Canadian Adverse Reaction Newsletter
Volume 11 Number 3 July 2001
Marketed Health Products Directorate
Heath Products and Foods Branch
In This Issue
Drug advisories now available on
the Web
Miconazole-warfarin interaction: increased
INR
New toll-free numbers to report ADRs
Rosiglitazone (Avandia): hepatic, cardiac and
hematological reactions
Adverse drug reaction
reporting - 2000: Part 2
Communiqué
Drugs of Current Interest
Dear Health Professional
Advisories now available on the Web
The Therapeutic Products Directorate (TPD) and the Biologic and Genetic
Therapies Directorate have started posting industry-issued "Dear Health
Professional" (DHP) letters on the TPD Web site in July 2000 in addition
to the health professional advisories that the Directorates already issued
and posted. A new Web page listing entitled "Advisories to Health Professionals"
was created on Mar. 23, 2001, and is divided into two sections: one for
messages originating from both directorates, and the second for messages
prepared in collaboration with both directorates and issued by industry.
DHP letters are an important source of information regarding the post-approval
safety and effectiveness of therapeutic products. Recognizing that the
public expects this type of information to be made more readily available
to all interested parties, we encourage you to share the following Web
site address with your colleagues:http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/index_e.html
Check the site for full information on the phenylpropanolamine advisory:
"Health Canada withdraws drug products containing phenylpropanolamine
(PPA) from the market."
Miconazole-warfarin
interaction: increased INR
Recent literature reports have identified the possibility of a serious
adverse interaction between vaginal miconazole and warfarin, with potentiation
of the anticoagulation effect. 1,2
The US Food and Drug Administration issued a "Talk Paper" to inform health
care professionals that women who take warfarin and use a miconazole vaginal
cream or suppository may be at risk of an increased prothrombin time (PT),
international normalized ratio (INR) and bleeding tendency.3
Hypoprothrombinemia in patients receiving oral anticoagulants in conjunction
with oral miconazole has been documented.4
Small amounts (< 2%) of miconazole are absorbed systemically when the
drug is applied vaginally in healthy women of childbearing age.5
However, recent published case reports of increased INR in 3 women aged
53, 61 and 72 years taking concurrent vaginal miconazole and warfarin,
with no identifiable cause for prolonged PT, led the authors to suggest
that absorption of vaginal miconazole may be increased in the presence
of atrophic vaginal epithelium, potentiating the risk of hypoprothrombinemia.
2
The Canadian Adverse Drug Reaction Monitoring Program (CADRMP) searched
its database for cases reporting concurrent use of miconazole (vaginal
and topical) and warfarin. As of March 2001, 2 case reports were identified.
The first was of a 52-year-old woman taking warfarin who presented to
hospital with a hemorrhage of the right kidney after 12 days of using
vaginal Monistat. The elevated PT and partial thromboplastin time, recorded
on admission, returned to normal after discontinuation of the vaginal
Monistat. The second case was of an 80-year-old man using topical miconazole
who had a cerebral vascular accident. The causality could not be established
because of multiple medical problems and concurrent medications.
Health Canada is taking steps to inform all health care professionals
of the potential interactions with intravaginal miconazole and anticoagulants.
The sponsors have been requested to update labelling, product monograph
and prescribing information for all vaginal products containing miconazole.
Because these products are available over the counter, product packaging
will include a consumer warning to "Consult a doctor or pharmacist before
use if you are taking the blood thinning medicine warfarin, because bleeding
or bruising may occur."
Written by: Mano Murty, MD, CCFP, FCFP, Bureau of Licensed Product Assessment
References
1. Thirion DJG, Zanetti
LAF. Potentiation of warfarin's hypoprothrombinemic effect with miconazole
vaginal suppositories. Pharmacotherapy 2000;20(1):98-9.
2. Lansdorp D, Bressers
HPHM, Dekens-Konter JAM, Meyboom RHB. Potentiation of acenocoumarol during
vaginal administration of miconazole. BR J Clin Pharmacol 1999;47:223-30.
3. US Food and Drug Administration
(FDA). FDA talk paper: FDA updates safety information for miconazole
vaginal cream and suppositories. Rockville (MD): FDA; 2001 Mar 5.
Available:  http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01071.html (accessed 2001 May 18).
4. Wells PS, Holbrook
AM, Crowther NR, Hirsh J. Interaction of warfarin with drugs and food.
