Canadian Adverse Reaction Newsletter, Volume 19 - Issue 4 - October 2009

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Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team

In this Issue:

• Intravenous immune globulin (IVIG): hemolytic reactions
• Antiviral medications and influenza A (H1N1): reporting adverse reactions
• Sildenafil (Revatio): medication incident
• Adverse reaction reporting form
• 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 stimulate adverse reaction reporting, as well as 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
Canada Vigilance Program
Phone: 1-866-234-2345
Fax: 1-866-678-6789

For more information on how to report an adverse reaction, visit the Reporting Adverse Reactions to Drugs and Other Health Products page.

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.

Some of the hyperlinks provided are to sites of organizations or other entities that are not subject to the  Official Languages Act. The material found there is therefore in the language(s) used by the sites in question.

Intravenous immune globulin (IVIG): hemolytic reactions

Canada is one of the world's highest per capita users of intravenous immune globulin (IVIG).^{Footnote 1} Since 1998, the Canadian Blood Services has reported a steady increase in the use of IVIG of 11.3% per year on average.^{Footnote 2} In the context of this increasing use, it is important for health care professionals to be aware of hemolysis, a rare but well-described adverse reaction (AR) associated with IVIG therapy. Product monographs for IVIG products on the Canadian market provide information on the risk of hemolysis.^{Footnote 4,Footnote 5,Footnote 6} In February 2009, criteria for a standardized case definition of IVIG-associated hemolysis were proposed by Héma-Québec and the Canadian Blood Services through the IVIG Hemolysis Pharmacovigilance Group "to assist in the investigation and reporting of suspected cases" (Table 1).^{Footnote 7,Footnote 8}

The primary constituent of IVIG is concentrated IgG made from large pools of human plasma. Several commercial brands of the product have been authorized for use in Canada as replacement therapy in cases of primary and secondary immune deficiencies and for idiopathic thrombocytopenic purpura. Some are also authorized for the treatment of chronic inflammatory demyelinating polyneuropathy. ^{Footnote 4,Footnote 5,Footnote 6,Footnote 9} IVIG is also being used off-label for a growing number of conditions.^{Footnote 10}

Using the case definition developed by the IVIG Hemolysis Pharmacovigilance Group, Health Canada analyzed all reports of hemolysis (reported as hemolytic anemia, hemolysis, spherocytic anemia, hemolytic reaction, decreased hemoglobin and hemolytic transfusion reaction) suspected of being associated with the use of IVIG that were received from Dec. 1, 2006, to Mar. 31, 2009. Of the 81 reports received, 20 involved cases that met the criteria for IVIG-associated hemolysis, 23 had an alternate possible cause for anemia, and 38 lacked the required laboratory work (32 of the 38 also had an alternate possible cause, 4 of which had a negative result of a direct antiglobulin test).

Table 2 provides an analysis of the 20 cases that met the definition of IVIG-associated hemolysis. Nine of the 20 patients received IVIG for labelled indications and 11 for off-label indications. The total dose ranged from 35 to 500 g. Patient age ranged from 7 months to 86 years. The number of men and women in the AR reports was equal; however, the patient exposure to IVIG is not known. The reported onset of hemolysis ranged from the day of IVIG infusion to 2 weeks afterwards. Hemoglobin levels dropped by 28 to 78 g/L (mean decrease 46 g/L, median 44 g/L).

Risk factors for hemolysis, as noted by the IVIG Hemolysis Pharmacovigilance Group,^{Footnote 7,Footnote 8} included blood group A (in 14 cases) or AB (in 6 cases) and a high total dose of IVIG (≥ 2 g/kg). Of the AR reports that included the total dose in grams per kilogram, 85% of the patients (11/13) received a total dose of ≥ 2 g/kg.

Health care professionals are encouraged to report to Health Canada ARs suspected of being associated with the use of IVIG and to include any available information relevant to hemolysis.

