Canadian Adverse Reaction Newsletter

Date: 2007-01-02

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

---

Contact
MHPD-DPSC

---

Canadian Adverse Reaction Newsletter

Volume 17 . Issue 1 . January 2007

Health Products and Food Branch
Marketed Health Products Directorate

In this Issue:
Levofloxacin: dysglycemia and liver disorders
Domperidone: heart rate and rhythm disorders
Case presentation: Green tea extract and hepatotoxicity
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 Monitoring Office free of charge
Phone: 866 234-2345
Fax: 866 678-6789

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.

Levofloxacin: dysglycemia and liver disorders

Levofloxacin, marketed in Canada since 1997, is a broad-spectrum fluoroquinolone antibiotic that is indicated for the treatment of certain respiratory tract, skin and urinary tract bacterial infections in adults.¹ Dysglycemia^2-4 and liver disorders^5,6 in association with levofloxacin have been reported in the literature.

From Jan. 1, 1997, to June 30, 2006, Health Canada received 22 domestic reports of dysglycemia suspected of being associated with levofloxacin. Described dysglycemic adverse reactions (ARs) included 1 report of diabetes mellitus, 2 reports of hyperglycemia alone, 16 of hypoglycemia alone and 3 of hyperglycemia and hypoglycemia combined. The majority of reported cases of dysglycemia involved patients with diabetes (15/22 [68%]), and the median age (for all cases that reported an age) was 71 years (range 26-92 years).

It is postulated that one of the mechanisms behind the development of hypoglycemia with levofloxacin may involve the inhibition of pancreatic β-cell potassium channels. This inhibition results in the release of insulin, which in turn could result in hypoglycemia.⁷ Disturbances of blood glucose levels are labelled in the product monograph.¹

With regards to liver disorders, from Jan. 1, 1997, to June 30, 2006, Health Canada received 44 domestic reports of liver and biliary disorders suspected of being associated with levofloxacin. Of these 44 cases, there were 5 cases of hepatic failure, 9 of hepatitis and 1 of hepatorenal syndrome. Five of these 15 cases of liver disorders were fatal. The remaining 29 reports included ARs of increased liver enzyme levels, cholestatic hepatitis and jaundice. The median time to onset of the 44 ARs was 5 days (range 1-39 days), which can be considered a short to intermediate time to onset. The median age (for all cases that reported an age) was 48.5 years (range 19-84 years). Liver and biliary disorders are labelled in the product monograph.¹

The mechanisms leading to the development of liver disorders with levofloxacin are not well defined. Although drug-induced liver diseases can mimic all forms of acute and chronic hepatobiliary diseases, a particular drug generally has a characteristic clinical and pathological signature and latency period when liver injury occurs. Most drug-induced liver disorders are similar to acute hepatitis, cholestasis, or mixed presentation.⁸ In the 44 cases reported to Health Canada, where sufficient information was provided, cases of hepatocellular, cholestatic and mixed liver injuries were observed. Drug-induced toxic effects are a common cause of liver injury. The early identification of an AR can prevent the occurrence of irreversible liver damage.⁸

Health Canada will continue to monitor ARs suspected of being associated with levofloxacin. Health care professionals are encouraged to report any cases of dysglycemia or liver disorder in patients receiving levofloxacin.

Melissa Hunt, BScH, MSc, Health Canada

References

1. Levaquin (levofloxacin) [product monograph]. Toronto: Janssen-Ortho Inc.; 2006.
2. Park-Wyllie LY, Juurlink DN, Kopp A, et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med 2006;354(13):1352-61. [ PubMed]
3. Friedrich LV, Dougherty R. Fatal hypoglycemia associated with levofloxacin. Pharmacotherapy 2004;24(12):1807-12. [ PubMed]
4. Garon N, Cloutier I. Une hypoglycémie associée à la lévofloxacine (Levaquin). Québec Pharmacie 2001;48(1):71-4.
5. Papastavros T, Dolovich LR, Holbrook A, et al. Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis. CMAJ 2002;167(2):131-6. [ PubMed]
6. Schwalm JD, Lee CH. Acute hepatitis associated with oral levofloxacin therapy in a hemodialysis patient. CMAJ 2003;168(7):847-8. [ PubMed]
7. Saraya A, Yokokura M, Gonoi T, et al. Effects of fluoroquinolones on insulin secretion and β-cell ATP-sensitive K⁺ channels. Eur J Pharmacol 2004;497(1):111-7. [ PubMed]
8. Kaplowitz N. Drug-induced liver injury. Clin Infect Dis 2004;38(Suppl 2):S44-8. [ PubMed]

Domperidone: heart rate and rhythm disorders

Domperidone is a peripheral dopamine antagonist structurally related to the butyrophenones with antiemetic and gastroprokinetic properties.¹ In Canada, Motilium (domperidone) was marketed in 1985 but has not been available since 2002. However, many generic brands are currently available.

