Canadian Adverse Reaction Newsletter, Volume 24 - Issue 2 - April 2014
Cat no H42-4/1-24-2E
Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team
In this Issue:
- Quetiapine and acute liver failure
- Azithromycin and drug reaction with eosinophilia and systemic symptoms
- Clopidogrel and acquired hemophilia
- Summary of advisories
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.
Quetiapine and acute liver failure
- Three published reports (one Canadian case and 2 international cases) indicated a probable causal association between quetiapine use and the occurrence of acute liver failure.
- Two international cases reported a fatal outcome. In the Canadian case, the patient's condition improved after discontinuing the drug.
- Health care professionals are encouraged to report to Health Canada any cases of liver failure suspected of being associated with quetiapine.
Quetiapine (Seroquel) is an atypical antipsychotic drug indicated for the management of the symptoms of schizophrenia and for the acute management of manic and depressive episodes associated with bipolar disorder.Footnote 1 The extended-release formulation is additionally indicated for the symptomatic relief of major depressive disorder when currently available approved antidepressant drugs have failed either due to a lack of efficacy and/or lack of tolerability.Footnote 2 In Canada, quetiapine has been marketed since December 1997.
Drug toxicity is a frequent cause of acute liver failure.Footnote 3 Acute liver failure has been defined as the development of severe acute liver injury accompanied by a prolonged prothrombin time (international normalized ratio greater than or equal to 1.5) and any degree of mental alteration occurring less than 26 weeks after the onset of illness in a patient without pre-existing cirrhosis.Footnote 3
As of Sept. 30, 2013, Health Canada received 3 reports of liver failure involving quetiapine use, one of which was published in the literatureFootnote 4 (Table 1). Of the two unpublished cases, one report was unassessable due to limited information and the other was considered inapplicable because it involved an acetaminophen overdose.
Quetiapine is extensively metabolized by the liver. Therefore, the quetiapine (Seroquel) Canadian product monograph (CPM) advises caution when using quetiapine in patients with pre-existing hepatic disorders, in patients treated with potentially hepatotoxic drugs, or if treatment-emergent signs or symptoms of hepatic impairment appear.Footnote 1 The CPM also describes the occurrence of asymptomatic transaminase elevations in some patients administered quetiapine. Liver failure is not mentioned in the CPM.
|Case||Age/sex||Dose||Reported indication||Duration of exposure||Outcome|
|1Footnote 4 Table 1 Footnote †||59/F||Unspecified||Hallucinations||6 weeks||Recovered|
|2Footnote 5 Table 1 Footnote ‡||58/F||100 mg daily||Unspecified (however patient had a history of bipolar disorder)||1 month||Died|
|3Footnote 6 Table 1 Footnote §||77/F||12.5 mg twice daily||Symptoms of agitation and severe insomnia||9 days||Died|
Based on the temporal association between the commencement of the medication and the onset of symptoms, and given the lack of plausible alternative causes, the existence of a causal relationship between quetiapine use and the occurrence of acute liver failure in the 3 published cases is probable. Two international cases reported a fatal outcome.Footnote 5 Footnote 6 In the Canadian case, the patient's condition improved after discontinuing the drug.Footnote 4 The exact mechanism of this reaction is unclear.
Health care professionals are reminded that this adverse reaction may be underreported and are encouraged to report to Health Canada any cases of liver failure suspected of being associated with quetiapine.
Marie-Thérèse Bawolak, PhD, Health Canada
- Footnote 1
Seroquel (quetiapine fumarate immediate-release tablets) [product monograph]. Mississauga (ON): AstraZeneca Canada Inc.; 2013.
- Footnote 2
Seroquel XR (quetiapine fumarate extended-release tablets) [product monograph]. Mississauga (ON): AstraZeneca Canada Inc.; 2013.
- Footnote 3
Abboud G, Kaplowitz N. Drug-induced liver injury. Drug Saf 2007;30(4):277-94. [PubMed]
- Footnote 4
Al Mutairi F, Dwivedi G, Al Ameel T. Fulminant hepatic failure in association with quetiapine: A case report. J Med Case Rep 2012;6(1):418. [PubMed]
- Footnote 5
El Hajj I, Sharara AI, Rockey DC. Subfulminant liver failure associated with quetiapine. Eur J Gastroenterol Hepatol 2004;16(12):1415-8. [PubMed]
- Footnote 6
Naharci MI, Karadurmus N, Demir O, et al. Fatal hepatotoxicity in an elderly patient receiving low-dose quetiapine. Am J Psychiatry 2011;168(2):212-3. [PubMed]
Azithromycin and drug reaction with eosinophilia and systemic symptoms
- A potentially life-threatening condition called drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in patients using azithromycin, though the number of reports is low.