Elaine Taylor, MD, Health Canada

Table 1: Criteria for the standardized case definition of hemolysis associated with the use of intravenous immune globulin (IVIG), as developed by the IVIG Hemolysis Pharmacovigilance Group ^{Footnote 7,Footnote 8}

Variable	Definition
Héma-Québec and the Canadian Blood Services are members of the group. Cases detected more than 10 days after treatment should also be reported when it is considered likely that the hemolytic process started within 10 days after treatment. Also known as direct Coombs test or DAT.
Onset	Within 10 days of IVIG administration
Laboratory signs	Drop in hemoglobin of ≥ 10 g/L Positive result of direct antiglobulin test At least 2 of: increased reticulocyte count increased lactate dehydrogenase level low haptoglobin level unconjugated hyperbilirubinemia hemoglobinemia hemoglobinuria presence of significant spherocytosis
Exclusion criteria	History or examination consistent with an alternate cause of anemia, including blood loss, other drug-induced hemolysis, anemia associated with chemotherapy for cancer, or hemolysis associated with an underlying disease Negative result of direct antiglobulin test Absence of other inclusion criteria, in particular evidence of hemolysis

Table 2: Summary of 20 reports of hemolysis suspected of being associated with IVIG that were submitted to Health Canada from Dec. 1, 2006, to Mar. 31, 2009, and that met the proposed case definition of IVIG-associated hemolysis ^{Footnote 7,Footnote 8}

Case	Patient age/sex	Blood group	Product and dose	Indication	Time to onset	Drop in hemoglobin, g/L	Intervention/ outcome
These data cannot be used to determine the incidence of adverse reactions (ARs) because ARs are underreported and neither patient exposure nor the amount of time the drug was on the market has been taken into consideration. Estimated from the beginning of the treatment. Off-label indication.
1	67/F	A	IGIVnex 90 g/d x 2 days; total dose 180 g	Idiopathic thrombocytopenic purpura (ITP)	1 day	32	Blood transfusion; recovered without sequelae
2	67/M	A	Gamunex/IGIVnex on days 1, 2, 3, 4, 5 and 12; total dose unknown	Chronic inflammatory demyelinating polyneuropathy (CIDP)	7 days	28	Unknown
3	60/M	A	Gamunex 40 g/d x 5 days; total dose 200 g (2 g/kg)	Guillain–Barré syndrome	About 1 day	51	Unknown
4	86/F	AB	Gamunex/IGIVnex 25 g/d x 5 days; total dose 125 g	Guillain–Barré syndrome	8 days	50	Unknown
5	13/F	AB	IGIVnex 55 g/d x 2 days; total dose 110 g (2 g/kg)	Multiple sclerosis	1 day	56	Recovered without sequelae
6	58/F	A	Gamunex 160 g over 2 days; total dose 160 g (2 g/kg)	ITP	3 days	50	Blood transfusion; prolonged hospitalization; recovered without sequelae
7	7 mo/M	AB	Gamunex 17.5 g/d on days 1 and 3; total dose 35 g	Kawasaki disease	3 days	35	Blood transfusion; recovered without sequelae
8	8/F	A	Gamunex 155 g over 8 days; total dose 155 g	Kawasaki disease	7 days	41	Involved or prolonged hospitalization; outcome unknown
9	64/F	A	Gamunex/IGIVnex 42.5 g/d x 3 days; total dose 127.5 g (1.5 g/kg)	Guillain–Barré syndrome	3 days	70	Blood transfusion; recovered
10	18/M	A	Gamunex 1g/kg daily x 2 days; total dose 170 g (2 g/kg)	ITP	Following infusion	32	Unknown
11	69/M	AB	IGIVnex 80 g/d on days 1 and 4; total dose 160 g	Myasthenia gravis	7 days	56	Blood transfusion; prolonged hospitalization; outcome unknown
12	3/M	A	Gamunex/IGIVnex 27.5 g/d on days 1 and 4; total dose 55 g (3.9 g/kg)	Kawasaki disease	5 days	32	Involved or prolonged hospitalization; recovered without sequelae
13	85/M	AB	Gamunex/IGIVnex 0.4 g/kg daily x 5 days; total dose 175 g (2.1 g/kg)	Myasthenia gravis	8 days	66	Blood transfusion; prolonged hospitalization; recovered without sequelae
14	76/F	A	Gamunex/IGIVnex 1 g/kg; total dose unknown	ITP	Same day	29	Blood transfusion; outcome unknown
15	74/M	A	Gamunex 27.5 g/d x 5 days; total dose 137.5 g (2.18 g/kg)	ITP	3 days	31	Death (not related)
16	42/M	A	Gamunex 100 g/d on days 1, 2, 7, 13 and 15; total dose 500 g (5.05 g/kg)	ITP	5 days	40	Involved or prolonged hospitalization; recovered without sequelae
17	57/M	A	Gamunex 150 g over 2 days; total dose 150 g (2 g/kg)	Renal transplant rejection	Within 2 weeks of treatment	39	Blood transfusion; recovered without sequelae
18	23/F	AB	Gammagard liquid 100 g/d on days 1, 2 and 4; total dose 300 g	Possible Guillain–Barré syndrome, facial weakness (not yet diagnosed)	4–14 days	78	Blood transfusion; prolonged hospitalization; recovered without sequelae
19	59/F	A	Gamunex 0.4 g/kg x 5 days; total dose 137.5 g (2.1 g/kg)	CIDP	6–10 days	49	Blood transfusion; hospitalization; outcome unknown
20	17/F	A	IGIVnex 70 g/d x 2 days; total dose 140 g (2.4 g/kg)	ITP	6 days	48	Blood transfusion; recovered without sequelae

