Canadian Adverse Reaction Newsletter
Volume 11 · Number 4 · October 2001

Marketed Health Products Directorate
Heath Products and Foods Branch

In This Issue

Antitubercular drugs: hepatobiliary reactions
Electronic subscription to the Newsletter and drug advisories 
Health professional advisories
Atypical antipsychotics: impaired glucose metabolism
Communiqué
 

Antitubercular drugs (isoniazid, rifampin and pyrazinamide): hepatobiliary reactions

According to the latest edition of the Canadian Tuberculosis Standards,¹ Canada has one of the lowest reported incidence rates of tuberculosis (TB) in the world. However, in Canada, the high-risk groups for Mycobacterium tuberculosis infection are HIV-positive people, Aboriginals, foreign-born people from countries with a high prevalence of TB, intravenous drug users and homeless people.

The Canadian Lung Association recommends 2 standard drug regimens for the treatment of TB: a combination of isoniazid (INH), rifampin (RI) and pyrazinamide (PY) (with or without ethambutol [EMB]) and a combination of INH and RI (with or without EMB).¹ Of these agents, INH, PY and RI have been associated with liver toxicity. INH and PY are considered to be major hepatotoxins, whereas RI is considered to be relatively less hepatotoxic but is a powerful enzyme inducer, which may enhance the hepatotoxicity of INH.² Severe and sometimes fatal hepatitis associated with regimens containing INH, PY and RI has been well documented. Two cases were recently published of liver failure in patients receiving combination therapy with RI and PY for latent TB; one patient died.³

The Canadian Adverse Drug Reaction Monitoring Program (CADRMP) reviewed 420 suspected domestic reports of hepatobiliary adverse reactions associated with different combinations of INH, PY and RI that were received from the time of their introduction in Canada to May 18, 2001. (Each report may have contained more than one of the following reaction terms; however, each report was included only under the most important reaction term):

· INH alone: 258 reports of hepatic reactions (7 deaths).

· PY alone: 4 reports: 2 of hepatitis, and 1 each of hepatic failure and jaundice.

· RI alone: 27 reports: 12 of jaundice, 6 of hepatitis, 5 of abnormal liver enzyme levels, 3 of hepatocellular damage (1 death), and 1 of hepatomegaly.

· INH and PY: 1 report of hepatic failure (1 death).

· INH and RI: 110 reports: 50 of abnormal liver enzyme levels (1 death), 27 of hepatitis (2 deaths), 18 of jaundice (2 deaths), 9 of hepatocellular damage (1 death), 2 each of hepatic failure and hepatomegaly, and 1 each of cholelithiasis and hepatic cirrhosis.

· RI and PY: 1 report of jaundice.

· INH, RI and PY: 19 reports: 7 of abnormal liver enzyme levels, 6 of hepatitis, 4 of jaundice and 1 each of hepatic coma and hepatic necrosis.

These reports suggest that liver toxicity may occur in patients receiving any of the drugs alone or in combination. The Canadian Tuberculosis Standards recommends baseline liver function testing when INH is used and regular monitoring only in patients who have pre-existing liver disease or a history of alcohol abuse or who are 35 years of age or older.¹ The usefulness of liver function monitoring to detect fulminant liver failure is a controversial issue and needs to be further investigated. However, health care professionals are reminded that monitoring for liver toxicity (either through liver enzyme measurement or clinical monitoring) is important during treatment with any antitubercular regimen.² It is essential to instruct patients to watch for symptoms suggestive of hepatitis (nausea, vomiting, stomach pain, lack of appetite, tiredness, dark urine or yellowing of the skin), and to stop taking their antitubercular medication and to consult their physician immediately if these symptoms occur.³

Written by: Duc Vu, PhD, and Lynn Macdonald, BSP, Bureau of Licensed Product Assessment.

References

1. Canadian Lung Association. Canadian tuberculosis standards. 5th ed. Ottawa: The Association; 2000.

2.Durand F, Jebrak G, Pessayre D, Fournier M, Bernuau J. Hepatotoxicity of antitubercular treatments: rationale for monitoring liver status. Drug Safety 1996;Dec 15(6):394-405.

3. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection. MMWR Mortal Morbid Wkly Rep 2001;50(15):289-91.

Electronic subscription to this Newsletter and drug advisories now available

You may now join the MedEffect e-Notice mailing list to subscribe electronically to this Newsletter and to receive notices of health professional advisories.

