Canadian Adverse Reaction Newsletter
Volume 14, Issue 4, October 2004
Health Products and Food Branch
Marketed Health Products Directorate
In this Issue:
Transdermal fentanyl (Duragesic): respiratory arrest in adolescents
Infliximab (Remicade) and etanercept (Enbrel): serious infections
and tuberculosis
Bitter orange (synephrine): cardiovascular reactions
Case presentations:
Ibutilide and torsades de pointes
Tubersol and anaphylaxis
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 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
Contact Health Canada
or a Regional AR Centre
free of charge
Phone: 866 234-2345
Fax: 866 678-6789
Email: cadrmp@hc-sc.gc.ca
Click here for the Adverse Reaction Reporting
Form
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.
Transdermal fentanyl (Duragesic): respiratory arrest
in adolescents
Health Canada has received 2 case reports of death suspected by the reporters
of being associated with the use of Duragesic (transdermal fentanyl system)
prescribed off-label to adolescents. In one case, a 15-year-old girl was
prescribed Duragesic 25 for chronic headache. She was discovered unresponsive
and with respiratory depression 21 hours after the first and only application.
She was resuscitated but suffered severe anoxic brain injury and died
2 days later. In the second case, a 14-year-old boy was prescribed Duragesic
25 for throat pain due to infectious mononucleosis. He was found in respiratory
arrest 14 hours after the first and only patch was applied. Resuscitative
efforts were unsuccessful.
Duragesic has been marketed in Canada since 1992 and is indicated for
the management of chronic pain in patients requiring continuous opioid
analgesia for pain that is not optimally managed with weak or short-acting
opioids.1 Duragesic is contraindicated
for the management of acute or postoperative pain and mild or intermittent
pain, and for use in opioid-naive patients. These contraindications and
the risk of serious and life-threatening hypoventilation are well labelled
in the Canadian product monograph. The use of Duragesic in children under
18 years of age is not recommended in Canada.1
A thorough understanding of the pharmacokinetics and delivery system
of Duragesic is essential to the safe prescribing of this product. The
Duragesic transdermal therapeutic system allows the continuous delivery
of the opioid analgesic fentanyl for up to 72 hours.1
It is a transparent patch comprised of a protective peel strip and 4 functional
layers. The protective peel strip is removed before use, and the patch
is attached to the skin via a silicone-based contact adhesive, which delivers
a loading dose of drug upon application. The fentanyl drug reservoir is
located behind a rate-control membrane. The drug diffuses through this
membrane and the adhesive to reach the skin. A fentanyl depot accumulates
in the upper skin layers, diffuses through to the dermis and is then available
for uptake into systemic circulation.2
In adults, the time from application to minimal effective serum concentrations
can range from 1.2 to 40 hours, and the time to reach maximum serum concentrations
can range from 12 to 48 hours. When the Duragesic patch is removed, fentanyl
continues to be absorbed into the systemic circulation from the cutaneous
depot.2 The serum fentanyl concentrations
decline gradually to about 50% in about 17 (range 13-22) hours.1
In the 2 cases reported to Health Canada, these opioid-naive adolescents
experienced severe respiratory depression 21 and 14 hours after application
of Duragesic 25 and died. Prescribers are reminded that this dosage delivery
system for fentanyl is not suitable for acute pain management or for opioid-naive
patients. Patients and their caregivers must be instructed in how to recognize
symptoms of serious opioid-related toxicity such as hypoventilation and
cognitive impairment.3
Barbara Raymond, BSc, MD; Iza Morawiecka, BScPhm, Health Canada
References
- Duragesic 25 (fentanyl transdermal system)
[product monograph]. Toronto: Janssen-Ortho Inc.; 2002.
- Grond S, Radbruch L, Lehmann KA. Clinical pharmacokinetics
of transdermal opioids: focus on transdermal fentanyl. Clin Pharmacokinet
2000;38(1):59-89.
- Kornick CA, Santiago-Palma J, Moryl N, Payne
R, Obbens EA. Benefit-risk assessment of transdermal fentanyl for the
treatment of chronic pain. Drug Saf 2003;26(13):951-73.