Antiviral medications and influenza A (H1N1): reporting adverse reactions

Reports of adverse reactions to antiviral medications are important. This information will be used to guide the safe and effective use of these drugs, particularly in certain patient groups (e.g., pregnant women and children < 1 year of age) for which only limited safety data may be available. Health care professionals are encouraged to report any suspected adverse reaction involving an antiviral medication to the Canada Vigilance Program:

• by calling toll-free at 1-866-234-2345
• by reporting online
• by completing a form that you can send by:
  • postage-paid mail or
  • fax toll-free to 1-866-678-6789

The form and postage-paid label are available at MedEffect Canada or by calling 1-866-234-2345.

Sildenafil (Revatio) and medication incident

In December 2008, Health Canada received a report of a medication incident related to Revatio and confusion over the drug's brand name. A medication incident is defined as any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer.^{Footnote 1}

A woman in her mid-50s sought care at an emergency department after experiencing chest pain. She had a history of primary pulmonary hypertension (PPH), and her medications included Revatio (sildenafil citrate). Following an electrocardiogram, the patient was given acetylsalicylic acid and sublingual nitroglycerin for treatment of cardiac ischemia. Intravenous nitroglycerin therapy was then started for continued chest pain and an elevated troponin T level. The emergency physician had reviewed the patient's medication list but did not recognize Revatio as a brand of sildenafil. An internist saw the patient shortly thereafter, realized the potential problem and stopped the nitroglycerin therapy. The patient experienced no adverse effects.^{Footnote 2}

The use of nitrates regularly or intermittently in any form (e.g., oral, sublingual, transdermal, by inhalation) is contraindicated in patients taking sildenafil citrate because of the risk of potentially life-threatening hypotension.^{Footnote 3,Footnote 4} A similar contraindication exists for other selective phosphodiesterase-inhibiting drugs such as vardenafil hydrochloride (Levitra) and tadalafil (Cialis).^{Footnote 5,Footnote 6} Sildenafil citrate is also marketed as Viagra for erectile dysfunction and is usually prescribed in 50-mg doses to be taken as needed about 30 to 60 minutes before sexual activity.^{Footnote 3} Revatio is indicated for the treatment of PPH, usually in 20-mg doses to be taken 3 times daily.^{Footnote 4}

Dual brand names for a single drug may pose particular risks for error when one of the products' names is much less widely recognized, as in this example. Practitioners are well aware of the brand name Viagra and its contraindications. However, the name Revatio is likely not as well recognized, particularly among those unfamiliar with the management of PPH. Patients with PPH may also present with concomitant coronary artery disease, increasing the risk of receiving a nitrate.^{Footnote 2} The potential severity of the drug interaction between nitrates and sildenafil indicates a heightened risk of significant patient harm should an error occur.

A number of drugs available on the Canadian market have dual brand names. Medication incidents have been documented with some of these products. For example, patients have received duplicate therapy when the same medication is available under more than one brand name.^{Footnote 2,Footnote 7}

Health care professionals are encouraged to include the generic names of medications when documenting, reviewing or sharing patient medication histories. Drug references should be consulted for unfamiliar names of health products. Patients or caregivers can be active participants in the prevention of errors by becoming familiar with both the brand and generic names of all medications they are taking. They should also document both names on an up-to-date list. Health care professionals should report all medication incidents, including near misses, to the Institute for Safe Medication Practices Canada and suspected adverse reactions to the Canada Vigilance Program (telephone 1-866-234-2345).

