Canadian Paediatric Surveillance Program: ADR Tips of the Month

Oral contraceptive pills are a common form of hormonal contraception for adolescents. Two types are available: a progestin-only method and a combined oral contraceptive (COC) method that includes a synthetic estrogen, like ethinyl estradiol, and a progestin, like norgestrel or levonorgestrel.

Physicians should be aware that:

the efficacy of COCs is reduced when taken concurrently with some antiepileptics, St. John’s Wort, medications to treat HIV, rifampin and griseofulvin, amongst others;
there is no evidence to date that concurrent use of these medications reduces the efficacy of the progestin-only method.

Please report all serious adverse drug reactions (ADRs).

References:
http://www.cps.ca/english/statements/AM/AH10-02.htm
http://aappolicy.aappublications.org/cgi/content/full/pediatrics;116/4/1026
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2004/lamictal_hpc-cps-eng.php

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November 2010
Did you know?

To monitor the safety profile of health products marketed in Canada and ensure that the benefits outweigh the risks, the Canada Vigilance Program (Health Canada's post-market surveillance program) collects and assesses reports of suspected adverse reactions to health products.

Reports of adverse reactions are submitted by health care professionals and consumers on a voluntary basis, either directly to Health Canada or via manufacturers of health products (or market authorization holders).

By participating in the CPSP ADR study, paediatricians and paediatric subspecialists are contributing important data to be shared with the Canada Vigilance Program.

Please report all serious adverse drug reactions (ADRs).

Reference: http://www.hc-sc.gc.ca/dhp-mps/medeff/vigilance-eng.php

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October 2010
Metoclopramide – Risk of tardive dyskinesia

High doses or long-term use of metoclopramide, a medication used to increase bowel motility, has been linked to tardive dyskinesia, which may include involuntary and repetitive movements of the body. Symptoms are rarely reversible and there is no known treatment.

Physicians should:

Be aware of the risks and discuss treatment options with family;
Avoid chronic use in all but rare cases where the benefit is believed to outweigh the risk;
Be reminded that recommended treatment should not exceed three months.

Please report all serious adverse drug reactions (ADRs).

Reference
www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm106942.htm

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September 2010
Adverse drug reactions in children: Why report?

Drugs are often prescribed in paediatrics for different indications than the ones for which they were originally approved, or even if they have only been approved for use in the adult population.

The lack of pharmacological research in the paediatric group is often associated with specific problems, including:

Under- or over-dosing in some age groups due to the lack of pharmacokinetics data.
Physiological variances between children and adults significantly influencing the actions, effectiveness and safety of medicines. Variances include:
- Absorption (oral, topical, rectal)
- Distribution (body composition, plasma protein binding, blood-brain barrier)
- Metabolism
- Excretion.

ADRs identified in adults are not necessarily the same as in the paediatric population.

Voluntary reporting is important to identify potential adverse drug reactions in children.

Please report all serious adverse drug reactions (ADRs).

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August 2010
St. John’s Wort (Hypericum perforatum) – Benefits and risks

St. John’s Wort has evidence of effectiveness in the treatment of mild to moderate depression.

Physicians should however be aware of:

Reported adverse effects, including hypertension, photosensitivity, mania and serotonin syndrome. Caution is needed in patients also treated with 5-hydroxythyrophan agonists such as sumatriptan.
Induction of cytochrome P450 3A4, a major enzyme responsible for approximately half of all oxidative drug metabolisms which may alter the response of medications, such as:
- antibiotics – clarithromycin, erythromycin
- anti-retroviral drugs – indinavir, saquinavir
- benzodiazepines – alprazolam, midazolam
- anti-rejection drugs – cyclosporine, tacrolimus
- cardiovascular drugs – amiodipine, nifedipine
- others – atorvastatin, haloperidol, methadone and quinine.

Some authorities recommend avoiding St. John’s Wort entirely in patients being treated with such drugs.

Please report all serious adverse drug reactions (ADRs).

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July 2010
Are serious paediatric ADRs occurring in Canada?

The answer is yes.

In 2009, the CPSP ADR study confirmed 45 cases of suspected serious paediatric adverse drug reactions.
The product groups most commonly associated with ADRs were anticonvulsant, anti-infective and antineoplastic agents.

