Canadian Adverse Reaction Newsletter
Volume 16 • Issue 3 • July 2006
Health Products and Food Branch
Marketed Health Products Directorate
In this Issue:
Adverse reactions in children: Why report?
Case presentations:
Extended-release methylphenidate withdrawal: priapism
Iodoquinol: hypertensive encephalopathy and seizures
Symposium on drug, food and natural health product interactions
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.
Adverse reactions in children: Why report?
| Key points: |
- Voluntary reporting is important to identify potential adverse reactions (ARs) in children
- Report all safety issues, including abuse and unsafe use of health products
- A plausible timeline from use of a health product to onset of an AR and a suspicion that they are related are sufficient to report an AR
- Include clinical information in the report to facilitate the causality assessment
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Like other patients using health products, children are also at risk of adverse reactions (ARs). In 2005, 7.3% of the domestic AR reports received by Health Canada described ARs associated with health products* in patients 18 years and younger (excluded were reports in which age was not indicated). ARs reported in adults do not always predict ARs in children.1 Several factors help explain why a child's risk of an AR differs from that of an adult when taking the same health product. Some ARs are specific to the paediatric population because of the growth and development that children undergo (e.g., enamel dysplasia with tetracyclines, gray syndrome with chloramphenicol), whereas other ARs occur in adults as well but are more common in children (e.g., dystonia with metoclopramide).2-6
Many health products used in paediatrics have not been developed and assessed specifically for this population and are prescribed to children outside the authorized indications listed in the product monographs (commonly referred to as off-label use).2,4,5 Furthermore, clinical trials, which usually enrol adults, may not be a reliable measure in revealing the risk of ARs in the paediatric population. Scientific evaluations of ARs in children are further complicated by the fact that there are fewer paediatric than adult patients in the general population.7 In addition, there are age-specific subgroups in the paediatric population that often require separate investigations;7 during childhood physiologic changes take place that may have an impact on the pharmacokinetic processes and pharmacodynamic effects of a compound.2 All of the above can result in a relative scarcity of prospectively generated safety information for health products prescribed to children.5,7
Therefore, voluntary reporting4 through the Canadian Adverse Drug Reaction Monitoring Program and other programs such as the Canadian Paediatric Surveillance Program ( www.cps.ca/english/CPSP/Studies/drugreactions.htm) and the Genotype-specific Approaches to Therapy in Childhood Program ( www.genomecanada.ca) remain important as postmarketing surveillance tools to help identify ARs in children. They can contribute to the identification of which types of health products are more likely to cause ARs in children.6 Spontaneous reporting systems may also uncover other types of health-product-related safety issues, such as drug abuse, unsafe drug use and the outcome of accidental drug exposure (Table 1, examples 6, 9 and 13).
The safe use of health products in children is a responsibility shared by various stakeholders, such as health care professionals, research communities, manufacturers, regulatory agencies, and parents and caregivers. Parents and caregivers need to be informed of the benefits as well as potential safety issues related to health products and be encouraged to report any observations to their health care providers to enable better monitoring for possible ARs. The prevention of ARs is highly dependent on communication from health care professionals to Health Canada.8 A plausible timeline from the use of a health product to the occurrence of an AR and a suspicion that the AR is related to its use are sufficient to report an AR. To help evaluate the causality of the association, it is useful to include clinical information in the report, such as the indication for therapy, the dose and therapy dates, concomitant medications, concurrent medical conditions, laboratory results, and the treatment and outcome of the AR.
Health Canada communicates safety information surrounding the use of health products in children in this newsletter; some examples are shown in Table 1. Paediatric safety issues are also conveyed through Health Canada's communications to health professionals and the public as well as those issued by manufacturers.9-11 The ongoing sharing of safety information through voluntary reporting of ARs is key to enhancing the benefit-risk profile of health products used in children.
* Includes pharmaceuticals, biologics (e.g., fractionated blood products as well as therapeutic and diagnostic vaccines), natural health products and radiopharmaceuticals.
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| Table 1: Examples of paediatric safety issues reported in the Canadian Adverse Reaction Newsletter (CARN) from 1991 to 2006* |
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| Example |
Title of article or case presentation |
CARN Issue |
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* The CARN index is available at www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/ar-ei_index_e.html.
