Canadian Adverse Reaction Newsletter
Volume 13, Number 3, July 2003
Marketed Health Products Directorate, Health Products and Foods Branch
In This Issue
Gatifloxacin (Tequin™): hypoglycemia and hyperglycemia
Serotonin syndrome
Summary of advisories
Case presentation: red yeast rice and rhabdomyolysis
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.
Newsletter and Advisories by email
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Gatifloxacin (Tequin™): hypoglycemia and hyperglycemia
Gatifloxacin (Tequin™) is a broad-spectrum antibacterial fluoroquinolone
with activity against gram-negative and gram-positive aerobic and anaerobic
microorganisms and is also effective against clinically important atypical
microorganisms.1 Health Canada's database
of spontaneous reports of adverse reactions indicates that hypoglycemia
and hyperglycemia have been reported more frequently with gatifloxacin
than with other quinolone antibiotics. Case reports of hypoglycemia associated
with gatifloxacin have also been published.2-5
The Canadian product monograph for Tequin™ was recently updated in
response to reported cases of serious, and in some cases life-threatening,
disturbances of glucose homeostasis.1
Health Canada received 28 reports of abnormal glucose metabolism associated
with gatifloxacin (44% of total reports received for the drug) from Feb.
21, 2001 (the date marketed in Canada), to Feb. 28, 2003: 19 were of hypoglycemia,
7 were of hyperglycemia and 2 were of both hypoglycemia and hyperglycemia
(Table 1). Twenty-five of the cases involved patients
with type 2 diabetes (determined from the patient's history or use of
concomitant medications), 2 involved nondiabetic patients, and in 1 case
the diabetic status was unknown. The 28 cases were serious, and 19 of
the patients were admitted to hospital or had a prolonged hospital stay
because of the reaction. The 2 patients who died (86 and 102 years of
age) had hyperglycemia, no prior history of diabetes and decreased renal
function at the time of the reaction.
Concomitant use of hypoglycemic agents was noted in 18 of the 19 cases
in which a hypoglycemic reaction was reported. The exact mechanism of
hypoglycemia is unknown, but some hypotheses include a possible increase
in the serum insulin level following the administration of gatifloxacin
or the existence of a possible interaction between glyburide and gatifloxacin.2-5
A postmarketing study of gatifloxacin involving more than 15 000 patients
reported an incidence of hypoglycemic events of 0.3 per 1000 among nondiabetic
patients and 6.4 per 1000 among diabetic patients.1
The corresponding rates for hyperglycemia were 0.07 per 1000 and 13 per
1000. All of these cases were reversible with appropriate treatment, which
included the discontinuation of gatifloxacin.1
Key points1
- Hypoglycemia and hyperglycemia have been reported following the use
of gatifloxacin, usually but not always in diabetic patients.
- Hypoglycemic reactions frequently occurred within the first day of
therapy and usually within 3 days. These reactions were reported in
diabetic patients receiving either sulfonylurea or non-sulfonylurea
oral hypoglycemic medications.
- Most hyperglycemic reactions occurred 4 to 10 days after the start
of therapy; very elderly patients (> 75 years of age) who may have
unrecognized diabetes, age-related decrease in renal function or underlying
medical problems or are taking concomitant medications associated with
hyperglycemia may be at particular risk.
- Blood glucose levels should be monitored carefully when gatifloxacin
is used in diabetic patients.
- Gatifloxacin therapy should be stopped and appropriate treatment started
immediately if any signs or symptoms of hypoglycemia or hyperglycemia
appear.
- Gatifloxacin is mainly eliminated by the kidneys; therefore, a reduced
dosage is recommended in patients with a creatinine clearance of less
than 0.67 mL/s (40 mL/min).
- Patients should be educated about these possible adverse reactions
with gatifloxacin.
Geneviève Létourneau, BPharm, Québec Regional AR Centre; Heather Morrison,
BSc, MLIS; Marielle McMorran, BSc, BSc(Pharm), Health Canada
References
1. Tequin™, gatifloxacin tablets [product monograph].
Montreal: Bristol-Myers Squibb Canada Inc.; 2002 Dec 24.
2. Parilo MA. Gatifloxacin-associated hypoglycemia.
J Pharm Technol 2002;18:319-20.
3. Hussein G, Perkins LT, Sternberg M, Bland C. Gatifloxacin-induced hypoglycemia:
a case report and review of the literature. Clin Res Regul Aff
2002;19(4):333-9.