Physicians should be aware that:

Adverse reactions to health products are considered to be suspicious, as a definite causal association often cannot be determined.
Spontaneous reports of ADRs cannot be used to estimate the incidence, because ADRs remain under-reported and patient exposure is unknown.

For more information on the ADR study, see pages 19-21 of the CPSP 2009 Results at www.cps.ca/English/surveillance/cpsp/Studies/2009Results.pdf.

Please report all serious adverse drug reactions (ADRs).

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June 2010
Did you know?

Product name suffixes help identify a modified-dosage formulation, a different dosing schedule or product strength. As an unintended consequence, these may contribute to confusion and medication errors. While no standard definitions exist, some of the most commonly used include:

AM	Non-drowsy
AQ	Aqueous
CD	Controlled delivery – extended release
CR	Controlled release
DS	Double strength
EX	Extra strength
HP	High potency
LA	Long acting
Lo	Low dose
M-Tab	Melt tab
PF	Preservative-free
PM	Nighttime
SR	Slow release
XL	Extended release
XR	Extended release

Please report all serious adverse drug reactions (ADRs).

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May 2010
Montelukast (SingulairTM): Risk of psychiatric adverse reactions

Montelukast sodium (SingulairTM), a leukotriene-receptor antagonist, is used in the treatment of asthma and seasonal allergic rhinitis. Adverse reactions related to self-injury, suicidality, depression, hostility or psychosis, suspected of being associated with the use of montelukast, were reported.

Physicians should:

Be aware of the risk of suicidality and other psychiatric adverse reactions with the use of montelukast.
Reduce or stop the drug immediately if psychiatric signs and/or symptoms appear.
Realize that, in some patients, the adverse reactions can reappear upon
re-introduction of the drug. Very close observation is recommended.

Reference
www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v19n3-eng.php#a1

Please report all serious adverse drug reactions (ADRs).

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April 2010
Complementary and alternative medicine

Complementary and alternative medicine (CAM) is a group of diverse medical and health care systems, practices and products that are not generally considered part of conventional medicine.

Most paediatric patients who receive CAM also receive conventional care.
CAM-related harms can be direct (e.g., anaphylactic reaction) or indirect, such as delays in diagnosis and/or treatment.
Concurrent use of natural health products (NHP) and conventional pharmaceuticals can result in an NHP-drug interaction.*
Paediatricians should have an open and respectful communication with families to learn about their CAM use.

* http://www.cpjournal.ca/doi/pdf/10.3821/1913-701X-142.5.224a

Please report all serious adverse reactions (ARs).

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March 2010
Topical anesthetics-induced methemoglobinemia

EMLATM and AMETOP GelTM and locally compounded products are used topically to provide analgesia prior to immunizations or minor skin procedures. Paediatric cases of methemoglobinemia (MHb) have been reported with topical anesthetics.

Physicians should:

Know that the risk of serious adverse effects increases with the concentration and the quantity of topical anesthetic used, such as:
- application to large area of the body
- application to abraded or diseased skin
- occlusion of the treated area with plastic wrap or dressing.
Be aware that MHb is an uncommon adverse reaction resulting in an impaired ability of red blood cells to bind and carry oxygen and may lead to cyanosis, weakness and coma.
Observe infants closely for signs and symptoms of MHb, such as pallor, cyanosis, headache, lethargy, respiratory depression, convulsions and cardiac arrhythmias.

Reference
www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/emla_ametop_hpc-cps-eng.php

Please report all serious adverse drug reactions (ADRs).

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February 2010
What are the possible actions taken by health product regulatory authorities?

Regulatory actions may vary depending on the nature, seriousness and frequency of the reaction, as well as the benefit-risk profile of the product. A range of regulatory actions may be taken by the regulatory authority, including:

Continued monitoring of the health product.
Risk management and minimization measures, such as labelling changes, change of indication, change in dosage, etc.
Risk communication, such as public and/or health professional communications.
Withdrawal of the product from the market.

Please report all serious adverse drug reactions (ADRs).