Go to:
http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/index_e.html
click "subscribe" and follow the instructions.

Health Professional Advisories

Health professional advisories are an important source of information on the post-approval safety and effectiveness of therapeutic products. The following is a list of links to recent advisories issued since June 2001 by the Therapeutic Products Directorate and the Biologics and Genetic Therapies Directorate of Health Canada and by industry:

• Aug. 17, 2001: Do not use products labelled to contain Aristolochia
• Aug. 15, 2001: Interaction between warfarin and vaginal miconazole
• Aug. 10, 2001: Voluntary withdrawal of Baycol
• Aug. 8, 2001: Market withdrawal of Baycol (cerivastatin)
• July 16, 2001: Cerivastatin (Baycol) and gemfibrozil - increased risk of rhabdomyolysis -- concomitant use contraindicated
• July 10, 2001: Clinically important safety labelling change for prescription strength of famotidine: dosage adjustments for patients with moderate and severe renal impairment
• July 9, 2001: Risk of severe liver injury associated with use of the antidepressant Nefazodone
• July 4, 2001: Important safety information on Amiodarone Intravenous
• July 3, 2001: Important safety information regarding bupropion (Zyban, Wellbutrin)
• June 28, 2001: Important safety information regarding Nefazodone HCl: severe and serious hepatic events
• June 20, 2001: Important safety information on Nefazodone HCl (from Bristol-Myers Squibb Canada Inc. and Linson Pharma Inc.)
• June 19, 2001: Hydroview IOL lens product (from Bausch & Lomb Canada Inc.)
• June 14, 2001: Advisory not to use products containing Ephedra or ephedrine
• June 2001: Drug products containing phenylpropanolamine: updated list

Atypical antipsychotics: impaired glucose metabolism

The new atypical antispychotics clozapine, olanzapine, quetiapine and risperidone are among the first-line treatments for managing psychotic disorders, mainly because they are associated with superior effectiveness in controlling the negative symptoms (blunted affect, emotional and social withdrawal) of schizophrenia.¹ Some atypical antipsychotics have been associated with impaired glucose metabolism.² Since 1994, there have been at least 29 published cases of impaired glucose metabolism associated with the use of clozapine and 26 with olanzapine^2,3 (other references are available upon request). Since February 1999, there have been 2 published cases in which risperidone was associated with diabetic ketoacidosis or elevated blood glucose levels,^4,5 and 2 published cases of new-onset diabetes mellitus with quetiapine.^2,6 In 1999, the results of a cross-sectional study revealed a possible association between type 2 diabetes and antipsychotics.⁷ Specifically, diabetes was diagnosed in 15.5% of schizophrenic patients treated with clozapine, 11% of those treated with olanzapine and 6% of those treated with risperidone.⁷

Clozapine, olanzapine, quetiapine and risperidone were introduced in Canada in 1991, 1996, 1997 and 1993 respectively. By June 7, 2001, a total of 37 domestic case reports of suspected impaired glucose metabolism associated with these drugs were reported to the Canadian Adverse Drug Reaction Monitoring Program. Patient characteristics and important adverse reactions are summarized in Tables 1 and 2 respectively.

In 17 of the 37 cases, the reactions occurred within 5 months of treatment onset. Similarly, in published cases, impaired glucose metabolism associated with atypical antipsychotics often occurred relatively soon following the start of treatment (i.e., in as little as 10 days with clozapine, 15 days with olanzapine and 1 month with quetiapine).² Of the 35 reports in which disorders of hyperglycemia were denoted, there were 4 cases of pre-existing diabetes; 24 cases were considered to be new onset on the basis of the evidence in the report, with 14 clearly noted as being new-onset diabetes mellitus. One of the cases occurred 2 weeks after discontinuation of risperidone therapy and involved an intentional overdose. There were 2 reports of hypoglycemia; both patients had a prior history of diabetes before this reaction.

Of the 10 cases in which "diabetic ketoacidosis" or "ketoacidosis" was reported (Table 2), the possibility of alcohol consumption or substance use was noted in 4 cases, and abnormal liver function test results were reported in 2 cases. Three of these 10 patients died.

