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Drugs and Health Products

Canadian Adverse Reaction Newsletter, Volume 22 - Issue 4 - October 2012

ISSN 1499-9447
Cat no H42-4/1-22-4E

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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.

Lyme disease test kits and limitations

Key points

  • Serologic test results are supplemental to the clinical diagnosis of Lyme disease and should not be the primary basis for making diagnostic or treatment decisions.
  • Lyme disease test kits have sensitivity and specificity limitations.
  • Health care professionals should be aware of these limitations and are encouraged to report suspected incidents, including false-positive and false-negative results, to Health Canada.

Lyme disease test kits are class II (IV being the highest risk class) in vitro diagnostic devices. The devices are intended for the detection of antibodies to Borrelia burgdorferi in human serum, plasma or cerebrospinal fluid.Footnote 1 They are used to provide serologic evidence of B. burgdorferi exposure.Footnote 1 Infection can result in dermatologic, neurologic, cardiac and musculoskeletal disorders.Footnote 2 Serologic testing is the only standardized type of laboratory investigation available to support the clinical diagnosis of Lyme disease in North America.Footnote 3 The public health agencies of Canada and the United States recommend a two-tiered approach for blood testing when Lyme disease is suspected.Footnote 3,Footnote 4,Footnote 5,Footnote 6,Footnote 7 The first tier consists of an enzyme immunoassay, such as an enzyme-linked immunosorbent assay (ELISA), or an indirect immunofluorescent assay. If the result of first-tier testing is negative, the sample is reported to be negative for antibodies to B. burgdorferi and is not tested further. If the result is positive or indeterminate, second-tier testing with a standardized Western blot is then performed.Footnote 3,Footnote 4,Footnote 5

As of June 2012, Health Canada received one incident report of false-negative serologic test results for 24 patients that may have delayed treatment. Timely recognition of Lyme disease and treatment are imperative to facilitate recovery and prevent long-term sequelae.Footnote 2,Footnote 7,Footnote 8

The currently available Lyme disease test kits have been found to have limitations of sensitivity and specificity, particularly when used on patients with acute infection, which is usually easily treated with antibiotics.Footnote 7,Footnote 9 Even when the conventional two-tiered testing approach is used, the sensitivity and specificity of the combined test results can be less than optimal.Footnote 9,Footnote 10,Footnote 11 In a comprehensive study of 280 serum samples from well-characterized Lyme disease patients, the sensitivity of the two-tiered approach was as low as 38% for the sera of patients who had erythema migrans during the acute phase and 67% during their convalescence after antimicrobial treatment.Footnote 10 In late Lyme disease, the sensitivity increased to 87% for the sera of patients with early neuroborreliosis and to 97% for the sera of patients with Lyme arthritis.Footnote 10

Many factors contribute to false-negative or false-positive serologic test results for Lyme disease.Footnote 1,Footnote 7,Footnote 9,Footnote 11,Footnote 12,Footnote 13,Footnote 14 In general, false-negative results have been attributed to (a) a slow antibody response early in the course of the disease, (b) genetic diversity of B. burgdorferi and (c) treatment with antibiotics. False-positive results have been attributed to (a) cross-reacting antibodies due to other conditions or infections and (b) the persistence of antibodies after disease resolution. Variability in serologic test results for Lyme disease may also be related to interlaboratory differences and lack of interassay standardization.Footnote 9,Footnote 13,Footnote 14

In contrast to the known HIV serologic testing using the two-tiered algorithm to confirm diagnosis, the Lyme disease test kits are not designed to screen patients or to establish a clinical diagnosis.Footnote 9,Footnote 12 A positive test result does notnecessarily indicate current infection with B. burgdorferi, and a negative result, especially early in the course of infection, does not exclude B. burgdorferi infection as the cause of illness.Footnote 9,Footnote 10,Footnote 11,Footnote 12 Serologic test results should be used to support a clinical diagnosis of Lyme disease and should not be the primary basis for making diagnostic or treatment decisions.Footnote 1,Footnote 11 Diagnosis should be based on patient history, which includes symptoms and exposure to the tick vector, and physical findings.Footnote 4,Footnote 11,Footnote 15

Health care professionals should be aware of the limitations of Lyme disease test kits and are encouraged to report suspected incidents, including false-positive and false-negative results, to Health Canada.

