ARCHIVED - Canadian Adverse Reaction Newsletter, Volume 20 - Issue 3 - July 2010
Cat no H42-4/1-20-3E
Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team
In this Issue
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
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.
Pregabalin (Lyrica): suicidal ideation and attempt
- Health Canada received 16 reports of suicidal ideation and 1 report of suicide attempt suspected of being associated with the use of pregabalin (Lyrica).
- The Canadian product monograph for Lyrica lists suicide attempt under "less common clinical trial adverse drug reactions" and describes it as being infrequent.
- Seven of the 16 cases included a positive dechallenge, and 1 case included a positive rechallenge.
Pregabalin (Lyrica) has analgesic, antiepileptic and anxiolytic activity.Footnote a1 Marketed in Canada since July 2005, pregabalin is indicated for the management of neuropathic pain associated with diabetic neuropathy, postherpetic neuralgia and pain associated with fibromyalgia in adults, and it may be useful in the management of central neuropathic pain. The Canadian product monograph for Lyrica lists suicide attempt under "less common clinical trial adverse drug reactions" and describes it as being infrequent.Footnote a1
From the date of marketing to Dec. 15, 2009, Health Canada received 16 reports of suicidal ideation and 1 report of suicide attempt suspected of being associated with the use of pregabalin (Table 1). Five cases are not described in the table because the reports contained limited information. One of these 5 cases reported a suicide attempt by a patient also taking opioids. Seven of the 16 cases included a positive dechallenge (abatement of symptoms of suicidality upon stopping or reducing the dosage of pregabalin) and one case included a positive rechallenge (reappearance of symptoms after reintroduction of pregabalin). Confounders identified in some of the cases included psychiatric disorders, history of depression and suicidal ideation, post-traumatic stress disorder and use of psychotropic medications. Patients with chronic pain are at increased risk of depression, which may lead to suicidal ideation and attempt, so the indication for taking pregabalin in these patients may also be a confounding factor.Footnote a2
In the United States, pregabalin is also indicated as adjunctive therapy in adults with partial onset seizures.Footnote a3 It is not approved for this indication in Canada. In December 2008 and April 2009, the US Food and Drug Administration communicated safety notices concerning the increased risk of suicidal behaviour and ideation in patients taking antiepileptic drugs, including pregabalin, for any indication.Footnote a4,Footnote a5
Health care professionals, patients and caregivers should be aware of adverse reactions suspected of being associated with pregabalin. Health Canada will continue to monitor adverse reactions and will communicate any new safety information or action resulting from its analysis.
Maria Longo, RPh, BScPharm, Health Canada
|Case||Patient age/sex||Dose||Indication||Onset of reaction||Concomitant health
NA = not available
|1||NA/F||25 mg/d||Chronic pain||< 1 day||Zopiclone,
|2||54/F||5 months at 25 mg/d, then increased to 75 mg/d||Pain control||1 day after dose increase||Oxycodone/ acetaminophen, clonazepam
History of fibromyalgia and back pain
(pregabalin therapy ongoing)
|3||46/M||150 mg twice daily||Pain||8 days||Citalopram, amitriptyline, lorazepam, clonazepam, fentanyl transdermal patch, morphine, diazepam
Post-traumatic stress disorder, marital problems, anxiety, depression, hypomania
|4||52/F||75 mg twice daily||Fibromyalgia||About 24 days||Alprazolam, temazepam, topiramate, clonazepam, fluoxetine, oxycodone/ acetaminophen, zopiclone, cetirizine, loperamide, ibuprofen, pentosan
History of depression and anxiety
|5||76/F||25 mg twice daily||Fibromyalgia||2 days||Risedronate, calcium, vitamin D, vitamins, omega-3, glucosamine
History of major depression, suicidal thoughts or attempts
|6||48/F||25 mg/d||Mood stabilizer||2 days||Mirtazapine
History of depression and suicidal ideation
|7||24/F||50 mg/d||Affective disorder, mood, sleep||2.5 months||History of depression and suicidal ideation||Not applicable (pregabalin therapy ongoing)||Unknown|
|8||54/F||25 mg/d||Fibromyalgia||18 days||Clonazepam, dimenhydrinate, acetaminophen/codeine/ caffeine, hyoscine, trimebutine, naratriptan, esomeprazole, cetirizine, meloxicam
History of bipolar depression and 2 suicide attempts
|9||78/M||25 mg three times daily||Chronic pain||2 days||No history of depression or other disorders||Positive||Positive|
|10||43/F||150 mg twice daily||Fibromyalgia||55 days||Tramadol
No history of suicidal thoughts
|11||48/F||100 mg twice daily||Pain||NA||Itraconazole, hydrocortisone, doxycycline
|12||59/F||Not reported||Neuropathy||NA||None||Not applicable (pregabalin therapy ongoing)||Not applicable|
Adverse incidents with injectable hyaluronic acid dermal fillers
- Health Canada received 32 reports of adverse incidents suspected of being associated with the use of temporary hyaluronic acid dermal fillers.