Schizophrenic patients may be predisposed to diabetes mellitus and associated disorders due to factors such as reduced physical activity, poor diet and co-existing illnesses.⁸ In addition, the involvement of concomitant medications such as divalproex sodium,^9,10 lithium¹⁰ and other drugs metabolized by the liver^11,12 cannot be ruled out as contributing to the abnormal glucose metabolism associated with clozapine^12,13 or olanzapine.^10,11 Other risk factors for hyperglycemia or ketoacidosis in patients taking clozapine or olanzapine may include being male, non-White and age of about 40 years.¹⁴

Obesity is another major risk factor for diabetes.¹⁴ Among the Canadian reports, there was a case of a 33-year-old man who took olanzapine (15 mg/d) and gained between 22 and 45 kg over 1 year after starting olanzapine therapy. It was reported that diabetes developed as a result of this weight gain.

It has been speculated that multiple receptor antagonism (dopamine, serotonin, histamine) may be involved in the development of non-insulin-dependent diabetes mellitus associated with atypical antipsychotics.² Specifically, antagonism of histaminic and possibly serotonergic receptors may induce weight gain, which in turn, may lead to changes in glucose metabolism, and that these changes may have a causal role in neuroleptic-induced hyperglycemia.¹¹ Serotonin antagonism may decrease the responsiveness of pancreatic -cells, which would result in low insulin levels and ensuing hyperglycemia.¹¹ Diabetes induced by atypical antipsychotics may be attributed to multiple factors, and the mechanism of action remains unclear.²

Atypical antipsychotics may be associated with new-onset diabetes mellitus and diabetic ketoacidosis. Patients may require glucose monitoring upon initiation and titration of antipsychotic medications, and regular monitoring thereafter.^15,16

Written by: Jenna Griffiths, MSc, PhD, and Pascale Springuel, BPharm, Bureau of Licensed Product Assessment.

References

1.Markowitz JS, Brown CS, Moore TR. Atypical antipsychotics. Part 1: pharmacology, pharmacokinetics, and efficacy. Ann Pharmacother 1999;33:73-85.

2. Liebzeit KA, Markowtiz JS, Caley CF. New onset diabetes and atypical antipsychotics. Eur Neuropsychopharm 2001;11:25-32.

3. Wehring H, Alexander B, Perry PJ. Diabetes mellitus associated with clozapine therapy. Pharmacotherapy 2000;20(7):844-7.

4. Croarkin PE, Jacobs KM, Bain BK. Diabetic ketoacidosis associated with risperidone treatment? Psychosomatics 2000;41:369-70.

5.Mohan D, Gordon H, Hindley N, Barker A. Schizophrenia and diabetes mellitus. Br J Psychiatry 1999;174:180-1.

6.Procyshyn R. New-onset diabetes mellitus associated with quetiapine. Can J Psychiatry 2000;45(7):668-9.

7.Zoler ML. Antipsychotics linked to weight gain, diabetes. Clin Psychiatr News 1999;27(2):20.

8.Mukhergee S, Decina P, Bocola V, Saraceni F, Scapicchio PL. Diabetes mellitus in schizophrenic patients. Compr Psychiatry 1996;37(1):68-73.

9. Isakov I, Klesmer J, Masand PS. Insulin-resistant hyperglycemia induced by clozapine. Psychosomatics 2000;41(4):373-4.

10. Bonanno DG, Davydov L, Botts SR. Olanzapine-induced diabetes mellitus. Ann Pharmacother 2001;35:563-5.

11. Goldstein LE, Sporn J, Brown S, Kim H, Finkelstein J, Gaffey GK, et al. New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics 1999;40(5):438-43.

12.Kamran A, Doraiswamy PM, Jane JL, Hammett EV, Dunn L. Severe hyperglycemia associated with high dose of clozapine. Am J Psychiatry 1994;151(9):1395.

13.Koval MS, Rames LJ, Christie S. Diabetic ketoacidosis associated with clozapine treatment. Am J Psychiatry 1994;151(10):1520-1.

14.Mir S, Taylor D. Atypical antipsychotics and hyperglycemia. Int Clin Psychopharmacol 2001;16(2):63-74.

15.Haupt DW, Newcomer JW. Risperidone-associated diabetic ketoacidosis. Psychosomatics 2001;42:279-80.

16.McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry 2001;46:273-81.