Sally Pepper, BSc Phm; Barry Jones, BPharm (Hons) MPS, Health Canada

Quarterly Summary of health professional and consumer advisories posted on Health Canada's Web site: June 2, 2009 – Aug. 21, 2009

Date	Product	Subject
Aug 20	Tumour necrosis factor (TNF) blockers	Update — risk of cancer in children and young adults
Aug 19	Foreign products	Alerts — Clarcon skincare products; Delima Raja Urat and Cao Gen Bai Lin Wan; New Whey liquid products; Stamina-Rx
Aug 14 & 20	Plavix (clopidogrel)	Potential interaction with proton pump inhibitors
Aug 13	Xolair (omalizumab)	Update — increased risk of cardiovascular problems
Aug 7	Buying drugs online	Update — risks of buying drugs online
Aug 5 & 6	Medtronic Paradigm Quick-set Infusion Sets	Recall on lot 8
July 29	Foreign products	Alerts — Air Ikan Haruan; XP Tongkat Ali Supreme; Neovidan
July 28 & Aug 5	Oral sodium phosphate products	Products no longer authorized for purgative use
July 24	Dophilus Chewable Tablets	Warning — milk allergy risk
July 17	Telzir (fosamprenavir)	Potential increased risk of myocardial infarction
July 10	Specific-Formula Arthro-Ace	Warning — unauthorized health product
July 9	Lantus (insulin glargine)	Update — ongoing safety review
July 4	Hardcore Energize Bullet	Warning — unauthorized energy drink
June 29	Foreign products	Alerts — Slimbionic, Xsvelten, Herbal Xenicol, BioEmagrecim; 999 Fitness Essence; Libimax; 24” ince, Light Some, Paiyouji, Pearl White Slimming, Reducing Weight Easily
June 26	pms – Phenobarbital (60 mg)	Recall — risk of accidental overdose
June 25	Piroxicam	Updated labelling — drug no longer to be used for acute pain or inflammation
June 24	Nutural Slim	Warning — unauthorized weight loss product
June 22	HIV Home Test Kit	Unlicensed medical device
June 18	Foreign product	Alert — Levemir insulin
June 17	Foreign products	Alert — Zicam Cold Remedy Nasal Gel, Zicam Cold Remedy Swabs and Zicam Cold Remedy Swabs, Kids Size
June 11	Raptiva (efalizumab)	Market withdrawal
June 10	Iron-containing products	Important labelling information
June 4	Slim Magic Herbal	Warning — unauthorized weight loss product
June 3	CellCept (mycophenolate mofetil)	Potential risk of pure red cell aplasia
June 3	Foreign products	Alerts — Fangocur Mineral Drink; Jia Yi Jian, Fortodol; Shan Dian Qiang Xiao Shou; Zencore Plus; Zhong Guo Shen Fang
May 18	Implantable pulse generators	Important safety information — Kappa and Sigma series

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Canadian Adverse Reaction Newsletter

Health Canada
Marketed Health Products Directorate
Address Locator 0701C
Ottawa ON K1A 0K9
Telephone: 613-954-6522
Fax: 613-952-7738

Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Jared Cousins, BSP
Alanna Maloney, BHSc
Mary Joy, RPh, BScPhm
Hoa Ly, BSc
Patricia Carruthers-Czyzewski, BScPhm, MSc

Acknowledgement
We thank the following members of the Expert Advisory Committee on the Vigilance of Health Products for their review of material for this issue: Colleen J. Metge, BSc(Pharm), PhD; Dugald Seely, ND, MSc; and Sylvia Hyland, RPh, BScPhm, MHSc. We also thank Kaitlyn Proulx and Darija Muharemagic, students in Biopharmaceutical Science, for their participation in the production of the newsletter.

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Reporting Adverse Reactions
Canada Vigilance Program
Telephone: 866-234-2345
Fax: 866-678-6789

Copyright
© 2009 Her Majesty the Queen in Right of Canada. 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.

Due to time constraints relating to the production of this publication, information published may not reflect the most current information.

ISSN 1499-9447; Cat no H42-4/1-19-4E

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.