Infliximab (Remicade) and etanercept (Enbrel): serious
infections and tuberculosis
Tumour necrosis factor-alpha (TNF-α) is a proinflammatory cytokine
synthesized in response to infectious or inflammatory stimuli.1
TNF-α antagonists have been shown to be effective in the treatment
of signs and symptoms of rheumatoid arthritis and other autoimmune diseases.1
Infliximab (Remicade) is indicated in adults for rheumatoid arthritis
(in combination with methotrexate), Crohn's disease and fistulizing Crohn's
disease.2 Etanercept (Enbrel) is indicated
for rheumatoid arthritis in adults and polyarticular juvenile rheumatoid
arthritis in patients aged 4 to 17 years.3
Serious infections, particularly tuberculosis (TB), are recognized risks
for patients receiving TNF-α antagonists, and warnings to that effect
are prominent in the product monographs.2,3
Many serious infections have occurred in patients taking immunosupressive
therapy concomitantly, which, in addition to the underlying disease, could
predispose them to infections.2,3
Health Canada received a total of 697 reports of suspected adverse reactions
(ARs) to infliximab and 536 to etanercept from Jan. 1, 2000, to May 31,
2004 (Table 1). Reports of infection were considered
serious when the infection was life threatening or resulted in death,
disability, hospital admission or prolonged hospital stay (as defined
in the Food and Drug Regulations). The types of serious infections
are listed in Table 2. Reports of TB comprised those
of new cases (infliximab 3, etanercept 0), reactivation of latent TB (infliximab
3, etanercept 0) and cases in which the patient was prescribed antituberculous
medication (infliximab 4, etanercept 2). There were 4 reports of pulmonary
or pleural TB (infliximab 4, etanercept 0), 4 reports of extrapulmonary
TB (infliximab 4, etanercept 0) and 4 reports in which the type of TB
was not specified (infliximab 2, etanercept 2).
A number of registries have been established to assist in assessing the
long-term safety and efficacy of TNF-α antagonists.4,5
In France the program is particularly interested in infections and lymphomas.4
In Alberta a systematic approach has been developed to collect data on
effectiveness and ARs for all Alberta patients receiving these agents
for the treatment of rheumatoid arthritis.5
Health care professionals are reminded of the following important safety
information included in the Enbrel and Remicade product monographs:2,3
- Caution should be exercised when considering the use of TNF-α
antagonists in patients with chronic infection, a history of recurrent
or latent infection, including TB, or an underlying condition that may
predispose them to infection.
- TNF-α therapy should not be initiated in patients with a clinically
important, active infection.
- New infections should be closely monitored and therapy discontinued
if the infection becomes serious.
Patients should be instructed in how to recognize early signs and symptoms
of infection and be advised to seek medical attention when they occur.
| Table 1: Reports submitted to Health Canada
of infections suspected of being associated with infliximab and etanercept
from Jan. 1, 2000, to May 31, 2004* |
| Variable |
Infliximab |
Etanercept |
| Total no. of AR reports |
697 |
536 |
| No. of AR reports with infection |
188 |
109 |
| No. of AR reports with serious infection
(no. of deaths†) |
132 (14) |
82 (7) |
Note: AR = adverse reaction.
*These data cannot be used to determine the incidence of ARs
or to make quantitative drug safety comparisons between the products
because ARs are underreported and neither patient exposure nor the
amount of time the drug was on the market has been taken into consideration.
† Causality assessment is difficult because of multiple factors such
as confounding factors, complexity of the cases as well as the quality
and the completeness of the information included in the reports. |
| Table 2: Types of serious infections described
in the reports submitted to Health Canada for infliximab and etanercept
from Jan. 1, 2000, to May 31, 2004* |
| Type of infection † ‡ |
Infliximab |
Etanercept |
| Abscess |
20 |
10 |
| Cellulitis |
11 |
3 |
| Encephalitis or meningitis |
2 |
1 |
| Fungal infections |
14 |
2 |
| Pneumonia |
36 |
30 |
| Pyelonephritis or cystitis |
7 |
8 |
| Sepsis |
36 |
15 |
| Septic arthritis |
7 |
4 |
| Tuberculosis |
10 |
2 |
*These data cannot
be used to determine the incidence of ARs or to make quantitative
drug safety comparisons between the products because ARs are underreported
and neither patient exposure nor the amount of time the drug was on
the market has been taken into consideration.
†Because of limited information in the reports, some infections
could not be classified and are not included.
