and a physician or pharmacist contacted immediately. The product monograph also states that, if severe behaviour and mood-related changes such as agitation including aggressive behaviour (e.g., temper tantrum in children) occur, a physician or pharmacist should be consulted.Footnote 1

Health care professionals and consumers are encouraged to consult the product monograph of montelukast, including the consumer information section, for information regarding behaviour and mood-related ARs.

Patrice Tremblay, MD, Health Canada

Footnotes

Footnote 1

Singulair, montelukast (as montelukast sodium) [product monograph]. Kirkland (QC): Merck Frosst Canada Ltd; 2009.

Return to footnote 1 referrer

Footnote 2

Next link will take you to another Web site Singulair (montelukast sodium) [prescribing information].Whitehouse Station (NJ): Merck & Co., Inc.: 2008. (accessed 2009 May 11).

Return to footnote 2 referrer

Footnote 3

Next link will take you to another Web site Early communication about an ongoing safety review of montelukast (Singulair). Rockville (MD): US Food and Drug Administration: 2008 Mar 27 (accessed 2009 May 11).

Return to footnote 3 referrer

Footnote 4

Next link will take you to another Web site QuarterWatch: 2008 quarter 2. Alexandria (VA): Institute for Safe Medication Practices; 2009 Jan 15. (accessed 2009 May 11).

Return to footnote 4 referrer

Intravitreal injection of triamcinolone acetonide and serious ocular adverse reactions

Triamcinolone acetonide is a synthetic corticosteroid primarily used for its marked anti-inflammatory action.Footnote 1 It was authorized for use in Canada as a 10-mg/mL suspension (Kenalog 10) in 1966, and as a 40-mg/mL suspension (Kenalog 40) in 1973. Currently, generic products are also available. In Canada, the 40-mg/mL suspension has been authorized for intramuscular and intra-articular administration or for injection into tendon sheaths or ganglia. It is indicated for systemic corticosteroid therapy in conditions such as dermatoses, or rheumatoid arthritis and other connective tissue disorders.Footnote 1

Intravitreal or intraocular injection of this product is not an authorized route of administration in Canada. Diabetic macular edema, cystoid macular edema and choroidal neovascularization secondary to age-related macular degeneration are among the conditions for which the use of intravitreal injection of triamcinolone has been reported.Footnote 2,Footnote 3 In 2007, a safety notice was published in France regarding the occurrence of serious ocular adverse reactions (ARs) following intravitreal injections of the 40-mg/mL suspension.Footnote 4

Topical ophthalmic, oral and intravenous corticosteroids have long been associated with ocular ARs. Local injections of steroids, even at sites far from the eye, have been associated with eye complications such as the development of cataract, glaucoma, and even retinal and choroidal emboli.Footnote 5

Intravitreal injection of triamcinolone has several reported complications. Immediate complications include retinal detachment and vitreous hemorrhage. Complications developing later include cataract progression, steroid-induced glaucoma and endophthalmitis.Footnote 2 Triamcinolone persists for long periods. Low concentrations were found in samples of aqueous humor up to 1.5 years after intravitreal injection.Footnote 6 Cases of increased intraocular pressure requiring medical intervention following intravitreal injection have also been reported. Patients with a history of primary open-angle glaucoma are at a higher risk of increased intraocular pressure.Footnote 2

A number of ocular ARs following intravitreal injection of triamcinolone in Canada have been reported in scientific literature.Footnote 2 They included increased intraocular pressure requiring glaucoma medication (60 cases), cataract progression requiring extraction (12), endophthalmitis (1) and temporary occlusion of the central retinal artery (1).

From Jan. 1, 1973, to Jan. 31, 2009, Health Canada received 1 report of serious ocular ARs suspected of being associated with combined photodynamic therapy and intravitreal injection of triamcinolone. The case involved a 13-year-old girl in whom increased intraocular pressure, retinal hemorrhage and reduced visual acuity developed following two injections of triamcinolone given about 3 months apart.

Although underreporting of ARs is well documented, voluntary reporting is one of the most common ways to monitor the safety and effectiveness of marketed health products. Health care professionals are encouraged to report to Health Canada any ocular ARs suspected of being associated with triamcinolone.

Nadiya Jirova, MSc, Health Canada

Footnotes

Footnote 1

Kenalog-40 Injection (sterile triamcinolone acetonide suspension) [product monograph]. Montreal (QC): Westwood Squibb; 1992.

Return to footnote 1 referrer

Footnote 2

Baath J, Ells AL, et al. Safety profile of intravitreal triamcinolone acetonide. J Ocul Pharmacol Ther 2007;23(3):304-10. [Next link will take you to another Web site PubMed]

Return to footnote 2 referrer

Footnote 3

Chaudhary V, Mao A, et al. Triamcinolone acetonide as adjunctive treatment to verteporfin in neovascular age-related macular degeneration. A prospective randomized trial. Ophthalmology 2007;114(12):2183-9. [Next link will take you to another Web site PubMed]

Return to footnote 3 referrer

Footnote 4

Next link will take you to another Web site Information importante de pharmacovigilance. Rueil-Malmaison (France): Bristol-Myers Squibb; 2007 Aug 6. Available: (accessed 2009 Apr 29).