4. Baker SE, Hangii MC. Possible gatifloxacin-induced hypoglycemia. Ann
Pharmacother 2002;36:1722-6.
5. Menzies DJ, Dorsainvil PA, Cunha BA, Johnson DH. Severe and persistent
hypoglycemia due to gatifloxacin interaction with oral hypoglycemia agents.
Am J Med 2002;113(3):232-4.
6. Meltzer S, Leiter L, Daneman D, Gerstein HC, Lau
D, Ludwig S, et al. 1998 clinical practice guidelines for the management
of diabetes in Canada. CMAJ 1998;159(8 Suppl):S1-29.
Table 1: Reports submitted to Health Canada of
suspected adverse reactions (ARs) of hypoglycemia and hyperglycemia associated
with gatifloxacin (Tequin™) from Feb. 21, 2001, to Feb. 28, 2003*
|
Variable
|
Hypoglycemia
n = 19
|
Hyperglycemia
n = 7
|
Hypoglycemia
and
hyperglycemia
n = 2
|
|
| Mean age (and range) of patients, yr |
74 (49–87)
|
75 (52–102)
|
70 (61–79)
|
| Female:male ratio |
1:1
|
4:3
|
1:1
|
| Blood glucose values reported, mmol/L† |
1.4-3.8
|
15-58
|
3.0-14
|
| Onset of reaction after start of gatifloxacin
therapy (no. of reports) |
< 24 h (16)
24–72 h (2)
> 72 h (1)
|
< 4 d (3)
4–10 d (4)
|
< 24 h (2)
|
| Reaction terms reported‡ (no. of reactions) |
Hypoglycemia (18), tremor (2), hypoglycemic coma
(1), NPN (serum creatinine) increased (1), confusion (1), paresthesia
(1), dyspnea (1), nausea (1), convulsions (1), ataxia (1)
|
Hyperglycemia (7), dehydration (2), plasma osmolality
increased (2), NPN (serum creatinine) increased (2), renal function
abnormal (2), diabetic coma (1), malaise (1), electrolyte abnormality
(1), respiratory insufficiency (1), tachycardia (1), atelectasis
(1), bundle branch block (1), cardiac failure (1), confusion (1),
polydipsia (1), polyuria (1), nausea (1)
|
Hypoglycemia (2), hyperglycemia (2)
|
| Outcome reported (no. of reports) |
Recovered: 17
Unknown: 2
|
Recovered: 5
Death: 2
|
Recovered : 1
Not yet recovered: 1
|
| History of diabetes (no. of reports) |
Type 2: 18
Unknown: 1
|
Type 2: 5
None: 2
|
Type 2: 2
|
Concomitant use of hypoglycemic agent,
no. of reports§ |
18
|
2
|
2
|
| Creatinine clearance < 0.67 mL/s (40 mL/min),
no. of reports¶ |
8
|
3
|
---
|
*These data cannot be used to determine the incidence of ARs
because ARs remain underreported and total patient exposure is unknown.
†Normal range for fasting or before-meal glucose level is 3.8–6.1
mmol/L in nondiabetic patients; target range in diabetic patients
is 4–7 mmol/L.6
‡Several reaction terms may be listed per AR report. Reaction terms
are based on the "preferred term" of the World Health Organization
(WHO) Adverse Reaction Dictionary (WHOART).
§Hypoglycemic agents: glyburide, glicazide, tolbutamide or insulin.
¶Renal function was reported in 13 of the 28 cases: decreased renal
function (11), renal function in normal range (2) and unknown (15).
|
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening disorder of excessive
serotonergic activity. It usually occurs when 2 or more serotonin-modifying
agents are used in combination, but it has also been reported with the
use of a single agent.1 For example, the
concomitant use of meperidine, certain migraine medications (e.g., triptans),
dextromethorphan (DM) and sibutramine can potentially precipitate symptoms
of serotonin excess in patients being treated with selective serotonin
reuptake inhibitors (SSRIs).2,3
Table 1 lists some of the products that enhance
serotonergic activity.
From Jan. 1, 1998, to Dec. 30, 2002, Health Canada received 53 reports
of suspected serotonin syndrome. Serotonin syndrome was most often reported
with the use of SSRIs (33), monoamine oxidase inhibitors (MAOIs) (10)
and venlafaxine (9). Some of these reports involved combinations of these
drugs. Four of the 53 cases were fatal.