Rana Filfil, PhD, Health Canada

References

Footnotes

Footnote 2

Next link will take you to another Web site Establishing the performance characteristics of in vitro diagnostic devices for the detection of antibodies to Borrelia burgdorferi. Silver Spring (MD): Office of In Vitro Diagnostic Device Evaluation and Safety, Center for Devices and Radiological Health, US Food and Drug Administration; 2011.

Return to footnote 1 referrer

Footnote 2

Steere AC. Next link will take you to another Web site Lyme disease. N Engl J Med 1989;321(9):586-96. [PubMed]

Return to footnote 2 referrer

Footnote 3

Johnson BJB. Laboratory diagnostic testing for Borrelia burgdorferi infection. In: Halperin JJ (editor). Lyme disease: an evidence-based approach. Cambridge (MA): CAB International; 2011. p. 73-88.

Return to footnote 3 referrer

Footnote 4

Canadian Public Health Laboratory Network. Next link will take you to another Web site The laboratory diagnosis of Lyme borreliosis: guidelines from the Canadian Public Health Laboratory Network. Can J Infect Dis Med Microbiol 2007;18(2):145-8. [PubMed]

Return to footnote 4 referrer

Footnote 5

US Centers for Disease Control and Prevention (CDC). Next link will take you to another Web site Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 1995;44(31):590-1. [PubMed]

Return to footnote 5 referrer

Footnote 6

US Centers for Disease Control and Prevention (CDC). Next link will take you to another Web site Case definitions for infectious conditions under public health surveillance. MMWR Recomm Rep 1997;46(RR-10):1-55. [PubMed]

Return to footnote 6 referrer

Footnote 7

Wormser GP, Dattwyler RJ, Shapiro ED, et al. Next link will take you to another Web site The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43(9):1089-134. [PubMed]

Return to footnote 7 referrer

Footnote 8

Hovius JWR, van Dam AP, Fikrig E. Late manifestations of Lyme borreliosis. In: Fratamico PM, Smith JL, Brogden KA (editors). Sequelae and long-term consequences of infectious diseases. Washington (DC): ASM Press; 2009. p. 9-25.

Return to footnote 8 referrer

Footnote 9

Aguero-Rosenfeld ME, Wang G, Schwartz I, et al. Next link will take you to another Web site Diagnosis of Lyme borreliosis. Clin Microbiol Rev 2005;18(3):484-509. [PubMed]

Return to footnote 9 referrer

Footnote 10

Bacon RM, Biggerstaff BJ, Schriefer ME, et al. Next link will take you to another Web site Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2-tiered testing using whole-cell lysates. J Infect Dis 2003;187(8):1187-99. [PubMed]

Return to footnote 10 referrer

Footnote 11

Brown SL, Hansen SL, Langone JJ, et al.Lyme disease test kits: potential for misdiagnosis. US Food and Drug Administration Medical Bulletin; 1999 (summer).

Return to footnote 11 referrer

Footnote 12

Next link will take you to another Web site FDA public health advisory: assays for antibodies to Borrelia burgdorferi: limitations, use, and interpretation for supporting a clinical diagnosis of Lyme disease. Washington (DC): US Food and Drug Administration; 1997. Publication no. 1997-520-050.

Return to footnote 12 referrer

Footnote 13

Ang CW, Notermans DW, Hommes M, et al. Next link will take you to another Web site Large differences between test strategies for the detection of anti-Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. Eur J Clin Microbiol Infect Dis 2011;30(8):1027-32. [PubMed]

Return to footnote 13 referrer

Footnote 14

Mller I, Freitag MH, Poggensee G, et al. Next link will take you to another Web site Evaluating frequency, diagnostic quality, and cost of Lyme borreliosis testing in Germany: a retrospective model analysis. Clin Dev Immunol 2012:595427 [Epub 2011 Dec. 27]. [PubMed]

Return to footnote 14 referrer

Footnote 15

Public Health Agency of Canada. Next link will take you to another Web site Lyme disease fact sheet. Ottawa (ON): The Agency. (accessed 2012 Aug. 2).

