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Drugs and Health Products

Canadian Adverse Reaction Newsletter, Volume 23 - Issue 1 - January 2013

ISSN 1499-9447
Cat no H42-4/1-23-1E

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

In this Issue:

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 Next link will take you to another Web site Official Languages Act. The material found there is therefore in the language(s) used by the sites in question.

Pico-Salax (sodium picosulfate/magnesium citrate) and convulsions

Key points

  • Pico-Salax (sodium picosulfate/magnesium citrate) is an oral purgative indicated for the clearance of the bowel prior to x-ray examination, endoscopy or surgery.
  • Health Canada received 11 reports of convulsions suspected of being associated with Pico-Salax.
  • Health care professionals are encouraged to inform patients of the importance of drinking a variety of clear fluids containing electrolytes, and not just water alone, while using this medication.

Pico-Salax contains sodium picosulfate and magnesium citrate (also referred to as citric acid and magnesium oxide) and is available as a nonprescription oral purgative indicated for the clearance of the bowel prior to x-ray examination, endoscopy or surgery.Footnote 1 In addition to Pico-Salax, there are 4 other marketed medications containing sodium picosulfate/magnesium citrate in Canada: Picodan, Purg-Odan, Picoflo and Oral Purgative.

Pico-Salax acts as an osmotic laxative, stimulates peristalsis and has a powerful "washing out" effect within 3 to 6 hours or less of administration.Footnote 1 The diarrhea produced by the medication can lead to dehydration and loss of electrolytes, particularly sodium which may result in hyponatremia and convulsions.Footnote 1,Footnote 2,Footnote 3 Elderly and debilitated individuals are particularly at risk. Pico-Salax may also decrease the absorption of oral medications due to an increase in gastrointestinal transit rate, and may be associated with convulsions in patients taking anticonvulsants.Footnote 1

As of June 30, 2012, Health Canada received 11 reports of convulsions suspected of being associated with Pico-Salax. In 5 cases, patients developed hyponatremia, of which 4 drank mainly water as a means of rehydration. In another 3 cases, patients with a history of seizures had their convulsions controlled by anticonvulsants prior to taking Pico-Salax. No deaths were reported in any of the cases, however 6 patients required hospital care. In one case, the patient had a history of alcohol consumption and withdrawal. Another case was unassessable due to limited information. Patient age ranged from 36 to 74 years. Age was not reported in 2 cases.

Several articles in the literature reported incidents of seizures and hyponatremia or emphasized the risk of electrolyte disturbances when using sodium picosulfate/magnesium citrate.Footnote 4,Footnote 5,Footnote 6,Footnote 7 It is important to replace electrolytes as well as fluids when rehydrating.Footnote 8 Both the risk of hyponatremia and decreased drug absorption are well described in the prescribing and consumer information for Pico-Salax.Footnote 1 The prescribing and consumer information for Pico-Salax have also been updated to emphasize the need to drink a variety of clear fluids containing electrolytes, and not just water alone. Health Canada is currently working to align the prescribing information for all other sodium picosulfate/magnesium citrate products.

Health care professionals are encouraged to inform patients of the importance of replacing fluid and electrolyte losses with the intake of a balanced electrolyte solution and are reminded of the risk of convulsions suspected of being associated with the use of Pico-Salax or any product containing sodium picosulfate/magnesium citrate.

Anne Cornet, MD, FRCP(C), Health Canada

References

Footnote 1

Pico-Salax (Magnesium oxide, citric acid and sodium picosulfate) [prescribing information] [prescribing information]. North York (ON): Ferring Pharmaceuticals; 2012.

Return to footnote 1 referrer

Footnote 2

Hoy SM, Scott LJ, Wagstaff AJ. Next link will take you to another Web site Sodium picosulfate/magnesium citrate: A review of its use as a colorectal cleanser. Drugs 2009;69(1):123-36. [PubMed]

Return to footnote 2 referrer

Footnote 3

Sanders G, Mercer SJ, Saeb-Parsey K, et al. Next link will take you to another Web site Randomized clinical trial of intravenous fluid replacement during bowel preparation for surgery. Br J Surg 2001;88(10):1363-5. [PubMed]

Return to footnote 3 referrer

Footnote 4

Frizelle FA, Colls BM. Next link will take you to another Web site Hyponatremia and seizures after bowel preparation: report of three cases. Dis Colon Rectum 2005;48(2):393-6. [PubMed]