Ann Intern Med 1994;121:676-83.
5. Daneshmend TK. Systemic
absorption of miconazole from the vagina. J Antimicrob Chemother
1986;18:507-11.
New health professional/consumer
toll-free telephone and fax lines to report ADRs
Effective August 1, 2001, an improvement to facilitate the receipt of
drug safety information will be implemented, with the introduction of
toll-free telephone and fax access. Health professionals and consumers
may use these numbers to report adverse drug reactions (ADRs). Calls will
be automatically routed to the appropriate regional or national ADR centre.
Reporting access for manufacturers will continue to be through the existing
national ADR centre direct lines.
Health professionals/consumers contact us toll free
at:
Telephone: 866 234-2345
Fax: 866 678-6789
Rosiglitazone (Avandia): hepatic,
cardiac and hematological reactions
Rosiglitazone maleate (Avandia), an oral antidiabetic agent approved
for sale in Canada on Mar. 21, 2000, is a member of the thiazolidinedione
class of drugs. It improves sensitivity to insulin in muscle and adipose
tissue and inhibits hepatic gluconeogenesis.1 Use of rosiglitazone
is indicated as monotherapy in patients with type 2 diabetes mellitus
not controlled by diet and exercise alone. The drug is also indicated
for use in combination with metformin or a sulfonylurea when, in addition
to diet and exercise, any one of rosiglitazone, metformin or a sulfonylurea
alone do not result in significant improvement of glycemic control. For
patients inadequately controlled by a maximum dose of metformin or a sulfonylurea,
rosiglitazone should be added to, not substituted for, either metformin
or a sulfonylurea.1
Troglitazone (Rezulin), another thiazolidinedione, was associated with
severe hepatotoxicity and liver failure and was withdrawn from the US
market in March 2000 (troglitazone was never marketed in Canada). Although
the mechanism of this toxicity remains unknown, it has been suggested
that chemically reactive metabolites of troglitazone covalently bind to
hepatic proteins, which causes oxidative stress and liver injury.2
In addition to the potential risk of liver toxicity, thiazolidinediones
can cause fluid retention, which can exacerbate congestive heart failure.
Upon the market launch of Avandia, the sponsor issued a Dear Health Professional
letter3 to inform about the potential risk
of liver toxicity with thiazolidinediones and to provide recommendations
for the monitoring of liver function test results and symptoms of heart
failure in patients at risk for congestive heart failure. Rosiglitazone
is contraindicated in patients with serious hepatic impairment and is
not indicated for combination use with insulin.1
It is also not indicated for use in patients with New York Heart Association
class III and IV cardiac status (congestive heart class III and IV) unless
the expected benefit is believed to outweigh the potential risk. 3
The Avandia product monograph includes recommendations for liver enzyme
monitoring in all patients:
· baseline liver enzymes and liver enzymes every 2
months for the first 12 months
· liver enzymes periodically thereafter
· more frequent liver monitoring in patients with mild liver enzyme elevations;
proceed with caution
· do not initiate therapy in patients with increased baseline liver enzyme
levels (alanine aminotransferase [ALT] level > 2.5 times the upper limit
of normal)
· if at any time ALT levels increase to > 3 times the upper limit of normal,
liver enzymes should be rechecked as soon as possible
· if ALT levels remain > 3 times the upper limit of normal, discontinue
Avandia.1
Between March 2000 and Feb. 23, 2001, the CADRMP received 166 domestic
reports of suspected adverse drug reactions associated with rosiglitazone;
38 were classified as serious4 -- fatal
outcomes (3 cases), liver and biliary disorders (10), cardiovascular disorders
(20) and hematological disorders (8) -- and are summarized here:
Reported fatal outcomes: In the first case of death, a 51-year-old
man who was positive for hepatitis B surface antigen, negative for hepatitis
B e antigen, positive for hepatitis B e antibody and had relatively normal
baseline liver enzyme values (aspartate aminotransferase [AST] 43 [normally
< 40] U/L; alkaline phosphatase [AP] 85 [normally < 125] U/L) took
rosiglitazone for 6 months and experienced a marked increase in liver
enzyme levels (AST 1102 U/L, AP 135 U/L and bilirubin 79 [normally <
25] mol/L). Rosiglitazone was discontinued, and the man died 1 week later
from liver failure. Concurrent medications included metformin, glyburide
and amlodipine.