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January 2010
Fluticasone (Flovent^TM) – Risk of adrenal suppression

Fluticasone is used in the management of asthma. Cases of adrenal insufficiency have been reported in children with the utilization of inhaled corticosteroids.

Physicians should:

Know that systemic absorption of inhaled corticosteroids can lead to suppression of endogenous glucocorticoids and cause adrenal insufficiency/crisis.
Realize that presenting signs and symptoms can be vague, like anorexia and fatigue, or more severe, like hypoglycemia, hypotension, convulsion and death.
Prescribe only the lowest effective dose of the medication.
Manage adrenal suppression by careful tapering of the dose, since an abrupt discontinuation of the medication could precipitate a crisis.

Please report all serious adverse drug reactions (ADRs).

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December 2009
Need information on licensed natural health products?

In the past, natural health products (NHPs) have not been closely monitored; however, Canada has taken a leadership role in regulating NHPs and in providing data to clinicians and consumers.

Physicians can find the following information on licensed NHPs on the Health Canada website:

Name
License holder
Natural product number (NPN) or homeopathic medicine number (DIN-HM)
Medicinal and non-medicinal ingredients
Dosage form
Recommended use or purpose
Risk information such as cautions, warnings, contra-indications and known adverse reactions

Reference: www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/lnhpd-bdpsnh-eng.php

Please report all serious adverse drug reactions (ADRs).

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November 2009
Important possible side effects associated with Tamiflu^TM – oseltamivir phosphate

Adverse effects to oseltamivir in children are uncommon. However, there are concerns that children and adolescents with influenza may be at increased risk of unusual neurological or psychiatric events shortly after beginning oseltamivir phosphate, a neuraminidase inhibitor antiviral drug.

Reported adverse events include agitation, anxiety, nightmares, seizures, confusion, delirium, hallucinations or abnormal behaviour, including self-harm in some users.

Physicians should:

Advise patients and families of potential side effects and unusual behaviours.
Ensure that affected patients are promptly assessed and monitored.
Participate in epidemiological data collection to advance knowledge of possible adverse events related to neuraminidase inhibitor drugs.

Please report all serious adverse drug reactions (ADRs).

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October 2009
What are look-alike sound-alike health product names?

Some marketed health products appear similar when written or spoken, known as a look-alike sound-alike (LA/SA) issue. The name confusion is one of the most frequent causes of dispensing errors (29%) that can result in ADRs.

To avoid LA/SA confusion, physicians should:

Write prescriptions clearly.
- by printing the name of the product in block letters,
- by not using abbreviations,
- by using electronic prescriptions;
include more information about the product
- both brand name and generic name,
- strength, dosage and directions clearly indicated;
ensure that patient/family member understands why the medication has been prescribed.

Reference
www.hc-sc.gc.ca/dhp-mps/brgtherap/activit/fs-fi/lasa-pspcs_factsheet-faitsaillant-eng.php

Please report all serious adverse drug reactions (ADRs).

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September 2009
Fentanyl-induced muscular rigidity

Analgesia is an important component of pain management in newborn care. Intravenous administration of fentanyl carries the risk of thoracic muscular rigidity, leading to inadequate ventilation, severe hypoxemia, respiratory acidosis, secondary bradycardia and hypotension, and death.

Physicians should:

Have resuscitative equipment readily available.
Give slow bolus fentanyl injection.
Respond rapidly to first signs of respiratory or cardiovascular effects by the use of:
- Assisted or controlled mechanical ventilation.
- A specific narcotic antagonist to reverse the apnea, e.g. naloxone.
- A neuromuscular blocking agent compatible with the patient’s condition to eliminate the diaphragm and intercostal rigidity.
- An anticholinergic medication to counteract the bradycardia, e.g. atropine.
Provide longer surveillance to ensure the effects of fentanyl have completely disappeared.

Please report all serious adverse drug reactions (ADRs).

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August 2009
Why is pharmacovigilance important?

Pharmacovigilance consists of information gathering, monitoring and evaluation of data, and risk management throughout a drug product’s life cycle.

The goals of the process include:

Record of suspicions from clinicians
Early detection of signals
Appropriate and timely causality assessment
Minimization of negative effects to health of paediatric patients
Timely drug recall, if judged appropriate.