Domperidone is indicated for the symptomatic management of upper gastrointestinal motility disorders associated with chronic and subacute gastritis and diabetic gastroparesis. It may also be used to prevent gastrointestinal symptoms associated with the use of dopamine agonist antiparkinsonian agents.¹ In addition, the off-label clinical use of antidopaminergic drugs to induce and maintain adequate lactation in breast-feeding women has been suggested.^2,3

From Jan. 1, 1985, to Aug. 15, 2006, Health Canada received 9 domestic reports of heart rate and rhythm disorders suspected of being associated with the use of domperidone. Reports involved patients aged 2 months to 74 years (median age 45 years). Two reports described prolongation of the QT interval, and 4 described Torsade de Pointes; 4 of these 6 reports indicated corrected QT intervals (QTc). The 3 remaining reports included adverse reactions (ARs) of arrhythmia, atrial fibrillation, ventricular tachycardia, bradycardia and palpitation. In 8 of the cases, domperidone was used for gastrointestinal motility disorders and diabetic gastroparesis; the indication for use was not reported for 1 case. At the time of reporting, 5 patients had recovered, and the outcome was unknown in 4 cases. Most reports revealed the use of multiple concomitant medications and complex medical histories; therefore, causality in these cases is difficult to establish.

Arrhythmia is labelled in the product monograph of Motilium, but QT prolongation and Torsade de Pointes are not.¹

Domperidone has been reported in the medical literature to induce QTc prolongation and Torsade de Pointes.^4,5 Some non-drug-related factors that may be associated with QT prolongation include female sex, advanced age, bradycardia, cardiac disease and electrolyte disturbance.⁶

The main metabolic pathway of domperidone is via cytochrome P450 3A4 (CYP3A4). Studies of interactions have shown marked CYP3A4 inhibition by ketoconazole, which results in an increased plasma concentration of domperidone and a slightly prolonged QT interval.⁷ Other examples of CYP3A4 inhibitors include macrolide antibiotics, HIV protease inhibitors, selective serotonin reuptake inhibitors (SSRIs) and grapefruit juice.^1,6,8 The combined use of multiple drugs that prolong the QTc interval can also increase the risk for Torsade de Pointes.⁹

Attention should be paid to any drug interactions and clinical risk factors that could result in an exaggerated prolongation of the QT interval. Health Canada continues to monitor ARs suspected of being associated with the use of domperidone and is working with the manufacturers of generic domperidone to update their product monographs.

Ilhemme Djelouah, BScPhm, DIS, AFSA, Medical Biology (University of Paris V); Christianne Scott, BPharm, MBA, Health Canada.

References

1. Motilium (domperidone maleate tablets) [product monograph]. Toronto: Janssen-Ortho Inc.; 2001.
2. Petraglia F, De Leo V, Sardelli S, et al. Domperidone in defective and insufficient lactation. Eur J Obstet Gynecol Reprod Biol 1985;19(5):281-7. [PubMed]
3. Da Silva OP, Knoppert DC. Domperidone for lactating women. CMAJ 2004;171(7):725-6. [ PubMed]
4. Straus SM, Sturkenboom MC, Bleumink GS, et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur Heart J 2005;26(19):2007-12. [ PubMed]
5. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350(10):1013-22. [ PubMed]
6. Adverse Drug Reactions Advisory Committee (ADRAC). Medicines and QT prolongation. Aust Adv Drug Reactions Bull 2005;24(6):22.
7. Motilium (dompéridone). In: Le Dictionnaire Vidal. 82nd ed. Paris: Vidal; 2006.
8. Medicines Control Council. Interaction between ketoconazole and domperidone and the risk of QT prolongation - important safety information. S Afr Med J 2006;96(7):596. [ PubMed]
9. Pham CP, de Feiter PW, van der Kuy PH, et al. Long QTc interval and torsade de pointes caused by fluconazole. Ann Pharmacother 2006;40(7-8):1456-61. [ PubMed]

 

How to report an adverse reaction?

There are multiple ways to report an adverse reaction (AR) to Health Canada. To report an AR, go to the AR Reporting page on MedEffect*.

*The Adverse Reaction Reporting Form is also available in the CPS (Canadian Compendium of Pharmaceuticals and Specialties).