Serotonin syndrome often presents soon after initiation of, or changes
in, serotonergic therapy, with an onset of < 24 hours in about 75% of
patients.1,2,4
The syndrome is diagnosed on a clinical basis where there is known exposure
to serotonergic agents, demonstration of specific signs and symptoms and
exclusion of other medical and psychiatric conditions.1,5
The clinical presentation is usually marked by the triad of cognitive
or behavioural changes (confusion, agitation, lethargy, coma), autonomic
instability (hyperthermia, tachycardia, diaphoresis, nausea, vomiting,
diarrhea, dilated pupils) and neuromuscular changes (myoclonus, hyperreflexia,
tremor).1,4,5
There is a broad range in both the severity and constellation of symptoms.2
Similarities between serotonin syndrome and neuroleptic malignant syndrome
can present the clinician with a diagnostic challenge when serotonergic
and neuroleptic drugs are used concurrently.2 Serotonin syndrome is often
self-limited with a good outcome, particularly if it is recognized early,
therapy with the suspected serotonergic agent(s) is discontinued and supportive
care is provided.1,4
Serotonin (5-hydroxytryptamine, 5-HT) levels are increased by various
mechanisms (e.g., increased 5-HT synthesis, increased 5-HT release, inhibition
of 5-HT reuptake, inhibition of 5-HT metabolism, postsynaptic receptor
stimulation).2 Interactions in which drugs,
herbal products or foods inhibit the metabolism and excretion of serotonergic
agents may also precipitate serotonin syndrome by increasing the concentration
of these serotonergic drugs (e.g., serotonin syndrome was reported after
concomitant use of citalopram and clarithromycin6).
Symptoms of serotonin syndrome have also been reported with the concomitant
use of 5-HT3 receptor antagonists (e.g., dolasetron, granisetron,
ondansetron) with serotonergic agents (e.g., fentanyl, mirtazapine, paroxetine,
sertraline).7,8 In addition,
possible serotonin toxicity after withdrawal of clozapine, a 5-HT2A
receptor antagonist, in a patient taking a serotonergic agent (clomipramine)
has been reported.9
Case example: sibutramine and serotonin syndrome
Meridia® (sibutramine), a serotonin and norepinephrine reuptake
inhibitor, is an antiobesity agent.3 Health
Canada received 87 reports of suspected adverse reactions associated with
the use of sibutramine from February 2001, when it was marketed in Canada,
to Dec. 31, 2002. Three of the 87 cases reported serotonin syndrome. In
one case, sibutramine was taken concomitantly with fluoxetine. In the
second case, sibutramine was taken with sertraline but the sertraline
was stopped 2 days before the symptoms appeared. In the third case, no
concomitant drugs were reported. There were no reports of a fatal outcome.
Concomitant use of sibutramine and other agents with serotonergic activity
such as MAOIs, centrally acting drugs for the treatment of psychiatric
disorders (e.g., antidepressants, antipsychotics) or herbal remedies (e.g.,
St. John's wort) is contraindicated in the Canadian product monograph
for Meridia®.3 At least 14 days
should elapse between discontinuation of these drugs and initiation of
treatment with sibutramine.3 A 5-week discontinuation
period is required for fluoxetine.3 Despite
these contraindications, 8 of the 87 cases involving sibutramine reported
the concomitant use of SSRIs (citalopram [1], fluoxetine [1], fluvoxamine
[1], sertraline [3]) and other serotonergic drugs (amitriptyline [1],
lithium [1]).
Key points:
- Successful management of serotonin syndrome relies on prevention,
early recognition, prompt treatment by the discontinuation of the suspected
serotonergic agent(s) and institution of supportive care.1,5
- The concomitant use of agents that inhibit the metabolism of a serotonergic
drug, thus causing its accumulation, should be considered as a potential
precipitating factor for serotonin syndrome.
- Health care professionals are encouraged to consult the product monographs
of serotonergic agents for contraindications and for recommendations
for washout periods when switching serotonergic agents.
Pascale Springuel, BPharm; Marielle McMorran, BSc, BScPharm, Health Canada
References
1. Mason PJ, Morris VA,
Balcezak TJ. Serotonin syndrome presentation of 2 cases and review of
the literature. Medicine 2000;79:201-9.
2. Ener RA, Meglathery SB, VanDecker WA, Gallagher
RM. Serotonin syndrome and other serotonergic disorders. Pain Medicine
2003;4(1):63-74.