Return to footnote 4 referrer

Footnote 5

Dillon CE, Laher MS. Next link will take you to another Web site The rapid development of hyponatraemia and seizures in an elderly patient following sodium picosulfate/magnesium citrate (Picolax). Age Ageing 2009;38(4):487. [PubMed]

Return to footnote 5 referrer

Footnote 6

Parente F, Marino B, Crosta C. Next link will take you to another Web site Bowel preparation before colonoscopy in the era of mass screening for colo-rectal cancer: A practical approach. Dig Liver Dis 2009;41(2):87-95. [PubMed]

Return to footnote 6 referrer

Footnote 7

Sarre R. Bowel preparation. Australian Prescr 2005;28(1):16-7.

Return to footnote 7 referrer

Footnote 8

McQuaid KR. Chapter 15. Gastrointestinal Disorders. In: Papadakis MA, McPhee SJ, Rabow MW, editors. Next link will take you to another Web site CURRENT Medical Diagnosis & Treatment 2013. 52nd ed. New York: McGraw-Hill. (accessed 2012 October 4).

Return to footnote 8 referrer

Risperidone and rhabdomyolysis independent of neuroleptic malignant syndrome

Key points

  • Health Canada received 5 reports of rhabdomyolysis without the presence of neuroleptic malignant syndrome suspected of being associated with the use of risperidone.
  • Four of the 5 cases included a positive dechallenge.
  • Health Canada is currently working with the manufacturer with the aim of updating the product label for risperidone.

Risperidone is an atypical antipsychotic agent indicated for the treatment or management of schizophrenia, inappropriate behaviour associated with severe dementia and manic episodes associated with Bipolar I disorder.Footnote 1 All atypical antipsychotics marketed in Canada, including risperidone, can trigger neuroleptic malignant syndrome (NMS), and rhabdomyolysis can be part of this syndrome.

Rhabdomyolysis refers to the disintegration of striated muscle and the consequent release of muscular cell contents such as myoglobin into extracellular fluid and circulation. Myoglobin is normally bound to plasma globulins, of which a small amount may be excreted in the urine. When a massive amount of myoglobin is released, and the binding capacity of plasma proteins is surpassed, myoglobin is filtered by the glomeruli and eventually reaches the tubules, where it can cause obstruction and may lead to renal failure.Footnote 2 Clinical signs and symptoms of rhabdomyolysis include muscle pain, weakness, and dark red-coloured urine. Serum creatine phosphokinase (CPK) levels are also typically markedly elevated and can be used to assess the presence and intensity of muscle damage.Footnote 2,Footnote 3

Other atypical antipsychotics including clozapine, olanzapine, quetiapine, aripiprazole and one paliperidone product are currently labelled for the risk of rhabdomyolysis independent of NMS, as well as part of NMS, in their respective Canadian product monographs.Footnote 4,Footnote 5,Footnote 6,Footnote 7,Footnote 8 Risperidone and ziprasidone are not labelled for the risk of rhabdomyolysis independent of NMS.Footnote 1,Footnote 9

As of June 30, 2012, Health Canada received 5 reports of rhabdomyolysis independent of NMS suspected of being associated with risperidone (Table 1). All but one patient had recovered at the time of reporting. No deaths were reported.

Table 1: Summary of 5 reports of rhabdomyolysis independent of neuroleptic malignant syndrome suspected of being associated with the use of risperidone submitted to Health Canada as of June 30, 2012Table 1 footnote
Case Age/sex Daily dose, mgTable 1 footnote Onset of reactionTable 1 footnote Peak serum creatine phosphokinase, IU/L DechallengeTable 1 footnote

Table 1 footnotes

Table 1 footnote 1

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.

Return to table 1 footnote referrer

Table 1 footnote 2

Total daily dose at the time of reaction onset.

Return to table 1 footnote referrer

Table 1 footnote 3

Estimated from the beginning of treatment.

Return to table 1 footnote referrer

Table 1 footnote 4

Response to withdrawal of the drug. Abatement of the reaction after the drug is stopped or the dose is reduced is considered a positive dechallenge.

Return to table 1 footnote referrer

Table 1 footnote 5

Concomitant use of irbesartan was reported.

Return to table 1 footnote referrer

Table 1 footnote 6

Concomitant use of valsartan was reported.