- Health Canada received one report of DRESS suspected of being associated with azithromycin.
- Early diagnosis and prompt discontinuation of the offending drug are important to achieve the best outcome in patients with DRESS.
- Distinguishing DRESS from other life-threatening cutaneous drug reactions is important because treatment varies among these conditions.
Azithromycin (Zithromax) is a widely prescribed macrolide antibiotic. It is indicated for the treatment of a variety of bacterial infections, including acute otitis media, pharyngitis and tonsillitis, acute bacterial exacerbations of chronic obstructive pulmonary disease, pneumonia, skin and skin structure infections, and genitourinary tract infections.Footnote 7
Drug reaction with eosinophilia and systemic symptoms (DRESS) describes a heterogeneous group of rare but severe adverse reactions to medications.Footnote 8 It is most commonly seen in anticonvulsant-treated patients with reported incidences ranging from 1 in 1000 to 1 in 10,000 exposures, and a mortality rate of about 10 to 20%.Footnote 9 DRESS typically presents between 2 weeks and 2 months after the initiation of the drug and is associated with fever, a severe skin disease with characteristic infiltrated papules and facial edema or an exfoliative dermatitis, lymphadenopathy, hematologic abnormalities (hypereosinophilia and atypical lymphocytes) and multiorgan involvement (e.g., liver, kidney).Footnote 9 Footnote 10 Footnote 11 The pathogenesis of DRESS is unknown. A definitive diagnosis of DRESS is difficult due to the high variability in clinical presentations, but different guidelines have been published describing the diagnostic criteriaFootnote 11 Footnote 12.
As of November 30, 2013, Health Canada received one report of DRESS suspected of being associated with azithromycin. The report describes a 60-year-old female who experienced DRESS 18 days after taking azithromycin to treat pharyngitis.
Some cases of DRESS involving azithromycin have been published in theFootnote 8 Footnote 13 Footnote 14 Footnote 15 One case involved an eight-year-old boyFootnote 15 and another, a two-year-old girl.Footnote 8 The latter case resulted in death.Footnote 8
DRESS is not currently labelled in the Canadian product monograph for Zithromax, but other severe cutaneous allergic reactions (e.g., Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) are labelled.Footnote 7 Health Canada is currently working with the manufacturer with the aim of updating the Canadian product monograph regarding this safety information.
Early diagnosis and prompt discontinuation of the offending drug are important to achieve the best outcome in patients with DRESS.Footnote 9 Footnote 16 Distinguishing DRESS from other potentially life-threatening cutaneous drug reactions such as SJS and TEN is important because treatment varies among these conditions.Footnote 16 Treatment for DRESS may involve supportive measures (e.g., fluid and nutritional support) and/or systemic corticosteroid therapy depending on the severity of the condition.Footnote 9 Footnote 16 Footnote 17
Health care professionals are reminded that this adverse reaction may be underdiagnosed and underreported, and they are encouraged to report to Health Canada any cases of DRESS suspected of being associated with azithromycin.
Jiazhen Minnie Dai, PhD, Health Canada
- Footnote 7
Zithromax (azithromycin dihydrate) [product monograph]. Kirkland (QC): Pfizer Canada Inc.; 2013.
- Footnote 8
Walsh S, Diaz-Cano S, Higgins E, et al. Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? A review of clinicopathological features of 27 cases. Br J Dermatol 2013;168(2):391-401. [PubMed]
- Footnote 9
Criado PR, Avancini J, Santi CG, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system. Isr Med Assoc J 2012;14(9):577-82. [PubMed].