An ADR report denotes a temporal association but does not prove causation. Such an association is sufficient to make a report.

Please report all serious adverse drug reactions (ADRs).

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July 2009
Purple glove syndrome – Rare complication of intravenous phenytoin

Progressive distal limb edema, discoloration and pain are rare complications occurring after intravenous phenytoin use and are known as the purple glove syndrome.

Physicians should:

Identify manifestations early to prevent damage to hand and arm.
Limit infusion of phenytoin to a rate of less than 50 mg/min.
Treat with elevation and warm compresses to relieve pressure and restore blood flow.
Proceed with surgical procedures, such as fasciotomy or amputation in rare cases, if conservative management is unsuccessful.

Please report all serious adverse drug reactions (ADRs).

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June 2009
When to report an ADR

Clinicians are encouraged to report an ADR when the event...

Is serious, with one or more of the following criteria:
- Potentially life-threatening
- Results in death
- Requires or prolongs hospitalization
- Results in residual disability
- Is considered medically important.
Requires urgent medical attention.
Is unusual or unexpected.
Has no obvious explanation at the time of reporting.

Please report all serious adverse drug reactions (ADRs).

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May 2009
Ibuprofen – Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

The CPSP has received recent reports of SJS and TEN suspected with the use of ibuprofen in the treatment of fever in children.

Diseases include a macular red rash, blisters on mucous membranes, and small areas of peeling skin (SJS) or large areas of peeling skin (TEN). Both are rare and can be life-threatening.

Physicians should:

Discontinue ibuprofen immediately, if suspected.
Hospitalize children, in a burn unit when possible.
Consult with a physician expert in the management of SJS.
Provide scrupulous care to avoid infection.
Replace fluids and salts, which are lost through the damaged skin, intravenously.

Reference: www.merck.com/mmhe/sec18/ch203/ch203e.html

Please report all serious adverse drug reactions (ADRs).

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April 2009
What is pharmacovigilance?

Pharmacovigilance is the process relating to the detection, assessment, understanding and prevention of adverse events following drug administration.

Clinicians are key players in pharmacovigilance when they:

Report spontaneous adverse events to Health Canada (passive surveillance).
Participate monthly in the CPSP ADR study (active surveillance).

Please report all serious adverse drug reactions (ADRs).

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March 2009
Desmopressin (DDAVP®) – Risk of hyponatremia

Desmopressin is used in the management of primary nocturnal enuresis. Recent cases of hyponatremia with the risk of convulsions and death have been reported with the intranasal formulation.

Physicians should:

Know that desmopressin may lead to water intoxication and/or hyponatremia.
Prescribe only the lowest effective dose of the oral formulation.
Adjust carefully fluid intake and desmopressin dosage when increased water intake can be expected, such as in hot climate or during intense exercise.
Pay attention to prodromal symptoms (headache, nausea and vomiting) and advise patients to discontinue desmopressin immediately and seek medical assessment.

Reference: www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/desmopressin_hpc-cps-eng.php

Please report all serious adverse drug reactions (ADRs).

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February 2009
How are drugs tested in Canada before marketing?

The pre-marketing drug evaluation testing process involves five sequential steps:

Laboratory research (in vitro)
Animal studies (in vitro)
Phase 1 trial in 10 to 100 individuals to assess toxicity only
Phase 2 trial in 50 to 500 individuals to assess effectiveness and safety
Phase 3 trial in 300 to 30,000 individuals to further assess effectiveness and safety.

Physicians should know that:

Most drugs are not tested in children prior to marketing;
Post-marketing surveillance is essential to detect rare ADRs.

Please report all serious adverse drug reactions (ADRs).

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January 2009
Codeine and breast milk transmission

Although products containing codeine have been used for many years, their safety has recently been questioned in the context of a fatal adverse reaction in a breastfed infant (1).

To exert analgesic effects, codeine is metabolized to morphine. Certain ethnic groups are at higher risks of being ultra-rapid metabolizers and having higher-than-expected morphine levels in breastmilk (2).