Return to footnote 15 referrer

Antiandrogens and hepatotoxicity

Key points

  • A recent safety review conducted by Health Canada suggested that hepatotoxicity remains an important safety concern for all antiandrogen drugs.
  • The frequency of these adverse reactions and their clinical features appear to differ from one drug to another.
  • Health care professionals should be aware of the risk of hepatotoxicity associated with the use of these products.

Antiandrogens are a class of drugs used in androgen deprivation therapy for the treatment of advanced or metastatic prostate cancer. They are classified into two groups: nonsteroidal antiandrogens (flutamide, bicalutamide and nilutamide) and steroidal antiandrogens (cyproterone acetate).Footnote 1 Both groups work by competing with circulating androgens for receptor sites within the prostate cell, thus promoting apoptosis and inhibiting prostate cancer growth. Steroidal antiandrogens have the added ability of suppressing the production of testosterone. Depending on the drug, antiandrogens are indicated for use in monotherapy, or in combination with radiotherapy, luteinizing hormone-releasing hormone analogues or orchiectomy for complete androgen blockade.Footnote 2,Footnote 3,Footnote 4,Footnote 5

Antiandrogen drugs have been on the Canadian market for more than 20 years. Flutamide was approved by Health Canada in 1984 for the treatment of advanced stage B2 and stage C prostatic carcinoma and metastatic stage D2 prostate cancer.Footnote 2 Cyproterone acetate was approved in 1987 for the treatment of advanced prostatic carcinoma.Footnote 3 Bicalutamide and nilutamide were approved in 1996 and 1997 respectively for the treatment of metastatic stage D2 prostate cancer.Footnote 4,Footnote 5 Although the risk of hepatotoxicity and hepatic failure is currently labelled under the Warnings and Precautions sections of the Canadian product monographs for flutamide,Footnote 2 cyproterone acetate,Footnote 3 bicalutamideFootnote 4 and nilutamide,Footnote 5 a recent safety review conducted by Health Canada suggested that hepatotoxicity remains an important safety concern.

As of Mar. 31, 2012, Health Canada received 25 case reports of hepatotoxicity in men aged 60-98 years old that were suspected of being associated with antiandrogens, 24 of which were serious (Table 1). The most common adverse reactions included jaundice, increased liver enzyme levels, nausea, hepatic necrosis, ascites and hepatitis. One report of hepatotoxicity, excluded from Table 1, involved a woman using an antiandrogen for hirsutism.

The risk of hepatotoxicity with the use of antiandrogens has also been described in the clinical literature. Although both steroidal and nonsteroidal antiandrogens have been associated with hepatotoxicity, the frequency of these adverse reactions, and their clinical features, appear to differ from one drug to another.Footnote 1,Footnote 6,Footnote 7 For example, the results of an observational study  showed a higher occurrence of hepatotoxicity among patients taking flutamide than among those taking cyproterone acetate (15.3% v. 9.5%, p = 0.034).Footnote 8 Furthermore, this study found that the occurrence of serious hepatotoxicity (defined as an elevation in liver enzyme levels greater than 6 times the upper limit of normal) was 4.8% with the use of flutamide and 3.8% with cyproterone acetate. Serious hepatotoxicity is reported to be rare with bicalutamide and nilutamide.Footnote 1

Data from published clinical studies and case reports from the Canada Vigilance database consistently suggest that the risk of hepatotoxicity has been associated with all antiandrogen products marketed in Canada. Health care professionals should be aware of the risk of hepatotoxicity associated with the use of these products.