Marielle McMorran, BSc, BSc(Pharm); Michel Trottier BScPhm, RPEBC, RPh,
Canadian Adverse Drug Reaction Monitoring Program (CADRMP), Health Canada
Why do surveillance for adverse drug reactions?
- Pre-market clinical drug trials often do not include children
- Many drug products are not labelled for use in specific paediatric age groups
- Data on a drug safety profile is critical in improving care in the paediatric population
- Adverse drug reactions are a major cause of childhood morbidity and mortality, yet alarmingly less than 5% are ever reported to regulators
Canadian Paediatric Surveillance Program
ADR Tip of the Month 03/2004 |
References
- Titchen T, Cranswick N, Beggs S. Adverse drug reactions to nonsteroidal anti-inflammatory drugs, COX-2 inhibitors and paracetamol in a paediatric hospital. Br J Clin Pharmacol 2005;59(6):718-23. [ PubMed]
- De Zwart LL, Haenen HE, Versantvoort CH, et al. Role of biokinetics in risk assessment of drugs and chemicals in children. Regul Toxicol Pharmacol 2004;39(3):282-309. [ PubMed]
- Strolin Benedetti M, Baltes EL. Drug metabolism and disposition in children. Fundam Clin Pharmacol 2003;17(3):281-99. [ PubMed]
- Kimland E, Rane A, Ufer M, et al. Paediatric adverse drug reactions reported in Sweden from 1987 to 2001. Pharmacoepidemiol and Drug Saf 2005;14(7):493-9. [ PubMed]
- Vernacchio L, Mitchell AA. Epidemiology of adverse drug effects. In: Yaffe SJ, Aranda JV, editors. Neonatal and pediatric pharmacology - therapeutic principles in practice. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 813.
- Choonara I, Gill A, Nunn A. Drug toxicity and surveillance in children. Br J Clin Pharmacol 1996;42(4):407-10. [ PubMed]
- Rose K. Better medicines for children - Where are we now, and where do we want to be? Br J Clin Pharmacol 2005;59(6):657-9. [ PubMed]
- Peterson RG, Turner C. The physician's role and responsibility in reporting adverse drug events in children. Paediatr Child Health 2003;8:213-4.
- Important safety information on Strattera (atomoxetine hydrochloride) and the potential for behavioral and emotional changes, including risk of self-harm. Ottawa; 2005 Sept 28. Available: www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2005/index_e.html (accessed 2006 Apr 13).
- Important safety information on Adderall XR. Ottawa; 2005 Aug 31. Available: www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2005/index_e.html (accessed 2006 Apr 18).
- Health Canada endorsed important safety information on Xigris [drotrecogin alfa (activated)]. Ottawa; 2005 May 6. Available: www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2005/index_e.html (accessed 2006 Apr 18).
CASE PRESENTATIONS
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.
Extended-release methylphenidate (Concerta) withdrawal:
suspected association with priapism
A 16-year-old boy taking extended-release methylphenidate (Concerta), with no history of sexual dysfunction, experienced priapism (a painful, persistent and abnormal erection unaccompanied by sexual desire or excitation) that would last up to 24 hours whenever he forgot to take his medication. He had been taking 54 mg of the drug daily for about 1 year for attention deficit hyperactivity disorder (ADHD) and was not taking any other medications. The priapism would resolve after he took his medication. Treatment with extended-release methylphenidate was continued because the product worked well in controlling his ADHD. The patient did not appear to have any sexual dysfunction when he remembered to take his medication. Priapism is not labelled in the Canadian product monograph.1
A case of priapism associated with withdrawal from sustained-release methylphenidate has been reported in the literature.2
References
- Concerta (extended-release methylphenidate) [product monograph]. Toronto : Janssen-Ortho Inc.; 2006.