Return to table 1 footnote referrer

1Table 1 footnote 31/M 4.5 17 days 14 000 Positive
2 16/M 0.5 19 months 1 023 Positive
3 54/F Unknown < 2 months 39 000 Positive
4 44/F 6 5 years 8 974 Negative
5Table 1 footnote 42/M 1.5 10 years 6 000 Positive

Reports of significant and transient elevation of CPK in stable patients without the presence of NMS involving risperidone and other antipsychotics have been described in the literature.Footnote 3,Footnote 10,Footnote 11 However, the exact pathophysiological mechanism that mediates this association remains unclear. There are individual vulnerability factors involved in the development of rhabdomyolysis in the presence of antipsychotics.Footnote 12 It has also been proposed, based on animal studies, that the accumulation of serotonin in skeletal muscle can play a role in the development of muscle injury.Footnote 11

Health Canada is currently working with the manufacturer with the aim of updating the product label for risperidone. Health professionals should be aware of the risk of rhabdomyolysis without the presence of NMS suspected of being associated with the use of risperidone. Health Canada encourages the reporting of adverse reactions through the Canada Vigilance Program.

Shirley Chou, MSc, MD, FRCSC; Emir Al-Khalili, BA, BScPhm, Health Canada

References

Footnote 9

Risperdal (risperidone) [product monograph]. Toronto (ON): Janssen Inc.; 2011.

Return to footnote 1 referrer

Footnote 10

Vanholder R, Sever MS, Erek E, et al. Next link will take you to another Web site Rhabdomyolysis. J Am Soc Nephrol 2000;11(8):1553-61. [PubMed]

Return to footnote 2 referrer

Footnote 11

Yasui N, Kondo T, Otani K, et al. Rhabdomyolysis without neuroleptic malignant syndrome induced by additional treatment of risperidone. Hum Psychopharmacol Clin Exp 1998;13(8):575-7.

Return to footnote 3 referrer

Footnote 12

Clozaril (clozapine) [product monograph]. Dorval (QC): Novartis Pharmaceuticals Canada Inc.; 2012.

Return to footnote 4 referrer

Footnote 13

Zyprexa (olanzapine) [product monograph]. Toronto (ON): Eli Lilly Canada Inc.; 2012.

Return to footnote 5 referrer

Footnote 14

Seroquel (quetiapine) [product monograph]. Mississauga (ON): AstraZeneca Canada Inc.; 2012.

Return to footnote 6 referrer

Footnote 15

Abilify (aripiprazole) [product monograph]. Montreal (QC): Bristol-Myers Squibb Canada; 2012.

Return to footnote 7 referrer

Footnote 16

Invega (paliperidone) [product monograph]. Toronto (ON): Janssen Inc.; 2012.

Return to footnote 8 referrer

Footnote 17

Zeldox (ziprasidone) [product monograph]. Kirkland (QC): Pfizer Canada Inc.; 2011.

Return to footnote 9 referrer

Footnote 18

Holtmann M, Meyer AE, Pitzer M, et al. Next link will take you to another Web site Risperidone-induced marked elevation of serum creatine kinase in adolescence: A case report. Pharmacopsych 2003;36(6):317-8. [PubMed]

Return to footnote 10 referrer

Footnote 19

Meltzer HY, Cola PA, Parsa M. Next link will take you to another Web site Marked elevations of serum creatine kinase activity associated with antipsychotic drug treatment. Neuropsychopharmacol 1996;15(4):395-405. [PubMed]

Return to footnote 11 referrer

Footnote 20

Jermain DM, Crismon ML. Next link will take you to another Web site Psychotropic drug-related rhabdomyolysis. Ann Pharmacother 1992;26(7-8):948-54. [PubMed]

Return to footnote 12 referrer

Docetaxel and serious respiratory-related adverse reactions

Key points

  • Health Canada received 31 reports of pneumonitis, interstitial lung disease, lung infiltration or respiratory failure suspected of being associated with docetaxel.
  • The Canadian product monograph for docetaxel (Taxotere) has recently been strengthened to further emphasize the potential for pulmonary toxicity.
  • Early recognition of respiratory-related adverse reactions associated with docetaxel may lead to earlier treatment and improved patient outcomes.

In Canada, docetaxel (Taxotere) is an injectable chemotherapy drug that was first marketed on December 31, 1995. It is currently indicated for the treatment of breast, non-small cell lung, ovarian and prostate cancer, as well as squamous cell carcinoma of the head and neck.Footnote 1 Currently, there is one generic product marketed in Canada under the name of Docetaxel for Injection.