- Footnote 10
Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS). Semin Cutan Med Surg 1996;15(4):250-7. [PubMed]
- Footnote 11
Kardaun SH, Sekula L, Valeyrie-Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol 2013;169(5):1071-80. [PubMed]
- Footnote 12
Shiohara T, Iijima M, Ikezawa Z, et al. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007;156(5):1083-4. [PubMed]
- Footnote 13
Cascaval RI, Lancaster DJ. Hypersensitivity syndrome associated with azithromycin. Am J Med 2001;110(4):330-1. [PubMed]
- Footnote 14
Pursnani A, Yee H, Slater W, et al. Hypersensitivity myocarditis associated with azithromycin exposure. Ann Intern Med 2009;150(3):225-6. [PubMed]
- Footnote 15
Bauer KA, Brimhall AK, Chang TT. Drug reaction with eosinophilia and systemic symptoms (DRESS) associated with azithromycin in acute Epstein-Barr virus infection. Pediatr Dermatol 2011;28(6):741-3. [PubMed]
- Footnote 16
Husain A, Reddy BY, Schwartz RA. DRESS syndrome: Part II. Management and therapeutics. J Am Acad Dermatol 2013;68(5):709.e1-9e. [PubMed]
- Footnote 17
Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an update. Dermatology 2003;206(4):353-6. [PubMed]
Clopidogrel and acquired hemophilia
Clopidogrel (Plavix) is a platelet aggregation inhibitor indicated for conditions such as myocardial infarction, stroke or established peripheral arterial disease, acute coronary syndrome and atrial fibrillation.Footnote 18Footnote *
Acquired hemophilia is a rare bleeding disorder caused by autoantibodies directed against plasma coagulation factors, most notably factor VIII (i.e., acquired hemophilia A).Footnote 19 While the cause is unknown in half of patients, associations with malignancy, pregnancy, autoimmune disease and drugs have been described.Footnote 20 Footnote 21 Clinically, it is characterized by spontaneous and often severe bleeding in patients with no history of bleeding.Footnote 21 Control of acute bleeding is a priority because of the high risk of early mortality.Footnote 19
Typical laboratory findings of acquired hemophilia A include a prolonged activated partial thromboplastin time (aPTT) and a low factor VIII level.Footnote 22 The thrombin and prothrombin times are normal, as are both the platelet count and function. Investigation for an antifactor VIII inhibitor should be considered if indicated by a prolonged aPTT.Footnote 20 Management involves treatment of active bleeding and suppression of the inhibitory antibody.Footnote 19 Footnote 21
In September 2013, the manufacturer of Plavix advised physicians in the UK of 11 cases of acquired hemophilia A and one case of acquired hemophilia B in patients treated with clopidogrel since the launch of the product.Footnote 23 Patients were 65 to 81-years-old. In some cases, no previous history of abnormal hemostasis had been reported. Time to onset ranged from a few days to 4 months after starting clopidogrel treatment. No fatal cases were reported.
As of Sept. 30, 2013, there were no reports of acquired hemophilia suspected of being associated with clopidogrel in Canada.
Health care professionals should be aware of the potential association between acquired hemophilia and the use of clopidogrel.
- Increased bruising should not be attributed to the antiplatelet action of clopidogrel, unless the platelet count and coagulation screen are found to be normal.Footnote 20
- In cases of confirmed isolated aPTT prolongation with or without bleeding, acquired hemophilia should be considered.Footnote 18
- Patients with a confirmed diagnosis of acquired hemophilia should be managed and treated by specialists, and clopidogrel should be discontinued.Footnote 18
Acquired hemophilia has been included in the Warnings and Precautions and certain Post-Market Adverse Drug Reactions sections of some of the clopidogrel Canadian product monographs.Footnote 20 Footnote 25 Footnote 26 Footnote 27 Footnote 28 Footnote 29 Footnote 30
Ilhemme Djelouah, RPh, BScPhm, DIS Medical Biology (University of Paris V), Health Canada
- Footnote 18
Plavix (clopidogrel) [product monograph]. Laval (QC): sanofi-aventis Canada Inc.; 2013.
- Footnote 19
Baudo F, Caimi T, de Cataldo F. Diagnosis and treatment of acquired haemophilia. Haemophilia 2010;16(102):102-6. [PubMed]
- Footnote 20
Haj M, Dasani H, Kundu S, et al. Acquired haemophilia A may be associated with clopidogrel. BMJ 2004;329(7461):323. [PubMed].
- Footnote 21
Foley PW, Pepperell D, Kazmi R, et al. Unsuspected acquired haemophilia in a patient with myocardial infarction. J R Soc Med 2004;97(11):542–3. [PubMed]
- Footnote 22
Giangrande P. Acquired haemophilia. Revised edition. In: Mahlangu J, ed. Treatment of Hemophilia. World Federation of Hemophilia. 2012;38:1-7.
- Footnote 23
Haemophilia risk with clopidogrel. Reactions Weekly 2013;1471(1):3.
- Footnote 24
Hwang HW, Kong JH, Yu DW, et al. A patient with acquired hemophilia A induced by clopidogrel. Korean J Hematol 2012;47(1):80-2. [PubMed]
- Footnote 25
Apo-Clopidogrel (clopidogrel) [product monograph]. Toronto (ON): Apotex Inc.; 2014.
- Footnote 26
Auro-Clopidogrel (clopidogrel) [product monograph]. Woodbridge (ON): Auro Pharma Inc.; 2013.
- Footnote 27
Mylan-Clopidogrel (clopidogrel)[product monograph]. Toronto (ON): Mylan Pharmaceuticals ULC; 2014.
