Canadian Adverse Reaction Newsletter, Volume 15 . Issue 1 . January 2005
Health Products and Food Branch, Marketed Health Products Directorate
In this Issue
Telithromycin and warfarin
Linezolid and neuropathy
Camphor and eucalyptus oils
Adverse reaction reporting
Natural weight loss product and myopathy
Ceftriaxone and immune hemolytic anemia in children
Case presentation: olanzapine and pulmonary embolism
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.
Telithromycin (Ketek) and warfarin: suspected interaction
Telithromycin (Ketek) is a novel antimicrobial that belongs to a new chemical family,
the ketolides.1 Ketolides are recent additions to
the macrolide-lincosamide streptogramin class1 and are designed to treat macrolide-resistant
respiratory tract pathogens.2 3The Ketek
product monograph states that, in a study involving healthy volunteers, there were no pharmacodynamic
or pharmacokinetic effects on racemic warfarin.1
From May 29, 2003 (the date of marketing in Canada) to Sept. 15, 2004, Health
Canada received 25 reports of suspected adverse reactions involving telithromycin. Seven
reports were of coagulation disorders, 6 of which involved an interaction with warfarin and
1 an interaction with an unspecified oral anticoagulant. The patients' ages ranged from 50 to
79 years. The international normalized ratio (INR) was increased in 6 of the 7 reports and
decreased in 1. Five patients had an INR that had previously been stabilized with warfarin;
in the other 2 reports this information was not provided. Depending on when the patient's INR
was due to be monitored, the change in INR was noted from 1 to 9 days after initiation of
telithromycin. In 6 of the 7 cases, changes in one or both of the warfarin and telithromycin
doses were required.
Telithromycin is metabolized by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by
cytochrome P450 1A (CYP1A).1
Warfarin exists as a racemic mixture of R- and S-warfarin. The S-isomer, metabolized by
CYP2C9, is primarily responsible for the hypoprothrombinemic activity. The R-isomer,
metabolized by CYP1A2 and to a lesser extent by CYP3A4, is less pharmacologically active
than the S-isomer, but significant drug interactions have resulted from inhibition of its
metabolism.2, 4
Proposed mechanisms of interaction between telithromycin and warfarin include the
presence of infection affecting the activity of cytochrome P450 and inhibition of the
metabolism of the warfarin R-isomer.1
Telithromycin is a substrate and inhibitor of CYP3A4. Its concentrations may be
increased with concomitant administration of CYP3A4 inhibitors (e.g., ketoconazole),
and telithromycin will increase the concentrations of other drugs metabolized by
CYP3A4.5
Antibiotics have been reported to decrease the intestinal flora that produce vitamin K,
reduced concentrations of which impair prothrombin production. Also, genetics, age,
diet (e.g., vegetables rich in vitamin K), fever, stress and concomitant medication could
modify the metabolism of warfarin and affect the intensity of the resulting
interaction.6
Although it has been stated that telithromycin does not interact with
warfarin,1, 7
the prothrombin time and INR should be monitored closely,2
especially in elderly patients, as should be the case whenever a new drug is
started in a patient taking warfarin.
Ilhemme Djelouah, BScPhm, DIS, AFSA, Medical Biology (University of Paris V); Iza Morawiecka, BScPhm,
Health Canada
References
1. Ketek (telithromycin) [product monograph]. Laval: Aventis Pharma Inc.; 2003.
2. Kolilekas L, Anagnostopoulos GK, Lampaditis I,
Eleftheriadis I. Potential interaction between telithromycin and warfarin. Ann Pharmacother
2004;38(9):1424-7.
3. Zuckerman JM. Macrolides and ketolides: azythromycin,
clarithromycin, telithromycin. Infect Dis Clin North Am 2004;18(3):621-49.
4. Michalets EL. Update: clinically significant cytochrome P-450 drug
interactions. Pharmacotherapy 1998;18(1):84-112.
5. Bearden DT, Neuhauser MM, Garey KW. Telithromycin: an oral
ketolide for respiratory infections. Pharmacotherapy 2001;21(10):1204-22.