3. Meridia®, sibutramine hydrochloride
monohydrate capsules [product monograph]. Saint-Laurent (QC): Abbott
Laboratories Ltd; 2002 Sept 6.
4. Langford NJ. Serotonin syndrome. Adverse Drug
React Bull 2002;217:831-4.
5. Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin
syndrome: a brief review. CMAJ 2003;168(11):1439-42.
6. Citalopram (Celexa) and clarithromycin (Biaxin):
interaction. Health Canada's Can
Adverse Drug React Newsl 2000;10(3):4. [Also in CMAJ 2000;163(1):88.]
7. Turkel SB, Nadala JG, Wincor MZ. Possible serotonin
syndrome in association with 5-HT3 antagonist agents. Psychosomatics
2001;42(3):258-60
8. Sorscher SM. Probable serotonin syndrome variant
in a patient receiving a selective serotonin reuptake inhibitor and a
5-HT3 receptor antagonist. J Psychopharmacol 2002;16(2):191.
9. Zerjav-Lacombe S, Dewan V. Possible serotonin syndrome
associated with clomipramine after withdrawal of clozapine. Ann Pharmacother
2001;35(2):180-2.
10. Linden CH, Burns MJ. Poisoning and drug overdosage.
In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL,
editors. Harrison's principles of internal medicine. 15th ed. New
York: McGraw-Hill; 2001. p. 2595-2616.
11. Serotonin syndrome. In: Chang W, Hurlbut KM, POISINDEX
Editorial Staff. Serotonin syndrome — toxicological managements.
POISINDEX System. Greenwood Village (CO): Micromedex; 1974-2003.
12. Duggal HS, Fetchko J. Serotonin syndrome and atypical
antipsychotics [letter]. Am J Psychiatry 2002;159(4):672-3.
Table 1: Products that enhance serotonergic activity*
Analgesics
Codeine, fentanyl, meperidine, pentazocine
Antidepressants
MAOIs
Moclobemide, phenelzine, tranylcypromine
SSRIs
Citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
Tricyclic antidepressants
Amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline
Other
Bupropion, mirtazapine, nefazodone, trazodone, venlafaxine
Antiparkinsonians
Amantadine, bromocriptine, levodopa, selegiline
Illicit drugs
Cocaine, hallucinogenic amphetamines such as, but not limited to, MDMA
("ectasy"), LSD, mescaline
Migraine therapy
Dihydroergotamine, naratriptan, rizatriptan, sumatriptan, zolmitriptan
Miscellaneous
Brompheniramine, buspirone, carbamazepine, dextramphetamine, dextromethorphan,
L-tryptophan, lithium, phentermine, reserpine, sibutramine, St. John's
wort, tetrabenazine
Note: Serotonin syndrome has also been reported
with dextropropoxyphene, droperidol and metoclopramide,1
linezolid,4 and 5-HT3 antagonists
(dolasetron, granisetron, ondansetron).7,8
There are reports of atypical antipsychotics (clozapine, olanzapine, risperidone)
associated with serotonin syndrome when used in combination with serotonergic
agents.1,9,12
Note: MAOI = monoamine oxidase inhibitor, SSRI = selective serotonin reuptake
inhibitor, MDMA = methylenedioxy-methamphetamine, LSD = lysergic acid
diethylamide.
*This list is not inclusive, some products not marketed in Canada (e.g.,
dexfenfluramine, fenfluramine, isocarboxazide, tramadol) are not included.
This list was developed from information in references 1, 2, 10 and 11.
Summary of health professional
and consumer advisories posted since Feb. 18, 2003.
Click here to view the advisories.
|
| Date |
Product |
Subject and type |
| May 27 |
Hua Fo / Vigor-Max |
Health Canada warns public not
to use Hua Fo Vigor-Max
— consumer
information |
| May 23 |
Servo 300/300A
ventilators |
Important advisory to users of
Siemens Servo 300 / 300A ventilators — Siemens Canada Ltd.
— health
professional advisory |
| May 8 |
Seavite |
Health Canada advises against
use of Seavite products containing iodine
— consumer
information |
| Apr 29 |
SARS |
Health Canada is advising Canadians
to be wary of products with claims concerning the prevention or treatment
of SARS
— consumer
information |
| Apr 28 & 2 |
Diathermy therapy |
Health Canada is advising Canadians
of a dangerous interaction between diathermy therapy and implanted
metallic leads
— notice
to hospitals and consumer
information |
| Apr 17 & 14 |
Permax® |
Important safety information regarding
Permax® (pergolide mesylate) and
cardiac valvulopathy — Eli Lilly Canada Inc. and Draxis Health
Inc.