Physicians should:

Use the lowest effective codeine dose, for the shortest period of time, if treatment is deemed necessary.
Alert parents to monitor infants carefully for sedation and seek immediate medical attention if concerned.
Be aware that no test is currently available for general use in Canada to identify ultra-rapid metabolizers of codeine.

References

1. www.motherisk.org/prof/commonDetail.jsp?content_id=839

2. www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_164-eng.php

Please report all serious adverse drug reactions (ADRs).

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December 2008
Did you know?

In Canada, 3,891,808 prescriptions were dispensed in pharmacies for the paediatric specialty in 2007. The top 10 medications, representing 33% of these prescriptions are:

Concerta
Ratio-Salbutamol HFA
Flovent HFA
Apo-Amoxi
Singulair
PMS-Methylphenidat
Adderall XR
Strattera
Dexedrine
Novamoxin

As more than 75% of prescribed pharmaceuticals in North America have never been tested in paediatric populations, post-marketing surveillance depends on the active participation of physicians.

Reference: www.imshealthcanada.com

Please report all serious adverse drug reactions (ADRs).

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November 2008
Minocycline-induced pseudo-tumor cerebri

For the treatment of acne, minocycline is among the top four oral antibiotics most commonly prescribed.

Minocycline has been associated with pseudo-tumor cerebri or idiopathic intracranial hypertension.

Physicians should:

watch for symptoms of nausea, headache, dizziness and blurred vision,
confirm the presence of papilledema,
stop the use of minocycline,
prevent visual loss with lumbar puncture, serial if necessary, acetazolamide and/or corticosteroids and/or surgery when visual loss is severe or unresponsive to medical therapy.

Please report all serious adverse drug reactions (ADRs).

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October 2008
Did you know?

Genetic factors contribute to most ADRs.

The cytochrome (CYP) P450 family of enzymes metabolizes more than half of the drugs that could cause ADRs.

Carbamazepine and phenytoin, by inducing CYP3A4, reduce the concentration of oral contraceptives.
- Other CYP3A inducers include St. John’s wort, rifampin, and ritonavir.
Macrolide antibiotics, by inhibiting CYP3A4, can increase the concentration of cyclosporin and increase the risk of renal damages.
- Other CYP3A inhibitors include grapefruit juice, ketoconazole, and fluconazole.

Please report all serious adverse drug reactions (ADRs).

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September 2008
Succinylcholine-induced major toxic effects

To facilitate rapid tracheal intubation, succinylcholine is a neuromuscular depolarizing relaxant frequently used in emergency medicine.

Succinylcholine has been associated with:

masseter muscular rigidity;
malignant hyperthermia;
cardiac arrest and death from hyperkalaemic rhabdomyolysis in infants and children with undiagnosed myopathies.

Physicians should:

monitor carefully for peaked T-waves (an early sign);
administer intravenous calcium, bicarbonate and glucose with insulin promptly;
hyperventilate and continue cardiopulmonary ressuscitation for a longer period.

Please report all serious adverse drug reactions (ADRs)

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August 2008
Did you know?

Non-immunological adverse drug reactions (ADRs) can be classified as either “pharmacological” or “idiosyncratic” reactions.

Pharmacological ADRs are:

most common;
usually dose-related;
occuring when drug concentration in plasma or tissue exceeds the “therapeutic window” or when there is increased sensitivity to the drug.

Idiosyncratic ADRs are:

less common though often serious;
not dose-dependent;
not showing simple relationship between the dose and the occurrence of toxicity or the severity of the reaction;
affecting many organ systems in isolation or combination.

Please report all serious adverse drug reactions (ADRs)

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July 2008
Carbamazepine-induced severe skin reactions

Carbamazepine is a very useful anti-epileptic medication.
Patients with the human leukocyte antigen (HLA) allele HLA-B*1502, found almost exclusively in individuals of Asian ancestry, particularly Han Chinese, have more frequent severe or even fatal skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, when taking carbamazepine.
Physicians should screen patients with Asian ancestry for HLA-B*1502 allele before initiating treatment with carbamazepine.

Reference: www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/tegretol_hpc-cps-eng.php

Please report all serious adverse drug reactions (ADRs).

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June 2008
ADRs in children – Similar or different to ADRs in adults?