6. Lauzon M. Place aux questions: Quels antibiotiques devraient-on
éviter lors de la prise de la warfarine? Québec Pharmacie 2004;51(4):302-4.
7. Fish DN. Telithromycin: a viewpoint by Douglas N.
Fish. Drugs 2004;64(15):1695-6.
Linezolid (Zyvoxam) and neuropathy
Linezolid (Zyvoxam), a synthetic antibacterial agent in a new class of antibiotics, the
oxazolidinones, has been marketed in Canada since Apr. 6, 2001.1
Linezolid is active against methicillin- and vancomycin-resistant gram-positive microorganisms.
2
The safety and efficacy of linezolid given for longer than 28 days have not been
evaluated in controlled clinical trials.1 Dosage and administration
guidelines recommend that treatment last no more than 28 consecutive days.1
Because of its activity against resistant organisms that cause osteomyelitis and prosthetic
joint infections, linezolid has been used in clinical practice for longer than the recommended
treatment course.2
The long-term use of linezolid has been associated with severe peripheral and optic
neuropathy.2-4In most cases the optic neuropathy resolved
after stopping the drug, but the peripheral neuropathy did not.4
Health Canada has received a report of a 71-year-old woman who received linezolid,
600 mg twice daily, for an acquired methicillin-resistant Staphylococcus aureus (MRSA)
infection. The patient received an initial 6-week course of linezolid, stopped treatment
for 4-5 months and was given the drug again for 8 months. Linezolid was stopped when the
patient was admitted to hospital with anemia, pure red cell aplasia and severe peripheral
neuropathy. She had initially noticed numbness in her feet a month previously. At the time
of the report, the anemia had resolved but the neuropathy had not. Novo-Hydrazide was also
considered a suspect drug.
Neuropathy (peripheral or optic) has rarely been reported in patients treated with
linezolid and has primarily occurred in patients treated for more than the maximum
recommended duration of 28 days.1 Myelosuppression including anemia is listed in the
product monograph under warnings and postmarketing experience.1
Pure red cell aplasia is not listed in the product monograph.1
Health care professionals must be aware of the potential for serious adverse reactions,
including neuropathy, when linezolid is used beyond its recommended duration.2
Spontaneous reporting of adverse reactions is an important aspect of postmarketing
surveillance and contributes to maintaining the most up-to-date safety information on
health products.
Debra Willcox, BSP, Health Canada
References
1. Zyvoxam (linezolid) [product mongraph].
Mississauga (ON): Pharmacia Canada Inc; 2002.
2. Rho JP, Sia IG, Crum BA, Dekutoski MB, Trousdale RT.
Linezolid-associated peripheral neuropathy. Mayo Clin Proc 2004;79(7):927-30.
Ann Allergy Asthma Immunol
3. Lee E, Burger S, Shah J, Melton C, Mullen M, Warren F,
Press R. Linezolid-associated toxic optic neuropathy: a report of 2 cases. Clin Infect Dis
2003;37(10):1389-91.
4. Bressler AM, Zimmer SM, Gilmore JL, Somani J. Peripheral
neuropathy associated with prolonged use of linezolid. Lancet Infect Dis 2004;4(8):528-31.
Safe use of health products containing camphor and eucalyptus oils
Camphor and eucalyptus oils are contained in many over-the-counter health
products, including topical rubs and products used for steam inhalation in the management
of coughs and colds. Because these products are generally thought to be without health
risks, they are often left accessible to young children, who may accidentally ingest them.
Simple precautions, such as carefully reading the product label warnings and storing the
products away from the reach of children, can help in preventing accidental poisonings.
Further consultation with a health care provider is advised with regard to the appropriate
use of these products. More information on this topic is available in the It's Your Health
article at
http://www.hc-sc.gc.ca/iyh-vsv/life-vie/camphor-camphre_e.html
Adverse reaction reporting by health professionals and consumers
Why report?
All marketed health products have benefits and risks. Although health products are
carefully tested for safety and efficacy before they are licensed, some adverse reactions*
may not become evident until the general population uses a health product under "real life"
circumstances. By submitting a suspected adverse reaction report, you are contributing to the
ongoing collection of safety and effectiveness information that occurs once health products
are marketed.