Eduardo del Campo, MD, Health Canada

Table 1: Summary of case reports of potential hepatotoxicity in men suspected of being associated with the use of antiandrogens submitted to Health Canada as of Mar. 31, 2012
  Outcome of serious cases
Antiandrogen Total no. of cases No. of serious cases Recovered Not recovered Death Unknown

Table 1 footnotes

  •  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.
  • No cases involving nilutamide were reported as of Mar. 31, 2012.
  • 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."
  • At time of reporting.
  • The total no. of cases, serious cases and deaths do not equal the sum of their columns because one report involved a patient taking both cyproterone acetate and flutamide in which the outcome was death.
Bicalutamide 2 2 0 1 0 1
Cyproterone acetate 9 9 2 1 6 0
Flutamide 15 14 7 1 6 0
Total 25 24 9 3 11 1

References

Footnotes

Footnote 2

Gillatt D. Le lien suivant vous amnera  un autre site Web Antiandrogen treatments in locally advanced prostate cancer: Are they all the same? J Cancer Res Clin Oncol 2006;132(Suppl 1):S17-26. [PubMed]

Return to footnote 1 referrer

Footnote 2

Euflex (flutamide) [product monograph]. Kirkland (QC): Merck Canada Inc.; 2011.

Return to footnote 2 referrer

Footnote 3

Androcur (cyproterone acetate) [product monograph]. Toronto (ON): Bayer Inc.; 2011.

Return to footnote 3 referrer

Footnote 4

Casodex (bicalutamide) [product monograph]. Mississauga (ON): AstraZeneca Canada Inc.; 2011.

Return to footnote 4 referrer

Footnote 5

Anandron (nilutamide) [product monograph]. Laval (QC): sanofi-aventis Canada Inc.; 2011.

Return to footnote 5 referrer

Footnote 6

Manso G, et al. Le lien suivant vous amnera  un autre site Web Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system. Pharmacoepidemiol Drug Saf 2006;15(4):253-9. [PubMed]

Return to footnote 6 referrer

Footnote 7

Thole Z. Le lien suivant vous amnera  un autre site Web Hepatotoxicity induced by antiandrogens: a review of the literature. Urol Int 2004;73(4):289-95. [PubMed]

Return to footnote 7 referrer

Footnote 8

Lin AD, Chen KK, Lin AT, et al. Le lien suivant vous amnera  un autre site Web Antiandrogen-associated hepatotoxicity in the management of advanced prostate cancer. J Chin Med Assoc 2003;66(12):735-40. [PubMed]

Return to footnote 8 referrer

Case Presentation

Recent Canadian cases are selected based on their seriousness, frequency of occurrence or the fact that the reactions are unexpected. Case presentations are considered suspicions and are presented to stimulate reporting of similar suspected adverse reactions.

Thalomid and posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome (PRES), also called reversible posterior leukoencephalopathy syndrome, is a neurological syndrome that typically includes the presence of headaches, visual disturbances, seizures, altered mental function and radiologic findings that commonly involve symmetrical posterior hemispheric edema.Footnote 1 It is often associated with abrupt hypertension and can also be seen in patients who are taking immunosuppressive drugs.Footnote 2 This syndrome is generally characterized by reversibility through control of the primary instigating factors.Footnote 1

Thalidomide (Thalomid) is an immunomodulatory agent used to treat multiple myeloma.Footnote 3 It has been suggested that its immunosuppressive effect on endothelial cells may be involved in the development of PRES.Footnote 2 Some cases of PRES suspected of being associated with thalidomide have been reported in literature.Footnote 2,Footnote 4,Footnote 5,Footnote 6

One of the published cases had been reported to Health Canada. It involved a 49-year-old woman who had been taking thalidomide 200 mg/d for maintenance therapy after autologous stem cell transplantation for multiple myeloma. She had been taking thalidomide for about 11 months before experiencing two focal motor seizures that evolved into a witnessed generalized tonic-clonic seizure. The seizure was terminated with the administration of lorazepam, and she was normotensive upon physical examination. The patient had also experienced anxiety and subjective short-term memory loss. Magnetic resonance imaging (MRI) of the brain showed findings consistent with PRES, including multiple foci of hyperintensity in the occipital and posterior parietal lobes on T2-weighted images. The patient was prescribed phenytoin, which was later switched to valproic acid because of a possible drug allergy. Three months later, a follow-up MRI revealed complete resolution of the hyperintensity changes on T2-weighted images. The valproic acid therapy was tapered, and the patient did not have any further seizures. Health Canada encourages the reporting of similar suspected adverse reactions to the Canada Vigilance Program.