In the second case, a 56-year-old woman with morbid obesity and angina
had shortness of breath after using rosiglitazone for 4 months. On admission
to hospital an electrocardiogram revealed sinus tachycardia with ventricular
premature contractions. The woman died 3 weeks later. The cause of death
was listed as probable pulmonary embolism. Concomitant medications included
insulin, irbesartan, hydrochlorothiazide, megestrol acetate and diltiazem.
In the third case a 75-year-old man with a history of hypertension took
rosiglitazone for an unspecified period of time. He was admitted to hospital
because of weakness, suffered a myocardial infarction and subsequently
died. Concomitant medications included metoprolol, furosemide and potassium.
Liver and biliary disorders: In all 10 cases of liver and biliary
disorders, the reported elevated liver enzymes ranged from less than 2
to more than 3 times the upper limit of normal. The duration of treatment
with rosiglitazone ranged from a few weeks to 6 months. At least 3 patients
had known hepatic disorders when rosiglitazone treatment was added. In
most cases, there was not enough clinical information to allow a meaningful
assessment of causality. Baseline liver function test results were not
always provided.
Cardiovascular disorders: Of the 20 cases of cardiovascular disorders,
8 were of congestive heart failure or heart failure. In 5 of these cases,
onset occurred within 3 days to 6 weeks after the start of rosiglitazone
(onset unknown in 3 cases). Patients recovered without sequelae in 3 cases
(recovery unknown in 5 cases). Cases of edema without heart failure were
also reported.
Hematological disorders: The following hematological reactions
were reported in 8 cases: anemia, iron deficiency anemia, decreased hemoglobin
concentration, leucopenia, neutropenia, pancytopenia, decreased platelet
production, prolonged prothrombin time (PT) and thrombocytopenia. Edema
was reported in 3 of the 8 cases. In the case of prolonged PT, warfarin
was a concomitant medication.
To minimize the risk of hepatic and cardiovascular adverse events, physicians
are advised to adhere to all recommendations listed in the product monograph
and to exercise caution when prescribing rosiglitazone to patients with
fluid retention, hypertension, mildly elevated liver enzyme levels or
underlying cardiac conditions. Also, patients should be instructed to
watch for signs of congestive heart failure (shortness of breath, swelling
of the lower extremities) and liver problems (nausea, vomiting, stomach
pain, lack of appetite, tiredness, dark urine or yellowing of the skin).
A second thiazolidinedione drug, pioglitazone (Actos), was approved for
use in Canada on Aug. 17, 2000. At product launch, similar warnings with
respect to the potential risk of liver toxicity were issued by the sponsor.5
Health care professionals are requested to report adverse reactions associated
with rosiglitazone and pioglitazone.
Written by: Marielle McMorran, BScPharm, and Duc Vu, PhD, Bureau of Licensed
Product Assessment
References
1.Avandia TM, rosiglitazone
tablets [product monograph]. Oakville (ON): SmithKline Beecham Pharma;
2000 May 9.
2.Kassahun K, Pearson
PG, Tang W, McIntosh I, Leung K, Elmore C, et al. Studies on the metabolism
of troglitazone to reactive intermediates in vitro and in vivo. Evidence
for novel biotransformation pathways involving quinone methide formation
and thiazolidinedione ring scission. Chem Res Toxicol 2001;14(1):62-70.
3.Dear Health Care
Professional Letter: Avandia. Oakville (ON): SmithKline Beecham Pharma;
March 2000.
4.Canadian Adverse
Drug Reaction Monitoring Programme guidelines for the voluntary reporting
of adverse drug reactions by health professionals. Ottawa: Therapeutic
Products Directorate, Health Canada. Available:
http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/guide/ar-ei_guide-ldir_e.html
5.Dear Healthcare
Professional Letter: Actos. Toronto: Eli Lilly Canada Inc; September
2000.
Adverse
drug reaction reporting -- 2000: Part 2
The CADRMP received 7361 domestic reports of suspected adverse drug reactions
(ADRs) in 2000 that met the minimum criteria of an ADR report (an identifiable
reporter, a patient [even if not precisely identified], a suspect drug
and a suspect reaction).1 A steady increase
in the reporting of ADRs in Canada over the past 5 years has been noted
(Fig. 1). The continued commitment of health care
professionals to report ADRs directly affects the success of the CADRMP
and is greatly appreciated.