- The reports included adverse incidents such as pain, edema, nodules, abscesses, as well as one case of lip necrosis and another of partial loss of vision.
- Health care professionals and patients should be aware of these types of adverse incidents.
Many types of dermal fillers are currently marketed in Canada. The types of materials in these injectable products vary from temporary (absorbable) to permanent (nonabsorbable) and from biologic to synthetic compounds.Footnote 1,Footnote 2 Each type of dermal filler has its own specific properties and longevity, as well as advantages and disadvantages.Footnote 3 Some dermal fillers contain lidocaine to reduce pain during injection.Footnote 1
Hyaluronic acid (HA) is a temporary dermal filler.Footnote 2 It is produced naturally by the body and is a major component of the extracellular matrix of the dermis.Footnote 2,Footnote 4 HA contributes to tissue hydrodynamics by creating space for the movement of cells.Footnote 4 It binds with water to fill out the skin.Footnote 2 HA dermal fillers are generally used for the correction of moderate to severe facial wrinkles and folds by injection into the mid- to deep layers of the dermis.Footnote 1,Footnote 5,Footnote 6,Footnote 7,Footnote 8,Footnote 9,Footnote 10
As of Mar. 15, 2010, over 30 temporary dermal fillers containing HA were licensed for sale in Canada. As of that date, Health Canada had received 32 reports of adverse incidents suspected of being associated with those particular HA dermal fillers. HA dermal fillers mentioned in the case reports were Elevess, Juvéderm, Juvéderm Ultra with Lidocaine, Juvéderm Ultra Plus with Lidocaine, Juvéderm Ultra Plus, Perlane, Restylane, Revanesse, Revanesse Ultra and Teosyal. The reports included adverse incidents such as pain, swelling or edema, nodules, abscesses, presence of pus or infection, skin discoloration or hyperpigmentation, lip necrosis, difficulty talking, swallowing or breathing, and partial loss of vision. The patients were 30 to 75 years old (median 50 years). Fifteen patients were reported to have had the injection of HA dermal filler for the first time. In 7 of the 32 cases, botulinum toxin type A for cosmetic use was also reported to have been used.
Most patients required treatments ranging from abscess drainage to administration of local or systemic drugs such as corticosteroids, antibiotics, antihistamines and anti-inflammatory drugs. In addition, several patients received a local injection of hyaluronidase in order to resolve nodular lesions. Eight patients recovered, and 19 were recovering or had not recovered at the time of reporting (outcome was not reported for 5 patients). Some of the adverse incidents persisted for weeks or months after the injection.
One patient who had received an injection of HA dermal filler (Restylane) into the lips reported gangrene and necrosis of the lips. Another patient experienced partial loss of vision after injection of Juvéderm Ultra with Lidocaine to the tear trough (lower eyelid), Juvéderm Ultra Plus with Lidocaine to the cheek and Juvéderm Ultra Plus to marionette lines (lines that extend from the outer corner of the mouth towards the chin). Botulinum toxin type A was injected into the chin and smoker's lines (vertical wrinkles above the upper lips) on the same day. A follow-up scan was normal, with no dermal filler detected intra-orbitally; no injury to the optic nerve was observed. The patient had not recovered at the time of reporting. A case of partial loss of vision was previously published.Footnote 11
Adverse incidents such as pain, swelling or edema, nodules, induration, abscesses, granuloma and skin discoloration are generally labelled in the instructions for use for various HA dermal fillers.Footnote 5,Footnote 6,Footnote 7,Footnote 8,Footnote 9,Footnote 10 These instructions contain warnings or contraindications with regard to injection into blood vessels. The glabella, the area between the eyebrows, is the injection site commonly believed to be at increased risk of skin necrosis.Footnote 12 This can be attributed to an interruption of vascular supply owing to compression or obstruction of blood vessels by direct injection into a vessel.Footnote 12
HA dermal fillers are the most popular temporary fillers, and their use is growing.Footnote 4,Footnote 13Footnote 14 They are considered to provide an effective, noninvasive and nonsurgical alternative for the correction of soft-tissue defects of the face.Footnote 13 The health care professional who injects dermal fillers must have proper training in their use and be aware of the types of adverse incidents that can occur, as well as contraindications.Footnote 12
Health Canada encourages the reporting of adverse incidents suspected of being associated with the use of HA dermal fillers, or any other medical devices, to the Health Products and Food Branch Inspectorate through the toll-free hotline (1-800-267-9675).