Docetaxel belongs to a group of antineoplastic medicines known as taxanes. It acts by disrupting the microtubular network essential for cell division.Footnote 1 Specifically, it promotes the assembly and stabilization of microtubules and leads to the production of microtubule bundles without normal function, resulting in the inhibition of mitosis in cells.

Several antineoplastic drugs, including docetaxel, have been known to induce pulmonary toxicity, which may result in a variety of pathological syndromes ranging from unspecified dyspnea to pulmonary pneumonitis that may lead to permanent pulmonary fibrosis and possible death.Footnote 2,Footnote 3 This type of drug-associated lung injury typically occurs as a result of cellular dysfunction which can trigger apoptosis or by impairing the cell and tissue repair sequence.Footnote 4

As of July 31, 2012, Health Canada received 31 reports of respiratory-related adverse reactions (ARs) suspected of being associated with docetaxel involving pneumonitis, interstitial lung disease (ILD), lung infiltration or respiratory failure. Among these cases, 23 patients required hospitalization. A fatal outcome was reported in 9 cases. Patient age ranged from 34 to 69 years. Age was not reported in 4 cases. Time to onset of the ARs varied from several days after one dose to several weeks after multiple doses.

Several cases of serious respiratory-related ARs in patients using docetaxel, either alone or in combination with other antineoplastic agents, have been reported in the literature*. Reported ARs included pneumonitis or interstitial pneumonitis, pulmonary infiltrates, acute respiratory distress syndrome, respiratory failure, ILD, interstitial infiltrates and pneumocystis pneumonia. Some of these cases resulted in fatal outcomes. For example, one article describes 4 patients who developed severe interstitial pneumonitis that could not be explained by any other cause other than docetaxel-associated toxicity.Footnote 5 None had metastatic disease to the lung, and all had normal liver function before receiving chemotherapy. The patients presented with symptoms of acute dyspnea and fever within 1 to 2 weeks of receiving docetaxel. All 4 patients eventually developed progressive interstitial infiltrates and respiratory failure. Two of the patients died of related complications.

The Canadian product monograph for Taxotere has been updated to include the potential for respiratory-related ARs in the Warnings and Precautions section, as well as the addition of pneumonitis, ILD, lung infiltration and respiratory failure in the Post-Market Adverse Drug Reactions section. Strengthening the product label is intended to alert health care professionals about the potential for an increased risk of serious respiratory-related ARs associated with docetaxel, as well as to promote earlier risk detection and possible intervention.

Health Canada is continuing to monitor ARs suspected of being associated with docetaxel and encourages health care professionals to report similar cases through the Canada Vigilance Program.

Cicely Gu, MD, PhD, Health Canada

*References available upon request

References

Footnote 21

Taxotere (docetaxel) [product monograph]. Laval (QC): sanofi-aventis Canada Inc.; 2012.

Return to footnote 1 referrer

Footnote 22

Briasoulis E, Pavlidis N. Next link will take you to another Web site Noncardiogenic pulmonary edema: An unusual and serious complication of anticancer therapy. Oncologist 2001;6(2):153-61. [PubMed]

Return to footnote 2 referrer

Footnote 3

Danson S, Blackhall F, Hulse P, et al. Next link will take you to another Web site Interstitial lung disease in lung cancer: Separating disease progression from treatment effects. Drug Saf 2005;28(2):103-13. [PubMed]

Return to footnote 3 referrer

Footnote 24

Charpidou AG, Gkiozos I, Tsimpoukis S, et al. Next link will take you to another Web site Therapy-induced toxicity of the lungs: An overview. Anticancer Res 2009;29(2):631-9. [PubMed]

Return to footnote 4 referrer

Footnote 25

Read WL, Mortimer JE, Picus J. Next link will take you to another Web site Severe interstitial pneumonitis associated with docetaxel administration. Cancer 2002;94(3):847-53. [PubMed]

Return to footnote 5 referrer

Case Presentation

Recent Canadian cases are selected based on their seriousness, frequency of occurrence or the fact that the reactions are unexpected. Case presentations are considered suspicions and are presented to stimulate reporting of similar suspected adverse reactions.

Ear drops containing peanut oil and suspected association with anaphylaxis

Health Canada received a report of a 7-year-old girl who experienced an anaphylactic reaction after being administered Cerumol ear drops by a parent. According to the report, she received 4 drops of Cerumol ear drops in each ear to loosen earwax. Within 4 minutes, she required her "blue inhaler" normally used for her asthma problems (product not specified), stating that it was too hard to breathe. She then collapsed, went into anaphylactic shock and was taken to the emergency room but was not hospitalized. The treatment she received while in the emergency room was not specified; however, after discharge she was administered diphenhydramine (Benadryl) at home for a couple of days. The report indicated that she had recovered. It was also reported that she had a known peanut allergy and that she was a regular user of ciclesonide (Alvesco) and montelukast (Singulair) for the treatment of her asthma.