Of the ADR reports received in 2000, 3343 were classified as serious,
and 202 had a fatal outcome. Adverse reactions are suspected associations
that reflect the opinion or observation of the individual reporter. A
report of a drug-reaction association does not necessarily mean that the
reaction was caused by the drug. Assessment of causality, which refers
to the association between the reported reactions and the suspected drug
product(s), must include an evaluation of other factors such as temporal
associations, the possible contribution of concomitant medications or
therapies, the underlying disease and the patient's medical history.
A summary of the most frequent drug products involved in the ADR reports
is provided in Table 1. The suspect or interacting drugs
were grouped according to the American Hospital Formulary Service classification
to provide a representation by pharmacologic-therapeutic classification.
The CADRMP received 20 or more reports for each active ingredient included
in the summary.
Table 1: Suspect products*
in reports of adverse drug reactions received in 2000, grouped by AHFS
classification
| Products (AHFS classification) |
% of reports |
| Central nervous system agents (28:00) |
46.5 |
| Anti-infective agents (8:00) |
10.3 |
| Cardiovascular drugs (24:00) |
8.4 |
| Hormones and synthetic substitutes
(68:00) |
7.2 |
| Unclassified therapeutic agents
(92:00) |
7.2 |
| Gastrointestinal drugs (56:00) |
5.5 |
| Antineoplastic agents (12:00) |
5.0 |
| Blood formulation and coagulation
(20:00) |
4.9 |
| Diagnostic agents (36:00) |
2.5 |
| Skin and mucous membrane agents
(84:00) |
1.3 |
| Antihistamine drugs (4:00) |
1.1 |
Note: CADRMP = AHFS = American Hospital Formulary
Service.
*Active ingredients mentioned in > 20 reports received
in 2000.
An ADR report may contain more than one reaction. In total, 18 349 suspected
serious and nonserious reactions were reported. All were assessed and
coded according to the World Health Organization Adverse Reaction Terminology
(WHO-ART). The 10 most frequently occurring types of reactions in the
year 2000 are represented by system organ class as follows: body (general
disorders) 16.4%, gastrointestinal 11.5%, dermatological 11.2%, central
and peripheral nervous system 11.2%, psychiatric 8.7%, respiratory 7.3%,
metabolic and nutritional 5%, liver and biliary 3.6%, heart rate and rhythm
3.1%, and urinary 2.6%. Reactions that were reported a minimum of 100
times were identified and then grouped by system organ class.
For additional information or to report an ADR, physicians, pharmacists,
other health professionals and consumers are invited to contact the CADRMP.
Written by: Heather Sutcliffe, BScPharm, and Lynn Macdonald, BSP,
Bureau of Licensed Product Assessment
Reference
1. Adverse drug reaction
reporting -- 2000:Part 1. Can Adverse Drug React Newsl 2001;11(2):1.
[Also in CMAJ 2001;164(7):1038].
COMMUNIQUÉ
The CADRMP wishes to provide feedback and increase awareness of recently
reported ADRs. The following cases have been selected on the basis of
their seriousness, or the fact that the reactions do not appear in the
official Canadian product monograph. (Reactions are expressed based on
the "preferred term" in the World Health Organization Adverse Reaction
Dictionary.)
Orlistat (Xenical) interaction
with coumarin derivatives: increased INR
Unexpected increases in the international normalized ratio (INR) were
noted after the administration of orlistat to patients taking either warfarin
or nicoumalone (Sintrom). Dosage adjustments of the coumarin derivatives
or discontinuation of orlistat resulted in the INR returning to normal.
Azithromycin (Zithromax): myocardial
infarction
Chest pain was reported after a first dose of azithromycin, and myocardial
infarction following the second dose.
DRUGS
OF CURRENT INTEREST
The purpose of the Drugs of Current Interest (DOCI) list is to stimulate
reporting for a selected group of marketed drugs in order to identify
drug safety signals. The maintenance of this list by the CADRMP facilitates
regular monitoring and constitutes one element of post-approval assessment
activities.