Ilhemme Djelouah, RPh, BScPhm, DIS Medical Biology (University of Paris V); Christianne Scott, BPharm, MBA, Health Canada
Oral iron supplements: skin reactions and other hypersensitivity reactions
- In Canada, oral iron supplements are regulated as natural health products.
- Health Canada received reports of skin and other hypersensitivity reactions suspected of being associated with the use of oral iron supplements.
- Some adverse reactions may be serious and may involve multiple systems.
Oral iron supplements are used to prevent or treat iron deficiencyFootnote c1 Iron deficiency is a common cause of anemia and can result from inadequate iron intake, malabsorption, blood loss or increased requirement (e.g., pregnancy)Footnote c2 Several different oral iron supplements exist, and depending on the source, their content of elemental iron may vary. The content of elemental iron in commonly used preparations is 11.6% for ferrous gluconate, 20% for ferrous sulfate and 33% for ferrous fumarateFootnote c1
In Canada, oral iron supplements are regulated as natural health productsFootnote c3 Health Canada has adopted the US Institute of Medicine's recommendations on the tolerable upper intake level for total elemental iron intake from food and supplements: 40 mg/d for children aged 0-13 years and 45 mg/d for people 14 and olderFootnote c4 The upper intake level is the maximum daily oral intake unlikely to result in adverse health effects in the general population. Higher doses may be recommended by health care professionals for the treatment of iron deficiency or iron deficiency anemia.
From Jan. 1, 1965, to Dec. 31, 2009, Health Canada received 108 reports of skin and other hypersensitivity reactions suspected of being associated with the use of oral iron supplements. The reactions included cutaneous and subcutaneous reactions (e.g., rash, pruritus, urticaria, hives, erythema, edema, photosensitivity), as well as some reactions involving multiple systems (e.g., cardiovascular, respiratory, gastrointestinal) with or without skin reactions, including anaphylaxis. Of these reports, 24 were considered serious; 8 of them were associated with a single-ingredient iron supplement without exposure to other suspected health products (Table 2). Some patients were using concomitant health products but none of these products was suspected of being associated with the adverse reactions (ARs).
Of the remaining 16 reports of serious ARs, one report described a patient with Stevens-Johnson syndrome suspected of being associated with the use of 4 different health products, including ferrous gluconate, acetylsalicylic acid, prednisone and ketorolac. One fatal case was reported that involved circulatory and respiratory collapse suspected of being associated with the use of health products including ferrous gluconate, chlorpromazine and furosemide. In this case, the patient had hemolytic anemia, a contraindicated health condition for the use of oral iron saltsFootnote c1
Cases of serious cutaneous and anaphylactic reactions (e.g., pustular drug eruption, photosensitization, generalized pruritus, pruriginous papules, urticaria, shortness of breath, hypotension) associated with single-ingredient iron products have been published
previously.Footnote c5,Footnote c6,Footnote c7,Footnote c8 Also, the Netherlands Pharmacovigilance Centre has received reports of cutaneous reactions (e.g., rash, urticaria, erythema, photosensitivity, hyperpigmentation) associated with the use of oral iron saltsFootnote c9
Other contributing factors may be involved in reactions to oral iron-containing products, including hypersensitivity to an excipient in the product such as a colorant (e.g., azo-dye Sunset Yellow).Footnote c10 In addition, several reports stated that the patients used other health products, or were using a multiple-ingredient product containing iron (e.g., multivitamin), which makes it difficult to assess the association with iron.
Health care professionals are reminded of potential adverse hypersensitivity reactions associated with the use of oral iron supplements. Although typically not serious, some reactions may be serious and may involve multiple systems. Patients who experience skin reactions or other types of hypersensitivity reactions with the use of oral iron supplements should consult their health care professional. Health care professionals and patients are encouraged to report ARs suspected of being associated with natural health products to Health Canada.