- Schwartz RH, Rushton HG. Stuttering priapism associated with withdrawal from sustained-release methylphenidate. J Pediatr 2004;144(5):675-6. [ PubMed]
Iodoquinol: suspected association with hypertensive encephalopathy and seizures
A 10-year-old boy with a 2.5-year history of occasional loose stools with vague intermittent abdominal and back pain received a diagnosis of a Dientamoeba fragilis trophozoites infection. The child had no history of seizures, hypertension, current use of prescription drugs or exposure to toxins. Allergy to dust mites and hay fever were reported. An oral suspension of iodoquinol (500 mg/5 mL, 5 mL 3 times daily for 20 days) was prescribed. The suspension was compounded according to a Professional Compounding Centers of America (PCCA) formula using diiodohydroxyquin powder provided by the PCCA ( www.pccarx.ca). According to the reporter, no information regarding potential adverse reactions (ARs) had been given with the prescription. The child had been taking 2 Quest chewable vitamins daily and 500 mg of vitamin C daily when the iodoquinol was started.
By day 14 of the iodoquinol therapy, the patient experienced worsening, painful abdominal cramps and muscle pain. A physician advised to continue treatment. Symptoms progressed, and pinaverium (50 mg 3 times daily) was prescribed. On day 19 of the iodoquinol therapy, new symptoms of pins-and-needles sensation in his feet, ataxic gait, foot drop, stiff legs, general weakness and headache developed. The patient was seen by another physician, and treatment with iodoquinol was advised to continue. That evening, the child experienced a seizure and was taken to hospital, where more tonic-clonic seizures occurred. His blood pressure on admission was 165/120 mm Hg. The iodoquinol therapy was stopped, and treatment with midazolam, phenytoin, clobazam, amlodipine, atenolol, cefotaxime, metronidazole, morphine and acetaminophen was started. The patient was admitted to the intensive care unit. A head CT scan and MRI were in keeping with findings seen in hypertensive encephalopathy. Results of other investigations, including CT of the abdomen and pelvis, blood work, microbiologic tests and chest radiograph, were normal.
After 12 days in hospital, the child was discharged with a normal blood pressure; the amlodipine and clobazam therapies, continued after discharge, were stopped within 2 months. The child followed physiotherapy for over a month. A subsequent MRI of the head indicated complete resolution of previous abnormalities. Five months later, results of a neurologic examination remained normal except for persistence of residual effects such as tingling and sensitivities in the child's legs. Other causes for the hypertension were eliminated.
A paediatric case of encephalopathy and seizures following iodoquinol use was published in 1993.1
References
- Fisher AK, Walter FG, Szabo S. Iodoquinol associated seizures and radiopacity. J Toxicol Clin Toxicol 1993;31(1):113-20. [ PubMed]
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Symposium on drug, food and natural health product interactions
Health Canada's Therapeutic Products Directorate (TPD) hosted a symposium in February 2006 to raise awareness about drug, food and natural health product (NHP) interactions. The symposium assembled internationally distinguished speakers and was attended by 260 participants from academia, industry and health care associations as well as consumer and patient advocacy groups.
The sessions addressed scientific and regulatory issues: adverse reactions due to drug-food-NHP interactions; mechanisms of action and means to evaluate the data; international surveillance strategies; and discussions on improvements to assist the consumer in avoiding these interactions.
The effort to increase awareness about drug-food-NHP interactions is a shared responsibility between government, industry, health care professionals and consumers. More dissemination of user-friendly information is required to assist the consumer in making informed choices about safe health product use. Health Canada will continue to work collaboratively to implement risk management strategies to minimize the potential risk of adverse interactions between drugs, foods and NHPs. For more information on the symposium, go to: www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/announce-annonce/index_e.html
Canadian Adverse Reaction Newsletter
Marketed Health Products Directorate
AL 0701C
Ottawa ON K1A 0K9
Tel 613 954-6522
Fax 613 952-7738
Health professionals/consumers report toll free:
Tel 866 234-2345
Fax 866 678-6789
Editorial Staff
Ann Sztuke-Fournier, BPharm (Editor-in-Chief)
Ilhemme Djelouah, BScPhm, DIS, AFSA, Medical Biology (University of Paris V)
Gilbert Roy, BPharm
Michel Gagné, BScPht
Michel Trottier, BScPhm, RPEBC, RPh
Christianne Scott, BPharm, MBA
Acknowledgements
Expert Advisory Committee on Pharmacovigilance, Regional AR Monitoring Offices and Health Canada staff.
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E-mail: mhpd-dpsc@hc-sc.gc.ca
Copyright
Her Majesty the Queen in Right of Canada, 2006. 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.
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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
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