Table 1:  Characteristics of patients with impaired glucose metabolism associated with atypical antipsychotics reported to the CADRMP as of June 7, 2001*

Characteristic	Clozapine n = 17+	Olanzapine n = 10	Quetiapine n = 3§	Risperidone n = 7
Mean age (and range), yr	45 (26-74)	34 (26-46)	30 (30)¶	48 (11-78)
Female:male ratio	6:10**	4:6	0:2**	6:1
Period of onset of impaired glucose metabolism	18 d to 6.5 yr	11 d to 5 yr	2.5 to 4 mo	2 d to 8 mo++
Daily dose of atypical antipsychotic	100 to 775 mg	7.5 to 30 mg	300 to 700 mg	1 to 6 mg++
Maximum recommended daily dose	900 mg	20 mg	750 mg	6 mg

Note: CADRMP = Canadian Adverse Drug Reaction Monitoring Program.
*These data cannot be used to determine the incidence of ADRs because neither the prescribing rate nor the amount of time the drug was on the market has been taken into consideration. Also, see caveat at the end of the newsletter.
⁺Concomitant medication was risperidone (6 mg/d) in 1 case.
Clozapine and olanzapine were reported as co-suspect medications in 1 case report, but from the evidence provided, olanzapine was considered the suspect drug.
§Quetiapine and risperidone were reported as co-suspect medications in 1 case report, but from the evidence provided, quetiapine was considered the suspect drug.
¶Age not specified in 1 case.
**Sex not specified in 1 case.
⁺⁺Case of overdose not included.

Table 2: Glucose-related reaction terms reported in the Canadian case reports associated with clozapine, olanzapine, quetiapine, risperidone

Drug; no. of reports

Reaction term *	Clozapine	Olanzapine	Quetiapine	Risperidone
Coma diabetic	-	2	-	-
Diabetes mellitus	8	2	1	1
Diabetic ketoacidosis/ ketoacidosis+	5	3	2	-
Hyperglycemia	4	3	-	3
Hypoglycemia	-	-	-	2
Labile blood sugar+	-	-	-	1

^*Based on the "preferred term" of the World Health Organization (WHO) Adverse Reaction Dictionary (WHOART). Each report may contain more than 1 of these reaction terms, however, reports were only included in the most significant category.
⁺Terminology other than WHO "preferred term" was used.
One case also involved "coma diabetic."

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.)

Brimonidine (Alphagan) ophthalmic drops: accidental ingestion

Accidental oral ingestion of brimonidine ophthalmic drops (about 2 mL) in a 28-month-old child caused decreased consciousness and apnea resulting in intubation, ventilation and surveillance in an intensive care unit for 40 hours. Recommendations for child-resistant packaging were made to the manufacturer. As an immediate option to reduce the risk of accidental exposure, consider dispensing these ophthalmic drops in childproof vials.

If you have observed any suspected ADRs with the drugs in the Communiqué or the DOCI list, please report them to the :

Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Adverse Reaction Information Unit
Bureau of Licensed Product Assessment
AL: 0201C2, Ottawa, ON K1A 1B9
Tel: (613) 957-0337 Fax: 613 957-0335
Consumers and Health Professionals may contact us Toll free at:
Tel: 866 234-2345, Fax: 866 678-6789
Email: cadrmp@hc-sc.gc.ca

The ADR form is available from the Compendium of Pharmaceuticals and Specialties and the National and Regional ADR Centres, and at:

ADR Reporting Form
ADR Guidelines

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@dpic.bc.ca

New Brunswick, Nova Scotia, Prince
Edward Island and Newfoundland
Atlantic Regional ADR Centre
C/O Queen Elizabeth II Health
  Sciences Centre
Drug Information Centre
1796 Summer St., Rm. 2421
Halifax NS B3H 3A7
Tel 902 473-7171
Fax 902 473-8612
adr@cdha.nshealth.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
FSax 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 or
888 265-7692
Fax 514 338-3670
cip.hscm@sympatico.ca

Other provinces and territories
CADRMP
National ADR 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

Health Professionals and Consumers may report Adverse Drug Reactions toll-free:
Tel: 866 234-2345
Fax: 866 678-6789

The Canadian Adverse Drug Reaction Newsletter is prepared and funded by the Therapeutic Products Directorate, Health Canada, and is published quarterly in CMAJ. It is also online, at

http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/publicat.html

Newsletter Editors: Ann Sztuke-Fournier, BPharm, and Marielle McMorran, BScPharm, 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.

ISSN 1492-8167, Cat. No. H42-4/1-11-4E-IN