References

Footnotes

Footnote 1

Hinchey J, Chaves C, Appignani B, et al. Next link will take you to another Web site A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334(8):494-500. [PubMed]

Return to footnote 1 referrer

Footnote 2

Pandey R, Patel A, Shah S, et al. Next link will take you to another Web site A rare complication in a case of multiple myeloma on therapy with thalidomide and dexamethasone -- reversible posterior lobe leukoencephalopathy. Leuk Lymphoma 2006;47(7):1431-4. [PubMed]

Return to footnote 2 referrer

Footnote 3

Thalomid (thalidomide) [product monograph]. Mississauga (ON): Celgene Inc.; 2012.

Return to footnote 3 referrer

Footnote 4

Kanard AM, Kane G, Thome SD, et al. Thalidomide associated with seizures and neuroradiologic features suggestive of reversible posterior leukoencephalopathy syndrome (RPLS) in the setting of multiple myeloma and renal failure [abstract 4618]. Blood 1999;94(10 Suppl 1):311b.

Return to footnote 4 referrer

Footnote 5

Tam CS, Galanos J, Seymour JF, et al. Next link will take you to another Web site Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am J Hematol 2004;77(1):72-6. [PubMed]

Return to footnote 5 referrer

Footnote 6

Chow S, Cheung CS, Lee DH, et al. Next link will take you to another Web site Posterior reversible encephalopathy syndrome (PRES) in a patient with multiple myeloma treated with thalidomide. Leuk Lymphoma 2012;53(5):1003-5. [PubMed]

Return to footnote 6 referrer

Quarterly Summary of health professional and consumer advisories

Health professional and consumer advisories posted on Health Canada's Web site: May 21, 2012 - August 19, 2012.
Date Product Subject

Table 1 footnotes

  •  Date of issuance. This date may differ from the posting date on Health Canada's Web site.
  • Posted on Health Canada's Web site on May 22, 2012. Not included in previous quarterly summary.
Aug 10 Hospital beds Update on the risk of patient entrapment
July 31 Calcitonin-containing drugs Potential cancer risk with long-term use
July 25 Weight-loss health products Unauthorized health products removed from sale at Burnaby's U-Box store
July 23 Pulmicort Turbuhaler
(budesonide)
Potential device failure
July 19 Vine Essence Recall : unauthorized natural health
product
July 16 Fu Fang Zaoren Jiaonang Unauthorized health product removed from sale
July 11 & 13 ImmuCyst (BCG vaccine) Update on facility issues and supply
status
July 9 & 12 Volibris (ambrisentan) Contraindication in patients with idiopathic pulmonary fibrosis
July 6 Lightning Rod Unauthorized health product removed from sale
June 29 ZXT Gold Bee Pollen Capsules Unauthorized health product removed from sale
June 28 Kleenex Luxury Foam Hand Sanitizer Recall: microbial contamination
June 26 Paclitaxel for injection, 300mg/50mL Glass vial defects for 3 lots
June 22 Counterfeit drugs Reminder of the possible health risks
June 21 Natural Vigor Maximum Recall: presence of undeclared dimethylhomosildenafil
June 15 Tuberculosis (BCG) vaccine Recall: manufacturing facility problems
June 11 & 14 HepaGam B [Hepatitis B
Immune Globulin (Human) Injection]
Possible risk of thrombotic events
June 1 Philips IntelliVue Patient
Monitors
Alarm problem with some units
May 29 & June 1 Privigen [Immune Globulin Intravenous (Human)] Association with risk of hemolysis and labeling updates
May 28 & 31 Xgeva (denosumab) Risk of severe symptomatic
hypocalcemia, including fatal case
May 23 X-Rock, Kaboom and One
For Her
Unauthorized health products removed from sale
May 15 Colleague Single and Triple Channel Volumetric Infusion Pumps Important safety information
May 21 to Aug 19 Foreign products 17 Foreign Product Alerts (FPAs) were posted on the Health Canada Web site during this period; FPAs are available online or upon request

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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)
Hoa Ly, BSc
Emir Al-Khalili, BA, BScPhm
Benjamin Pearson, BSc
Aleksandar Brezar, BSc
Sophie Bourbonnais, BScPht

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; and Yola Moride, PhD, FISPE.

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

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

Copyright
2012 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.