‡Several infection types (reaction terms) may be listed per
AR report. Reaction terms are based on the World Health Organization
Adverse Reaction Dictionary (WHOART). |
Heather Dunlop, MLIS, RN, Health Canada
References
- Khanna D, McMahon M, Furst DE. Safety of tumour
necrosis factor-α antagonists. Drug Safety 2004;27(5):307-24.
- Remicade (infliximab) [product monograph].
Malvern (PA): Centocor Inc.; 2004. Imported by Schering Canada Inc.,
Pointe-Claire (QC).
- Enbrel (etanercept) [product monograph].
Thousand Oaks (CA): Immunex Corp.; 2003. Distributed by Amgen Canada
Inc., Mississauga (ON) and Wyeth Canada, Montréal (QC).
- Lettre aux prescripteurs. Observatoire Ratio.
Observatoire national des infections et lymphomes survenant sous anti-TNFα.
23 January 2004. Available:
 http://afssaps.sante.fr/htm/10/filltrpsc/lp040201.pdf
(accessed 2004 June 21).
- Maksymowych WP. Reporting process of randomized
controlled trials [letter]. CMAJ 2004;170(9):1375.
Products containing bitter orange or synephrine: suspected
cardiovascular adverse reactions
Products containing bitter orange (Citrus aurantium) or synephrine
are used for their claims of promoting weight loss. However, these products
are not authorized by Health Canada for this indication. Synephrine, the
main active compound in bitter orange, is claimed to increase metabolism
and promote thermogenesis.1 Although
their effectiveness remains unclear,1
many products containing bitter orange are being promoted as "Ephedra/ephedrine
free," since the use of Ephedra has been restricted in Canada2
and prohibited in dietary supplements in the United States3
owing to adverse cardiovascular and cerebrovascular reactions.
Synephrine, a sympathetic a-adrenergic agonist, is structurally related
to ephedrine; thus bitter orange extract may be associated with a spectrum
of adverse reactions (ARs) similar to those associated with the use of
Ephedra/ephedrine.4 In animals,
synephrine use has been associated with dose-related cardiotoxicity, specifically
ventricular arrhythmias.5 A case of myocardial
infarction in a patient with no history of heart disease has been reported
in association with synephrine-containing products.6
Health Canada issued an advisory on a natural health product containing
synephrine and other stimulants, cautioning that synephrine may have cardiovascular
effects similar to those of ephedrine.4
Synephrine's cardiovascular effects may be increased when combined with
other stimulants such as caffeine.7 Previously,
Health Canada warned consumers about using Ephedra products containing
caffeine, for the same reasons,2 and
other reviews have reiterated this safety concern.8
From Jan. 1, 1998, to Feb. 28, 2004, Health Canada received 16 reports
in which products containing bitter orange or synephrine were suspected
of being associated with cardiovascular ARs, including tachycardia, cardiac
arrest, ventricular fibrillation, transient collapse and blackout. All
cases were considered serious. One involved a suspect product containing
bitter orange but no caffeine or Ephedra/ephedrine. In 7 cases
the suspect product also contained caffeine, and in 8 cases the suspect
product also contained both Ephedra/ephedrine and caffeine. Two
of the 16 patients died, both of whom had taken products containing Ephedra/ephedrine
and caffeine in addition to bitter orange. Evaluation of these reports
is challenging because of many factors such as the lack of information
on the ingested dose of synephrine, the contributory effects of other
(multiple) ingredients such as Ephedra and caffeine, and the
ambiguity of the reported information.
Consumers need to be aware of the potential serious ARs when using these
products containing bitter orange or synephrine and may wish to consult
their health care providers with regard to their use. Health care professionals
are encouraged to ask their patients to list the natural health products
they are taking and report to Health Canada any suspected ARs related
to the use of such products, including those claiming to promote weight
loss.
Scott Jordan, PhD, Mano Murty, MD, CCFP, FCFP, and Karen Pilon, RN, Health
Canada
References
- Blumenthal M, senior editor. Herbal medicine
- expanded Commision E monographs. 1st ed. Austin (TX): American
Botanical Council; 2000. p. 287-9.
- Health Canada reminds Canadians of the dangers
of Ephedra/ephedrine products. Ottawa: Health Canada; 2003 June
9. Available: http://www.hc-sc.gc.ca/english/protection/warnings/2003/2003_43.htm
(accessed 2004 July 5).