Reported adverse reaction information may contribute to:
- the identification of previously unrecognized rare, or serious adverse reactions;
- changes in product safety information, or other regulatory actions such as withdrawal of a
product from the Canadian market;
- international data regarding benefits, risks, or effectiveness of health products;
- health product safety knowledge that benefits all Canadians.
What to report?
Health Canada, through the Canadian Adverse Drug Reaction Monitoring Program, is responsible
for collecting and assessing adverse reaction reports for the following health products marketed
in Canada: pharmaceuticals, biologics (including fractionated blood products as well as therapeutic
and diagnostic vaccines), natural health products and radiopharmaceuticals.
You do not have to be certain that a health product caused the reaction in order to report it.
Adverse reaction reports are, for the most part, only suspected associations.
We want to know about all suspected adverse reactions, but especially if they are:
- unexpected adverse reactions, regardless of their severity
(not consistent with product information or labelling);
- serious adverse reactions †, whether expected or not;
- adverse reactions related to recently marketed health products
(on the market for less than 5 years).
When to report?
As soon as possible!
How to report?
Complete the adverse reaction reporting form which can be obtained at:
Submit the report:
- By toll-free fax: 1-866-678-6789
- By toll-free phone: 1-866-234-2345
- Calls are automatically directed to the National or a Regional Adverse Reaction (AR) Centre.
- By mail (see below for addresses of the National and Regional AR Centres)
Keep informed:
By subscribing to Health Canada's MedEffect e-Notice mailing list. You will automatically
receive the most recent Canadian Adverse Reaction Newsletter and health product advisories free
by e-mail. Go to
http://www.hc-sc.gc.ca/dhp-mps/medeff/subscribe-abonnement/index_e.html.
* adverse reaction = side effect
† A serious adverse reaction is one 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. Adverse reactions that require significant medical intervention to prevent one of
these outcomes are also considered to be serious.
National and regional adverse reaction centres
British Columbia
British Columbia Regional AR Centre
c/o BC Drug and Poison Information Centre
1081 Burrard St.
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,
and Newfoundland and Labrador
c/o Queen Elizabeth II Health Sciences Centre
Drug Information Centre
2421-1796 Summer St.
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
cadrmp@hc-sc.gc.ca
Reporting adverse incidents 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 and guidelines on mandatory and voluntary problem reporting
for Medical Devices.
Caffeine-containing natural weight loss product and myopathy
A 47-year-old woman experienced muscle twitching over 4 months while taking the
product Hydroxycut (Ephedra Free, by MuscleTech) for weight loss. The patient complained of
muscle pain and weakness. Examination indicated fasciculations of the calf muscles and a creatine
kinase (CK) level of 1021 (normally ≤ 190) U/L. Within 5 days of discontinuing the product,
muscle symptoms resolved, and the CK values approached normal. Although no pre-existing medical
conditions were noted, concomitant medications included Lomotil, Motilium, Nexium and Symbicort
Turbuhaler.
Although Hydroxycut is not authorized for sale in Canada, it is used as a weight loss or
bodybuilding product. The product was reformulated to be ephedra-free in January 2003. The new
formulation, according to the product label, contains calcium, chromium, potassium, Hydroxagen Plus
(which contains Garcinia cambogia extract, glucomannan, alpha lipoic acid, willow bark extract and
L-carnitine) and Hydroxy Tea (which contains green tea leaf extract, caffeine and guarana extract
standardized for 200 mg caffeine).
The association between caffeine intoxication and rhabdomyolysis has been documented.1
2Two cases of rhabdomyolysis associated with weight loss or bodybuilding products
that contain G. cambogia or guarana or both, as in Hydroxycut, have been reported in the literature.
One involved a product containing guarana, ephedrine, chitosan, Gymnema sylvestre, G. cambogia and
chromium,3while an earlier case was associated with a product containing guarana,
ginkgo and kava.4It is also possible that other ingredients contained in Hydroxycut
(Ephedra Free), such as G. cambogia (which contains hydroxycitric acid) and chromium picolinate, may play
a role in the development of rhabdomyolysis.5
Natural health products used for weight loss and bodybuilding may contain caffeine from a variety of natural
sources, including guarana, green tea, kola nut and yerba maté. Consumers may unknowingly increase their
intake of caffeine significantly and thereby increase their risk of caffeine-related adverse reactions, including
rhabdomyolysis.
