Canadian Adverse Reaction Newsletter, Volume 24 - Issue 2 - April 2014

ISSN 1499-9447
Cat no H42-4/1-24-2E

(PDF Version - 574 K)

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

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.

Quetiapine and acute liver failure

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 literature^{Footnote 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.

Two additional international cases of acute liver failure suspected of being associated with quetiapine use were published in the literature (Table 1).^{Footnote 5 Footnote 6}

Table 1: Summary of the 3 published reports (one Canadian case and 2 international cases) of acute liver failure suspected of being associated with quetiapine^{Table 1 Footnote *}

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
Table 1 Footnote * 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. Table 1 Return to footnote * referrer Table 1 Footnote † Concomitant medical conditions: Parkinson's disease; concomitant medications: carbidopa-levodopa, oxazepam and pramipexole (discontinued before administration of quetiapine). Table 1 Return to footnote † referrer Table 1 Footnote ‡ Concomitant medical conditions: diabetes mellitus, hypertension, hypothyroidism and gallstone pancreatitis for which the patient had undergone prior cholecystectomy; concomitant medications: metformin, ramipril, lithium and thyroid replacement therapy. Table 1 Return to footnote ‡ referrer Table 1 Footnote § No documented concomitant medical conditions; no concomitant medications. Table 1 Return to footnote § referrer

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

Azithromycin and drug reaction with eosinophilia and systemic symptoms

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 criteria^{Footnote 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 the^{Footnote 8 Footnote 13 Footnote 14 Footnote 15} One case involved an eight-year-old boy^{Footnote 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

Clopidogrel and acquired hemophilia

Background:

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}

Summary:

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.

Acquired hemophilia suspected of being associated with the use of clopidogrel has been reported in the scientific literature.^{Footnote 20 Note de bas de page 24}

As of Sept. 30, 2013, there were no reports of acquired hemophilia suspected of being associated with clopidogrel in Canada.

Next steps:

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

Quarterly Summary of health professional and consumer advisories

Health professional and consumer advisories posted between November 22, 2013 and February 24, 2014

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
Table 2 Footnote * Date of issuance. This date may differ from the posting date. Return to table 2 footnote * referrer Table 2 Footnote † Update to a previous advisory. Return to table 2 footnote † referrer

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Canadian Adverse Reaction Newsletter

Health Canada
Marketed Health Products Directorate
Address Locator 0701D
Ottawa ON K1A 0K9
Telephone: 613-954-6522
Fax: 613-952-7738

Editorial Team
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

Acknowledgement
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
Telephone: 1-866-234-2345
Fax: 1-866-678-6789

Copyright
© 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.

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