- FDA announces rule prohibiting sale of dietary
supplements containing ephedrine alkaloids effective April 12 [FDA statement].
Rockville (MD): US Food and Drug Adminstration; 2004 Apr 12. Available:
http://www.fda.gov/bbs/topics/NEWS/2004/NEW01050.html
(accessed 2004 June 28).
- Health Canada warns Canadians not to use
"Thermonex." Ottawa: Health Canada; 2004 May 28. Available: http://www.hc-sc.gc.ca/english/protection/warnings/2004/2004_30.htm
(accessed 2004 July 5).
- Calapai G, Firenzuoli F, Saitta A, Squadrito
F, Arlotta MR, Canstantino G, Inferrera G. Antiobesity and cardiovascular
toxic effects of Citrus aurantium extracts in the rat: a preliminary
report. Fitoterapia 1999;70:586-92.
- Nykamp DL, Fackih MN, Compton AL. Possible association
of acute lateral-wall myocardial infarction and bitter orange supplement.
Ann Pharmacother 2004;38(5):812-6.
- Bucci L, Shugarman AE, Feliciano J, Wright J.
Acute metabolic responses to synephrine-caffeine compared to ephedrine-caffeine.
Presented at the Conference on the Science and Policy of Performance-Enhancing
Products. NIH Office of Dietary Supplements; Bethesda, Md; Jan. 8-9,
2002. Available: http://ods.od.nih.gov/news/conferences/BucciPEPCRN
_Ephedra_Presentation_Jan02.pdf
(accessed 2004 June 27).
- Bitter orange. Natural Medicines Comprehensive
Database. Available: http://www.NaturalDatabase.com
(accessed 2004 June 27). Jellin JM, Gregory PJ, Batz F, Hitchens K,
et al. Pharmacist's letter/prescriber's letter. Natural Medicines Comprehensive
Database. 6th ed. Stockton (CA): Therapeutic Research Faculty; 2004.
p. 146-8.
New brochure on adverse reaction reporting
Health Canada has developed a new brochure on adverse reaction
reporting by health care professionals and consumers. The brochure
covers what and when to report,
how to submit a report, and how
to access safety information on marketed health products on the
Internet by subscribing to Health Canada's Health Prod Info
mailing list. This handy 1-page brochure can be posted in your institution
for ease of reference. You can print it from the Internet at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/ar-ei_broch-pamph_repor-sign_e.pdf. |
Case Presentations
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.
Ibutilide (Corvert): suspected association with torsades
de pointes
A 52-year-old man with no prior history of cardiac disease presented
to an emergency department with atrial fibrillation and congestive heart
failure. Concomitant medications reported were metoprolol and diltiazem.
The potassium level was 4 (normally 3.5-5.0) mmol/L, and the cardiac troponin
level was elevated. A decision to proceed with pharmacologic cardioversion
was made, and 2 doses of intravenous Corvert (ibutilide) were administered.
Sustained torsades de pointes developed, and electrocardioversion was
performed immediately. The patient's sinus rhythm reverted to normal,
but without mechanical cardiac output. Advance cardiac life support manoeuvres
were unsuccessful, and the patient died. He had no known contraindications
to the use of ibutilide. The autopsy revealed coronary artery disease
and aortic valvular stenosis, neither of which are noted contraindications
to the use of Corvert.
Ibutilide is a class III antiarrhythmic drug indicated for the conversion
of atrial flutter or atrial fibrillation to sinus rhythm, to be considered
as an alternative to electrocardioversion. The potential for ibutilide
to induce further arrhythmia is prominently labelled in the product monograph.1
Reference
- Corvert Injection (ibutilide fumarate injection)
[product monograph]. Kirkland (QC): Pfizer Canada Inc; 2003.
Tubersol and anaphylaxis
A 36-year-old woman experienced an anaphylactic reaction following a
Tubersol (Tuberculin Purified Protein Derivative [Mantoux]) skin test.