— health
professional advisory and consumer
information |
| Apr 10 |
Diane®-35 |
Important safety information about
Diane®-35 and the risk of venous
thromboembolism — Berlex Canada Inc.
— health
professional advisory and consumer
information |
| Apr 1 |
Fragmin® |
Clarification of dosing recommendations
for Fragmin® (dalteparin sodium
injection) — Pharmacia Canada Inc.
— health
professional advisory |
| Mar 18 |
Diethylstilbestrol
(DES) |
Advisory on diethylstilbestrol
(DES) and the risk of genital and
obstetrical complications
— health
professional advisory |
| Mar 12 |
Ethyol® |
Important safety information regarding
Ethyol® (amifostine) and severe
cutaneous reactions
— health
professional advisory |
| Mar 5 & Feb 28 |
Zoloft™ |
New safety information associated
with the use of Zoloft™ in patients taking
pimozide — Pfizer Canada Inc.
— health
professional advisory and consumer
information |
| Feb 28 |
Meridia® |
Health Canada reports back to
public on safety profile of Meridia® (sibutramine)
— consumer
information |
| Feb 19 |
Rapamune® |
New warning regarding Rapamune®
(sirolimus) and bronchial anastomotic
dehiscence including fatal cases — Wyeth Pharmaceuticals
— health
professional advisory |
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Case Presentation
Recent cases are selected based on their seriousness, frequency of occurrence
or the fact that the reactions are unexpected. Please report similar reactions.
Red yeast rice and rhabdomyolysis
A published case report of rhabdomyolysis in a stable 28-year-old female
renal transplant recipient was attributed to the presence of red yeast
rice (Monascus purpureus) in an herbal preparation.1
Her post-transplant problems included hypertension, hyperlipidemia and
obesity. The patient had a baseline serum creatinine value of 150 µmol/L
(normally 60–120 µmol/L) and was taking cyclosporine, azathioprine,
prednisone, enalapril, long-acting diltiazem and famotidine. She refused
statin therapy when dietary intervention failed to lower her lipid levels.
Without informing her health care professionals, the patient started consuming
an herbal preparation containing rice fermented with red yeast, ß-sitosterol,
dan shen root (Salvia miltiorrhiza) and garlic bulb (Allium
sativum) in an attempt to lower her cholesterol "naturally."
Routine blood work demonstrated a serum creatine phosphokinase (CPK) value
of 1050 U/L (normally < 130 U/L). A repeat test showed a CPK value
of 2600 U/L, but the patient denied any muscular symptoms. Upon further
questioning, she admitted to taking the herbal preparation for the previous
2 months and was instructed to discontinue its use. The CPK value declined
to 600 U/L in 2 weeks, and she remained clinically well.
Rice fermented with red yeast contains several types of mevinic acids,
including monacolin K, which is identical to lovastatin. Lovastatin is
known to be associated with myopathy and increases in CPK levels. Cyclosporine
is known to interfere with the metabolism of some statins through the
cytochrome P450 isoform 3A4 in the liver, thus resulting in increased
statin levels. The authors postulated that this interaction resulted in
the adverse effect seen in this patient.1
Reference
1. Prasad GVR, Wong T, Meliton
G, Bhaloo S. Rhabdomyolysis due to red yeast rice (Monascus purpureus)
in a renal transplant recipient. Transplantation 2002;74(8):1200-1.
How to report adverse reactions
To report a suspected adverse reaction (AR) to therapeutic products marketed
in Canada, health professionals should complete a copy of the AR
Reporting Form and forward it to the appropriate Regional
AR Centre by mail or by toll free fax (866 678-6789). Copies of the
form are also available from your Regional
AR Centre or the National
AR Centre, and the Canadian Compendium of Pharmaceuticals and Specialties
(CPS).
Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
AL 0201C2
Ottawa ON K1A 1B9
Tel 613 957-0337
Fax 613 957-0335
Health professionals/consumers report toll free:
Tel 866 234-2345
Fax 866 678-6789
Email: cadrmp@hc-sc.gc.ca
Editors
Ann Sztuke-Fournier, BPharm
Marielle McMorran, BSc, BScPharm
Acknowledgements
Expert Advisory Committee on Pharmacovigilance, AR Regional 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, 2003. 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 H42-4/1-13-3E
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.
|