Summary of health professional and consumer advisories posted
from Aug. 18 to Nov. 14, 2006

Date	Product	Subject and type
Nov 11	Acetaminophen	Acetaminophen Recall in the United States -- consumer information
Nov 10	Rituxan	Reports of Bowel Obstruction and Gastrointestinal Perforation with Rituxan (rituximab) -- Hoffmann - La Roche Limited -- consumer information and health professional communication
Nov 2	Natural health products	Health Canada advises consumers not to use four unauthorized natural health products that claim to treat serious diseases -- consumer information
Nov 2	Natural health products	Health Canada advises consumers not to use unauthorized products for sexual enhancement due to potential health risks -- consumer information
Oct 25	Syringe Infusion Pumps	Association of Syringe Infusion Pumps with a Risk of Delay in Detection of Downstream Occlusion -- notice to hospitals
Oct 25	Neutragel	Health Canada is advising consumers not to use a specific lot of Neutragel sodium fluoride gel due to mould contamination -- consumer information
Oct 24	Avastin	Association of Avastin (bevacizumab) with hypertensive encephalopathy and reversible posterior leukoencephalopathy syndrome (RPLS) -- Hoffmann - La Roche Limited -- consumer information and health professional communication
Oct 19	Lifescan test strips	Health Canada warns consumers about counterfeit Lifescan blood glucose test strips -- consumer information
Oct 13	CellCept	Association of CellCept (mycophenolate mofetil) and sirolimus containing immunosuppressant regimen with higher rate of acute rejection in cardiac transplant patients switched from calcineurin inhibitors -- Hoffmann - La Roche Limited -- consumer information and health professional communication
Oct 13	Intravenous health products	Health Canada warns consumers not to use unauthorized intravenous health products due to potential health risks -- consumer information
Oct 12	Natural health products	Health Canada advises consumers not to use two unauthorized natural health products due to heavy metal contamination -- consumer information
Oct 3 & Sept 29	Ketek	Updated safety information on Ketek (telithromycin) and hepatic events, aggravation of myasthenia gravis and syncope -- sanofi-aventis Canada Inc. -- consumer information and health professional communication
Sept 28	Insulin products	Health Canada - It's Your Health - Update - Insulin Products -- consumer information
Sept 27	Xylocaine 2% Jelly	Health Canada advises to stop using AstraZeneca Xylocaine 2% Jelly Single Use Plastic Syringes due to potential health risks -- consumer information
Sept 21	Gleevec	Important Safety Information on Gleevec (imatinib mesylate) -- Novartis Pharmaceuticals Canada Inc. -- consumer information and health professional communication
Sept 21	ADHD drugs	New information regarding uncommon psychiatric adverse events for all ADHD drugs -- consumer information
Sept 19	Libidus	Health Canada warns consumers not to use natural sex enhancer Libidus due to potential health risks -- consumer information
Sept 14	Jambrulin	Health Canada advises against use of the Ayurvedic medicinal product Jambrulin due to lead content -- consumer information
Aug 31	Chao Nongsu Qingzhi Jiaonang	Foreign Product Alert - Chao Nongsu Qingzhi Jiaonang (OPC Care) -- consumer information
Aug 31	Conting Qianweisu Slimming Herbs	Foreign Product Alert - Conting Qianweisu Slimming Herbs Capsule -- consumer information
Aug 30	Dietary supplement	Health Canada advises consumers not to use dietary supplement due to potential health risks -- consumer information
Aug 28	Alaris SE Pump	Important Safety Information on the Alaris SE Pump (formerly Signature Edition Infusion Pump) -- Cardinal Health -- notice to hospitals
Aug 24	Lipitor	Another batch of counterfeit Lipitor found in the United Kingdom -- consumer information
Aug 23	VG	Foreign Product Alert - VG -- consumer information
Aug 23	Meng Rong	Foreign Product Alert - Meng Rong -- consumer information
Aug 23	Yixinjiaonang	Foreign Product Alert - Yixinjiaonang -- consumer information
Aug 23	Reduce Weight	Foreign Product Alert - Reduce Weight -- consumer information
Aug 22 & 18	Rapamune	Association of a Rapamune (sirolimus) containing immunosuppressant regimen with a high rate of acute rejection in de novo renal transplant patients -- Wyeth Pharmaceuticals -- consumer information and health professional communication
Aug 21	Hydrogen peroxide	Health Canada warns against drinking hydrogen peroxide for medicinal use -- consumer information
Aug 18	Black cohosh	Health Canada is advising consumers about a possible link between black cohosh and liver damage -- consumer information
Aug 17	Medical Devices	Health Canada - It's Your Health - Buying Medical Devices over the Internet -- consumer information
July 18	Intubating Stylet	Important Safety Information on the recall of the Mallinckrodt Satin-Slip Intubating Stylet - 6 FR -- Tyco Healthcare Canada -- notice to hospitals

To receive the Newsletter and health product Advisories free by email, join Health Canada's MedEffect e-Notice.