Cerumol ear drops include a warning on the box and in the patient information leaflet indicating that the product contains peanut oil and instructs patients allergic to peanuts and soya not to use it. The label on the box and the bottle lists peanut oil as a non-medicinal ingredient. Despite this, the parent reported that she was unaware that Cerumol contained peanut oil.

Health professionals are encouraged to remind patients with food allergies to always check the list of medicinal and non-medicinal ingredients of health products, including topical preparations, such as creams, ointments and ear drops, and to consistently check for allergen warnings prior to using any product. Manufacturers sometimes change the ingredients used in familiar products. Different varieties and sizes of the same brand may contain different ingredients. Patients with peanut allergies should also be aware that licensed Canadian natural health products and pharmaceuticals may be labelled as containing arachis oil, which is another term for peanut oil.

Health Canada encourages the reporting of adverse reactions suspected of being associated with allergen-containing natural health products and pharmaceuticals to the Canada Vigilance Program.

Quarterly Summary of health professional and consumer advisories

Health professional and consumer advisories posted on Health Canada's Web site: August 20, 2012 - November 18, 2012.
Date* Product Subject
Nov 16 Prolia (denosumab) New safety information on the risk of atypical femoral fractures
Nov 7 & 13 Zocor (simvastatin) New safety recommendations on dosage
Oct 31 & Nov 5 Riata and Riata ST Silicone Endocardial Defibrillation Leads Updated safety information and recommendations
Oct 30 & Nov 2 Infanrix Hexa vaccine Recall: potential microbial contamination of one lot
Oct 30 Products from the New England Compounding Center Update on U.S. meningitis outbreak linked to contaminated health products
Oct 29 Carboplatin Injection, 600mg/60mL Recall: visible particles in one lot
Oct 26 & 31,  Nov 5 & 6 Agriflu and Fluad vaccines Suspension of distribution and related updates
Oct 25 Pollen Allergy or Tongqiao Biyan Pian Recall: arsenic levels exceed safety limit
Oct 19 Proton pump inhibitors and methotrexate New safety information: possible interaction
Oct 15 & 18,  Nov 6 Antimicrobial Foaming Hand Soap and X3 Clean Alcohol-Free Foaming Hand Sanitizer Recall: microbial contamination
Oct 15 & 17 Epicardial pacemaker leads Risk of cardiac strangulation in pediatric patients with implants
Oct 9 Insulin pumps It's Your Health: Insulin pumps
Oct 3 & 9 Zofran (ondansetron) Dosage restriction for intravenous use
Oct 1 & 4 Typhim Vi vaccine Recall: potentially lower than expected antigen content
Sept 18 Zhuifeng Tougu Wan Recall: unauthorized health product
Sept 17 Propofol Injectable Emulsion 1%, 10mg/mL Recall: presence of particulate matter in one lot
Sept 14 ImmuCyst (BCG vaccine) Update on supply status
Sept 10 HIV and STD home test kits Web site selling unauthorized home-use test kits
Sept 4 BiCNU (carmustine for injection, USP),100mg/vial Recall: overfilled vials
Aug 21 & 23 Gilenya (fingolimod) Stronger recommendations regarding first-dose cardiovascular monitoring

*Date of issuance. This date may differ from the posting date on Health Canada's Web site.

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Canadian Adverse Reaction Newsletter

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

Editorial Team
Patricia Carruthers-Czyzewski, BScPhm, MSc (Editor-in-Chief)
Jared Cousins, BSP
Hoa Ly, BSc
Emir Al-Khalili, BA, BScPhm
Benjamin Pearson, BSc
Aleksandar Brezar, BSc
Sophie Bourbonnais, BScPht

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; and Yola Moride, PhD, FISPE. We also thank Kristina Klinovski, BSc, and Rachel Mailhot, students in Occupational Therapy and Biomedical Sciences, respectively, for their participation in the production of the newsletter.

Suggestions?
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Reporting Adverse Reactions
Canada Vigilance Program
Telephone: 1-866-234-2345
Fax: 1-866-678-6789

Copyright
2013 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.