The tuberculin skin test was administred at 11:15 am. By 11:18 am the
injection site was red, raised and very itchy, with swelling of more than
5 cm in diameter. At 11:22 am the patient's face was flushed and red,
her lips had begun to swell, and she experienced a tingling sensation
around the mouth. At 11:43 am the patient was feeling lightheaded and
was experiencing nausea, intermittent hoarse voice, flushed face and tingling
of mouth. At 11:45 am the patient was given 0.5 mL Adrenalin, and at 12:05
pm she was transported to the hospital. All symptoms resolved. The patient
was kept in the emergency department for 2 hours and then sent home. It
was reported that she had no previous tuberculin skin test. She did have
a history of anaphylactic reactions to seafood and strawberries, but these
foods had not been consumed on the day of the reaction.
Reporting Adverse Reactions
Health professionals and consumers may report adverse reactions (ARs) to health products (pharmaceuticals, biologics, radiopharmaceuticals and natural health products) marketed in Canada toll-free:
Tel: 866-234-2345 - Fax: 866-678-6789
Calls will be automatically routed to the appropriate Regional or National
AR Centre. Copies of the AR Reporting Form are available from the Regional
or National AR Centre (see addresses below), the Canadian Compendium
of Pharmaceuticals and Specialties (CPS) and the Health Canada Web
site (http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/form/ar-ei_form_e.html)
British Columbia
British Columbia Regional AR Centre
c/o BC Drug and Poison Information Centre
1081 Burrard
Vancouver BC V6Z 1Y6
adr@dpic.ca
Saskatchewan
Saskatchewan Regional AR Centre
c/o Saskatchewan Drug Information Service
College of Pharmacy and Nutrition
University of Saskatchewan
110 Science Place
Saskatoon SK S7N 5C9
Sask.AR@usask.ca
Ontario
Ontario Regional AR Centre
c/o LonDIS Drug Information Centre
London Health Sciences Centre
339 Windermere Rd.
London ON N6A 5A5
adr@lhsc.on.ca
Québec
Québec Regional AR Centre
c/o Drug Information Centre
Hôpital du Sacré-Coeur de Montréal
5400, boul. Gouin ouest
Montréal (QC) H4J 1C5
pharmacovigilance.hsc@ssss.gouv.qc.ca
Atlantic
Atlantic Regional AR Centre
For New Brunswick, Nova Scotia, Prince Edward Island,
Newfoundland and Labrador
c/o Queen Elizabeth II Health Sciences Centre
Drug Information Centre
2421-1796 Summer Street
Halifax NS B3H 3A7
adr@cdha.nshealth.ca
All other provinces and territories
National AR Centre
Marketed Health Products Safety and Effectiveness Information Division
Marketed Health Products Directorate
Tunney's Pasture, AL 0701C
Ottawa ON K1A 0K9
Tel: (613) 957-0337 Fax: (613) 957-0335
cadrmp@hc-sc.gc.ca
Reporting adverse events associated with Medical Devices:
Health Products and Food Branch Inspectorate
Health Canada
AL 3002C
Ottawa, ON K1A 0K9
Medical Devices Hotline 800 267-9675
Visit Health Canada's Web site to obtain copies of the
Medical
Devices Problem Report Form
http://www.hc-sc.gc.ca/dhp-mps/compli-conform/prob-report-rapport/rep_md_prob-rap_inc_im_tc-tm_e.html and
guidelines
on mandatory and voluntary problem reporting for Medical Devices http://www.hc-sc.gc.ca/dhp-mps/compli-conform/prob-report-rapport/mavprfmd-rioevraim_tc-tm_e.html
Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
AL 0701B
Ottawa ON K1A 0K9
Tel 613 954-6522
Fax 613 952-7738
Health professionals/consumers report toll free
Tel 866 234-2345
Fax 866 678-6789
E-mail: cadrmp@hc-sc.gc.ca
Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Ilhemme Djelouah, BScPhm, DIS, AFSA, Medical Biology (University of Paris V)
Karen Kouassi, BSc, MSc
Gilbert Roy, BPharm
Acknowledgements
Expert Advisory Committee on Pharmacovigilance,
Regional AR Centres and Health Canada staff.
Suggestions?
Your comments are important to us. Let us know what you think by reaching us at
E-mail: cadrmp@hc-sc.gc.ca
Copyright
Her Majesty the Queen in Right of Canada, 2004. 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.
ISSN 1499-9447; Cat no H42-4/1-14-4E
USPS periodical postage paid at Champlain, NY, and additional locations.
Aussi disponible en français.
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.
|