Jenna Griffiths, MSc, PhD; Karen Pilon, RN, Health Canada
Reference
1. Wrenn KD, Oschner I. Rhabdomyolysis induced by a caffeine overdose. Ann Emerg Med 1989;18(1):94-7.
2. Kamijo Y, Soma K, Asari Y, Ohwada T. Severe rhabdomyolysis following massive ingestion of oolong
tea: caffeine intoxication with coexisting hyponatremia. Vet Hum Toxicol 1999;41(6):381-3.
3. Mansi IA, Huang J. Rhabdomyolysis in response to weight-loss herbal medicine. Am J Med Sci 2004;327(6):356-7.
4. Donadio V, Bonsi P, Zele I, Monari L, Liguori R, Vetrugno R, Albani F, Montagna P. Myoglobinuria
after ingestion of extracts of guarana, Ginkgo biloba and kava. Neurol Sci 2000;21(2):124.
5. Scroggie DA. Rhabdomyolysis associated with nutritional supplement use. In: VR Preedy VR, Watson RR,
editors. Reviews in food and nutrition toxicity. London: Taylor & Francis, 2003. p.121-8.
Ceftriaxone (Rocephin) and immune hemolytic anemia in children
Ceftriaxone (Rocephin), marketed in Canada since Dec. 31, 1987, is a third-generation cephalosporin indicated for the treatment of
susceptible strains of bacteria, as well as for prophylaxis against infections in patients undergoing
hysterectomy, coronary artery bypass surgery or biliary tract surgery.1
Immune hemolytic anemia (IHA) is a hypersensitivity adverse reaction (AR) known to occur in adults and children.
The Rocephin product monograph describes autoimmune hemolytic anemia as a rare AR (< 0.1% of cases),1
but does not mention IHA.
Ceftriaxone antibodies appear to be induced by an immune complex mechanism during a sensitization phase after initial exposure to the drug.
2 Intravascular hemolysis may be triggered after subsequent re-exposure. The signs and
symptoms of drug-induced IHA include severe hemolytic anemia, hemoglobinuria, hypotension, acute
renal failure, fever and back pain.3
From Jan. 1, 1988, to Sept. 15, 2004, Health Canada received 1 report of acute hemolysis
suspected of being associated with ceftriaxone. A young child with sickle cell disease had been
given a single dose of ceftriaxone (80 mg/kg body weight) intravenously for fever and cough, and
within 30 minutes developed a rash, pallor and decreased level of consciousness. Laboratory
examination showed a positive direct Coomb's test result, a hemoglobin level of 7 g/L
(the pre-infusion level was 110 g/L) and hemolyzed red blood cells. The following day, the patient
died despite resuscitation attempts. The only concomitant medication was a single oral dose of
erythromycin. The patient had been exposed to ceftriaxone in the past.
Nine pediatric cases of IHA associated with exposure to ceftriaxone were identified in the
literature, 6 of which were fatal.4-12One child with sickle cell anemia
received ceftriaxone on several occasions and experienced 6 episodes of unexplained transient
hemoglobinuria before the onset of the IHA.10
Drug-induced IHA is associated with a high mortality rate.3
Other than supportive care and red blood cell transfusion, there are few effective treatment options.
Reintroduction of the drug is contraindicated because of the high risk of recurrence of hemolysis,
which is often more severe.3
IHA associated with ceftriaxone is rare and has been reported to occur with repetitive,
intermittent use of this drug. Children with underlying conditions such as hemoglobinopathies
and immunodeficiencies are likely to require frequent treatment or prophylaxis with ceftriaxone,
which may place them at increased risk of IHA. The development of signs and symptoms of IHA,
including hemoglobinuria or unexplained anemia, should prompt health care professionals to consider
this diagnosis and the discontinuation of the suspect drug.3
Lise Watters, MD, FRCPC; Debra Willcox, BSP, Health Canada
References
1. Rocephin (ceftriaxone) [product monograph]. Mississauga (ON): Hoffman-La Roche Limited; 1997.
2. Arndt PA, Leger RM, Garratty G. Serology of antibodies to second- and third-generation cephalosporins
associated with immune hemolytic anemia and/or positive direct antiglobulin tests. Transfusion
1999;39(11-12):1239-46.