abacavir (Ziagen)
alteplase (Activase rt-PA)
amprenavir (Agenerase)
celecoxib (Celebrex)
clopidogrel (Plavix)
delavirdine (Rescriptor)
efavirenz (Sustiva)
etanercept (Enbrel)
Hypericum perforatum
(St. John's Wort)
indinavir (Crixivan) lopinavir/ritonavir
(Kaletra)
melanoma theraccine (Melacine)
meloxicam (Mobicox)
naratriptan (Amerge)
nevirapine (Viramune)
oseltamivir (Tamiflu)
pioglitazone (ACTOS)
ritonavir (Norvir)
rituximab (Rituxan)
rofecoxib (Vioxx) rosiglitazone
(Avandia)
saquinavir (Invirase)
trastuzumab (Herceptin)
zaleplon (Starnoc)
zanamivir (Relenza)
zolmitriptan (Zomig)
If you have observed any suspected ADRs with the drugs in the Communiqué
or the DOCI list, please report them to the :
Canadian Adverse Reaction Monitoring Program (CADRMP)
Bureau of Licensed Product Assessment
AL: 0201C2, Ottawa, ON K1A 1B9
Tel: (613) 957-0337 Fax: 613 957-0335
cadrmp@hc-sc.gc.ca
or to a participating regional ADR centre.
Consumers and health professionals may contact us free of charge by
phone 866 234-2345 or fax 866 678-6789.
The ADR form is available from the Compendium of Pharmaceuticals and Specialties
and the National and Regional ADR Centres, and at:
http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/form/ar-ei_form_e.html
British Columbia
BC Regional ADR Centre
c/o BC Drug and Poison
Information Centre
1081 Burrard St.
Vancouver BC V6Z 1Y6
tel 604 806-8625
fax 604 806-8262
adr@dpic.bc.ca
Ontario
Ontario Regional ADR Centre
LonDIS Drug Information Centre
London Health Sciences Centre
339 Windermere Rd.
London ON N6A 5A5
tel 519 663-8801
fax 519 663-2968
adr@lhsc.on.ca
New Brunswick, Nova Scotia, Prince
Edward Island and Newfoundland
Atlantic Regional ADR Centre
Queen Elizabeth II Health
Sciences Centre
Drug Information Centre
Rm. 2421, 1796 Summer St.
Halifax NS B3H 3A7
tel 902 473-7171- fax 902 473-8612
rxkls1@qe2-hsc.ns.ca
Saskatchewan
Sask ADR Regional Centre
Dial Access Drug Information Service
College of Pharmacy and Nutrition
University of Saskatchewan
110 Science Place
Saskatoon SK S7N 5C9
tel 306 966-6340 or 800 667-3425
fax 306 966-6377
vogt@duke.usask.ca
Québec
Québec Regional ADR Centre
Drug Information Centre
Hôpital du Sacré-Coeur de Montréal
5400, boul. Gouin ouest
Montréal QC H4J 1C5
tel 514 338-2961, ext. 2961 or 888 265-7692
fax 514 338-3670
cip.hscm@sympatico.ca
Other provinces and territories
National ADR Unit
Adverse Reaction Review and Information Unit
Bureau of Licensed Product Assessment
Finance Building, Tunney's Pasture
AL 0201C2
Ottawa ON K1A 1B9
tel 613 957-0337
fax 613 957-0335
cadrmp@hc-sc.gc.ca
The Canadian Adverse Drug Reaction Newsletter is prepared and funded
by the Therapeutic Products Programme, Health Canada, and is published
quarterly in CMAJ. It is also online, at
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/legislation/acts-lois/gazette2/index_e.html
| Please Note: A voluntary reporting system thrives
on intuition, lateral thinking and open mindedness. Most adverse drug
reactions (ADRs) can only be considered to be suspicions, for which a
proven causal association has not been established. Because ADRs are under
reported and because a definite causal association cannot be determined,
spontaneous ADR reports cannot be used to estimate the incidence of adverse
reactions. ADRs are nevertheless valuable as a source of potential new
and undocumented signals. Health Canada does not assume liability for
the accuracy or authenticity of the ADR information contained in the newsletter
articles. Furthermore, the Therapeutic Products Programme monitors and
assesses suspected ADRs as a means of continuously evaluating drug safety
profiles. Regulatory decisions are not made within the context of this
newsletter. |
Newsletter Editors: Ann Sztuke-Fournier, BPharm, and Marielle
McMorran, BSc(Pharm), Bureau of Licensed Product Assessment.
We thank the Expert Advisory Committee on Pharmacovigilance, the ADR
Regional Centres and the Therapeutic Products Directorate for their contributions
to these articles.
© Her Majesty the Queen in Right of Canada, 2001. This publication
may be reproduced without permission provided the source is fully acknowledged.
Aussi disponible en français.
ISSN 1492-8167, Cat. No. H42-4/1-11-3E-IN
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