Return to footnote 4 referrer

Footnote 5

Carnahan MC, Goldstein DA. Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol 2000;11(6):478-83. [Next link will take you to another Web site PubMed]

Return to footnote 5 referrer

Footnote 6

Jermak CM, Dellacroce JT, et al. Triamcinolone acetonide in ocular therapeutics. Surv Ophthalmol 2007;52(5):503-22. [Next link will take you to another Web site PubMed]

Return to footnote 6 referrer

Fentanyl transdermal patches and accidental child exposure

The fentanyl transdermal system is indicated in the management of persistent, moderate to severe chronic pain that cannot be managed by other means such as opioid combination products or immediate-release opioids.Footnote 3 The system has been marketed in Canada under the brand name Duragesic since 1992. In 2006, the generic products Ratio-Fentanyl and Ran-Fentanyl transdermal systems were introduced.

The safety of the fentanyl transdermal system is contingent on its use according to the conditions recommended in the Canadian product monographs. The "Warnings and precautions" section of the monographs were updated to include accidental exposure. Examples of accidental exposure include the transfer of a fentanyl transdermal patch while hugging, sharing a bed or moving a patient.Footnote 1,Footnote 2,Footnote 3

In December 2008, Health Canada received a report of suspected accidental fentanyl exposure in a healthy 19-month-old child. He was sleeping in the same bed as his mother, who was using a fentanyl patch for chronic pain. The patch inadvertently became attached to the child. He was taken to hospital and given naloxone 0.01mg/kg intramuscularly as required. The child was monitored overnight, and his condition improved after treatment.

Health care professionals, patients and caregivers should be aware of serious medical consequences, including death, that have occurred when people were accidentally exposed to a fentanyl transdermal patch.Footnote 1,Footnote 2,Footnote 3,Footnote 4

Maria Longo, RPh, BScPharm, Health Canada

Footnotes

Footnote 1

Duragesic (fentanyl transdermal system) [product monograph]. Markham (ON): Janssen-Ortho Inc; 2008.

Return to footnote 1 referrer

Footnote 2

Ran-Fentanyl (fentanyl transdermal system) [product monograph]. Mississauga (ON): Ranbaxy Pharmaceuticals Canada Inc; 2006.

Return to footnote 2 referrer

Footnote 3

Ratio-Fentanyl (fentanyl transdermal system) [product monograph]. Mirabel (QC): Ratiopharm Inc; 2008.

Return to footnote 3 referrer

Footnote 4

Little patches ... Big problems: Protecting children from unintentional harm. ISMP Medication Safety Alert 2005;4(9).

Return to footnote 4 referrer

Quarterly Summary of health professional and consumer advisories (posted on Health Canada's Web site: March 11 2009 to June 1, 2009)
Date Product Subject
May 25 Vitamin Maxum Matragen and Maxum Multi Vite Supplements Information for pregnant and breastfeeding women
May 15 Dobutamine Hydrochloride Recall - labelling error
May 15 Rofact Recall - labelling error
May 8 Tarceva Association with cases of gastrointestinal perforation, Stevens-Johnson syndrome, and corneal perforation
May 3 H1N1 flu virus products Counterfeit and unapproved products
May 1 & 3 Hydroxycut products Unauthorized products under review and update
Apr 21 Herceptin Association with oligohydramnios
Apr 21 Enbrel Association with histoplasmosis and other invasive fungal infections
Apr 3 BHM/Medi-Man Combi Sling Possible stitching failure
Apr 1 Mattresses Standards for improved fire resistance
Mar 27 Prefilled saline and heparin syringes Important safety information
Mar 27 Electronic cigarettes Health Canada advises not to use electronic smoking products
Mar 25 Phosphocol P32 Association with acute lymphocytic leukemia
Mar 24 & 25 Blood lancing devices Misuse of blood lancing devices
Mar 19 Silver Care toothbrushes and toothbrush refills Recall - addition to warning label
Mar 16 & 19 EVRA transdermal contraceptive system Drug-release information
Feb 12 AED Plus Defibrillator Urgent medical device correction
Jan 29 COLLEAGUE infusion volumetric pumps Urgent medical device correction

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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, RPh, BScPhm, DIS, AFSA, Medical Biology (University of Paris V)
Jared Cousins, BSP
Alanna Maloney, BHSc
Mary Joy, RPh, BScPhm
Candace Fisher, MSc

Acknowledgement
We thank the following members of the Expert Advisory Committee on the Vigilance of Health Products for their review of material for this issue: Colleen J. Metge, BSc(Pharm), PhD; Dugald Seely, ND, MSc; and Sylvia Hyland, RPh, BScPhm, MHSc. We also thank Kaitlyn Proulx and Darija Muharemagic, students in Biopharmaceutical Science, for their participation in the production of the newsletter.

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Reporting Adverse Reactions
Canada Vigilance Program
Telephone: 1-866-234-2345
Fax: 1-866-678-6789

Copyright
ę 2009 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.

Due to time constraints relating to the production of this publication, information published may not reflect the most current information.

ISSN 1499-9447; Cat no H42-4/1-19-3E

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.