Stephanie Jack, MSc; Hélène Lacourcière, MD; Danika Painter, PhD; Mimi Hum, RN, BNSc, Health Canada
|Case||Patient age/sex||Oral iron product||Daily dose, mg||Adverse reaction|
NA = not available
|1||NA/F||Fesofor (ferrous sulfate)||65||Severe rash all over body|
|2||33/M||Apo-Ferrous sulfate||120||Urticaria (hives around neck up to ears), dyspnea|
|3||64/M||Novo-Ferrosulfa (ferrous sulfate)||180||Heart rate increased, hyperhidrosis, discoloration, exfoliation and swelling of lips, respiratory rate increased, tongue discoloration, tongue exfoliation|
|4||66/M||Ferrous sulfate||120||Pustular rash on face, dysphonia, gastroesophageal reflux disease|
|5||77/F||Apo-Ferrous gluconate||70||Dysphagia, hypertension, swollen tongue, vomiting|
|6||32/F||Ferrous gluconate||35||Asthenia, chest discomfort, dizziness, dyspnea, oral hypoesthesia, tremor|
|7||15/F||Palafer (ferrous fumarate)||100||Anaphylactic reaction, cough, dyspnea, dysphonia, swollen and itchy eyes, hyperhidrosis, hypotension, rash, sneezing, urticaria|
|8||39/F||Proferrin (heme iron polypeptide)||22||Angioedema, dyspnea, peripheral edema, face swelling|
Quarterly Summary of health professional and consumer advisories
|May 17||Foreign products||Alerts - Botanical Slimming 100% Natural Soft Gel (Meizitang); Marsha Slim Plus; S&S Super Slender|
|May 12 & 17||Maalox Multi Action||Confusion with other Maalox liquid products|
|May 12||Tysabri||Association with multifocal leukoencephalopathy|
|May 12||Miracle Mineral Solution||Unauthorized health product|
|May 7||Rotavirus Vaccines||Presence of porcine circovirus DNA|
|May 4||Children & Infant's Motrin & Tylenol||Update - recall concerning manufacturing issues|
|May 3||Foreign products||Alerts - Ba Bao Xiao Ke Dan; Bao Shu Tang Wu Zi Yan Zong Wan; Lin Yan Yin Chiao; Man Power; 17 products sold through MuscleMaster.com; Seven Slim 7 Seshou (Qingchun Shaonüxing), (Jieshixing), (Guifurenxing), (Songchixing), Shoushen Jiaoguan-Tinei Yundong Wan (Jian Xiabanshen), (Jian Quanshen Feipang)|
|Apr 30 & May 5||Exelon Patch||Serious adverse events related to medication errors/misuse|
|Apr 28||Slim-30||Unauthorized health product|
|Apr 26||Promethazine hydrochloride injection||Revised labeling|
|Apr 15||Cuffed Shiley Tracheostomy Products||Urgent recall for certain lots|
|Apr 14 & 20||Invirase||Significant dose-dependent prolongations of QT and PR intervals|
|Apr 9||Adjuvanted H1N1 vaccine (Arepanrix)||New expiry date|
|Apr 9||Zeftera||Discontinuation of sale|
|Mar 31||West Pharm Therma Lean Fat Burner Energizer||Unauthorized health product|
|Mar 25||Herbal Diet Natural||Unauthorized health product|
|Mar 23||Ratio-Prednisolone eye drops||Recall - some bottles may contain particles|
|Mar 22||WinRho SDF||Association with intravascular hemolysis in the treatment of immune thrombocytopenic purpura|
|Mar 22||Avelox||Rare risk of severe liver injury|
|Mar 18||OneTouch SureStep Test Strips||Possibility of low test results|
|Mar 12||Medical device clocks||Update - reminder to switch to Daylight Savings Time|
|Mar 8 & 10||Fentanyl transdermal systems||Changes to dose conversion guidelines|
|Mar 8||Power-Max||Unauthorized health product|
|Mar 1||Foreign products||Alerts - Certain lots of sexual enhancement dietary supplements sold by Atlas Operations Inc.; 2H & 2D; 65 products sold through Bodybuilding.com; STRO Emperor Capsules; Tian Yang Xu Huo Oral Ulcer Capsule|
|Feb 19||OM Fusion health products||Unauthorized health products|
|Feb 18||Zinc-containing Poli-Grip||Association with myeloneuropathy and blood dyscrasias|
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Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
Address Locator 1701D
Ottawa ON K1A 0K9
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Jared Cousins, BSP
Mary Joy, RPh, BScPhm
Hoa Ly, BSc
Patricia Carruthers-Czyzewski, BScPhm, MSc
Gilbert Roy, BPharm
Christianne Scott, BPharm, MBA
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
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