- Footnote 28
Mint-Clopidogrel (clopidogrel) [product monograph]. Mississauga (ON): Mint Pharmaceuticals Inc.; 2014.
- Footnote 29
Ran-Clopidogrel (clopidogrel) [product monograph]. Mississauga (ON): Ranbaxy Pharmaceuticals Canada Inc.; 2014.
- Footnote 30
Sandoz Clopidogrel (clopidogrel) [product monograph]. Boucherville (QC): Sandoz Canada Inc.; 2014.
Quarterly Summary of health professional and consumer advisories
|DateTable 2 Footnote *||Product||Subject|
|Feb 19||Telzir (fosamprenavir calcium)||New recommendations regarding safe use|
|Feb 7||Gyrus Bovie Electrosurgical Generators||Possible fire hazard|
|Feb 5||Lithium||Risk of hypercalcemia and hyperparathyroidism|
|Feb 4||Aliskiren, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers||New warnings about combining these drugs|
|Feb 3||Cosopt (dorzolamide hydrochloride/timolol maleate) Preservative-Free Ophthalmic Solution||Potential risk of eye injury due to change in unit dose pipette design|
|Feb 3||Unauthorized health products||Products containing undeclared prescription drugs removed from Burnaby West Box store|
|Jan 30||Levonorgestrel-containing emergency contraceptive pills||Evaluation of the effectiveness in women over a certain weight|
|Jan 27||Arzerra (ofatumumab)||Recommendations to screen, monitor and manage Hepatitis B virus reactivation|
|Jan 24||Sandoz Glimepiride||Recall: mislabelling of boxes|
|Jan 17||Effient (prasugrel hydrochloride)||Increased risk of bleeding in patients treated in hospital for certain types of heart attacks|
|Jan 14||TRUEtrack blood glucose meters||Recall: potential error in displaying blood sugar levels|
|Jan 13||Hospira flexible intravenous containers||Potential for leakage in certain lots|
|Jan 10||Sandoz liquid injectable products||Potential presence of particulate matter in glass vials|
|Jan 10||Jevtana (cabazitaxel)||Potential for medication errors leading to overdose|
|Jan 3||Sublinox (zolpidem tartrate)||New dosage recommendations|
|Jan 3||Alive Vitamins - Royal Jelly 1200 mg||Recall: contamination with chloramphenicol|
|Dec 27||Revlimid (lenalidomide)||Risk of liver problems|
|Dec 24||Co-Fluvoxamine (100 mg)||Recall: some bottles may contain ciprofloxacin pills|
|Dec 19||Phenytoin Sodium Injection USP 50 mg/mL||Possible presence of particulate matter in 2 mL and 5 mL vials|
|Dec 18||Methotrexate Sodium Injection 25 mg/mL (2 mL)||Recall: possible presence of cracked vials|
|Dec 18||Unauthorized natural health product MaxHIMize||Contains bacteria and undeclared caffeine|
|Dec 17 & 23Table 2 Footnote †||Several natural health products||Recall: possible contamination with chloramphenicol|
|Dec 5 & Jan 24||Unlicenced laser hair removal products||Risk of eye damage|
|Dec 5Table 2 Footnote †||Natural health products sold by Lion King Health Enterprises Group Ltd.||Additional seized products found to contain hidden ingredients and unauthorized substances|
|Dec 3||Xeloda (capecitabine)||Risk of severe skin reactions|
|Nov 27 & 30||Marcaine (bupivacaine hydrochloride injection USP) 0.25% and 0.5%, Marcaine E (bupivacaine hydrochloride and epinephrine injection USP) 0.25% and 0.5%||Recall: possibility of embedded particles in the glass vial|
|Nov 27||Propofol-II Injectable Emulsion 1% (10 mg/mL), 1000 mg/100 mL||Recall: presence of particulate matter|
|Nov 22 & 25||Endometrin (100 mg progesterone effervescent vaginal tablets)||Recall: possible problems with effectiveness|
|November 22 to February 24||Foreign products||9 Foreign Product Alerts (FPAs) were posted during this period|
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Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
Address Locator 0701D
Ottawa ON K1A 0K9
Patricia Carruthers-Czyzewski, BScPhm, MSc (Editor-in-Chief)
Christianne Scott, BPharm, MBA
Jared Cousins, BSP
Hoa Ly, BSc
Emir Al-Khalili, RPh, BScPhm, MSc
Nicoleta Hosszu Ungureanu, MSc
We thank Sally Pepper, RPh, BScPhm, as well as Alexandre Pratt and Rachel Mailhot, students in Biomedical Sciences, for their participation in the production of the newsletter.
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Reporting Adverse Reactions
Canada Vigilance Program
© 2014 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.
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