3. Solal-Celigny P. Abnormal hematologic values. In: Benichou C, editor. Adverse drug reactions.
A practical guide to diagnosis and management. Chichester: John Wiley and Sons Ltd.; 1994. p. 13-30.
4. Mattis LE, Saavedra JM, Shan H, Shirey RS, Powell E, Oliva-Hemker MM. Life-threatenting
ceftriaxone-induced immune hemolytic anemia in a child with Crohn's disease. Clin Pediatr (Phila)
2004;43(2):175-8.
5. Citak A, Garratty G, Ucsel R, Karabocuoglu M, Uzel N. Ceftriaxone-induced haemolytic
anaemia in a child with no immune deficiency or haematological disease. J Paediatr Child Health 2002;38(2):209-10.
6. Viner Y, Hashkes PJ, Yakubova R, Segal-Kupershmit D, Luder AS. Severe hemolysis induced by
ceftriaxone in a child with sickle-cell anemia. Pediatr Infect Dis J 2000;19(1):83-5.
7. Meyer O, Hackstein H, Hoppe B, Gobel FJ, Bein G, Salama A. Fatal immune haemolysis
due to a degradation product of ceftriaxone. Br J Haematol 1999;105(4):1084-5.
8. Scimeca PG, Weinblatt ME, Boxer R. Hemolysis after treatment with ceftriaxone. J Pediatr 1996;128(1):163.
9. Moallem HJ, Garratty G, Wakeham M, Dial S, Oligario A, Gondi A, et al. Ceftriaxone-related fatal
hemolysis in an adolescent with perinatally acquired human immunodeficiency virus infection. J Pediatr 1998;133(2):279-81.
10. Bernini JC, Mustafa MM, Sutor LJ, Buchanan GR. Fatal hemolysis induced by ceftriaxone in a
child with sickle cell anemia. J Pediatr 1995;126(5 Pt 1):813-5.
11. Lascari AD, Amyot K. Fatal hemolysis caused by ceftriaxone. J Pediatr 1995;126(5 Pt 1):816-7.
12. Borgna-Pignatti C, Bezzi TM, Reverberi R. Fatal ceftriaxone-induced hemolysis in a child with acquired
immunodeficiency syndrome. Pediatr Infect Dis J 1995;14(12):1116-7.
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.
Olanzapine (Zyprexa): suspected association with pulmonary embolism
A 22-year-old man (weight 95 kg, height 1.78 m) was prescribed Zyprexa, 20 mg at bedtime. About 6 months
after the start of treatment he was admitted to hospital with a massive bilateral pulmonary embolism,
confirmed by chest CT. An electrocardiogram revealed a normal sinus rhythm. The patient did not have deep
venous thrombosis (DVT), and results of venous Doppler ultrasonography of the legs performed 3 days after
admission were normal. Celexa, 20 mg/d, was the only concomitant medication reported. The patient had a
prior history of depression, had borderline autism and smoked half a pack of cigarettes a day. His father
had a history of DVT. Results of tests for inherited DVT (e.g., tests for prothrombin gene mutation,
Factor V mutation, protein C, protein S and activated protein C resistance) were negative. The patient
was treated with Lovenox and then warfarin. Zyprexa was tapered off, and risperidone was gradually
started. Similar cases have been described in the literature.1 2
References
1. Waage IM, Gedde-Dahl A. Pulmonary embolism possibly associated with olanzapine treatment. BMJ 2003;327(7428):1384.
2. Curtin F, Phil M, Schulz P. Psychotropic drugs and fatal pulmonary embolism: a comment. Pharmacoepidemiol
Drug Safety 2004;13:659-60.
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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, 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 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 H42-4/1-15-1E
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.
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