ADR profile in children may be quite different compared to adults.
Very rare in children:
hepatic dysfunction with flucloxacillin;
blood dyscrasias with cotrimoxazole.
More common in children:
serum sickness with cefaclor;
serious skin reaction with lamotrigine.
Similar examples of differences in reaction profile are likely yet unknown.

Reference: Australian Adverse Drug Reactions Bulletin, Vol. 24, No. 5, October 2005

Please report all suspected adverse drug reactions (ADRs)

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May 2008
Medications as a trigger for anaphylaxis

The CPSP Anaphylaxis study confirmed >700 paediatric cases.
Medications accounted for 8% of confirmed cases.
Antibiotics, anticonvulsants and antineoplastic medications were the most common cases confirmed by the CPSP ADR study.
Anaphylaxis to a medication is classified as a serious and life-threatening event.
Epinephrine is the drug of choice and should be administered promptly.

Please report all suspected adverse drug reactions (ADRs)

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April 2008
Acetaminophen – Overdose with therapeutic use?

Many pharmaceutical products contain acetaminophen
Severe hepatotoxicity related to overdose in a therapeutic setting can occur.
Physicians should recommend to parents and/or patients to avoid:
- giving or taking concurrent medications as they may contain acetaminophen;
- exceeding the maximum daily dose;
- using more than a few days without consulting a health care professional.

Please report all suspected adverse drug reactions (ADRs).

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December 2006
Suspicious of an ADR? Report!

As a clinician, a high index of suspicion is a valuable tool in identifying possible ADRs.

You do not need to be entirely certain that the suspected drug has caused the reaction.

Continued vigilance in reporting ADRs can help increase our understanding of the scope of the problem and document a true incidence of ADRs in the paediatric population.

Please report all suspected adverse drug reactions (ADRs).

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November 2006
Infliximab (RemicadeTM) and hepatosplenic T-cell lymphoma

Hepatosplenic T‑cell lymphoma is a rare form of non‑Hodgkin’s lymphoma with only 150 cases published worldwide.

Six cases (including five deaths) were reported in American patients taking infliximab for Crohn’s disease.
Five of these reports were in patients aged 12 to 18 years.
All reported cases had concomitant or past use of other immunosuppressive agents, including azathioprine and 6-mercaptopurine.

More information is available from Health Canada at www.hc-sc.gc.ca.

Please report all serious adverse drug reactions (ADRs).

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October 2006
Why report?

By submitting a suspected adverse drug reaction report, you are an essential member of the post-marketing surveillance team and contribute to:

The collection of safety and efficacy data on medication use in children.
The identification of previously unrecognized, rare and/or serious adverse reactions.
Maintaining a comprehensive safety and effectiveness profile of products made available to Canadian children.

One reported case can make a difference and benefit all Canadian children and youth.

Please report all suspected adverse drug reactions (ADRs).

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September 2006
ADHD medications

Attention deficit hyperactivity disorder management includes psycho-educational measures and medications.

Products like amphetamine, methylphenidate and atomoxetine are cardiovascular stimulants that, in rare cases, are associated with serious arrhythmia, stroke, cardiac arrest or sudden death.

Physicians should:

Review family history for heart-related conditions or sudden cardiac death.
Enquire about involvement in strenuous exercises or activities.
Refrain from using ADHD drugs in the presence of:
- moderate to severe hypertension
- symptomatic cardiovascular disease
- known structural cardiac defects or
- hyperthyroidism.

Please report all serious adverse drug reactions (ADRs).

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August 2006
Signs and symptoms of serious ADRs

Serious adverse drug reactions include those that are fatal, life-threatening, resulting in significant disability or requiring hospitalization. The following are some examples:

Aplastic anemia and chloramphenicol
Arrythmia, QT prolongation and cisapride
Congenital malformations and isotretinoin
Immune hemolytic anemia and ceftriaxone
Necrotizing pancreatitis and valproic acid
Reye’s syndrome and acetylsalicylic acid
Seizures and camphor ingestion
Visual loss and ethambutol.

Please report any suspected adverse drug reactions (ADRs).

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July 2006
Neuroleptic malignant syndrome

Rare event associated with neuroleptic drugs
Potentially fatal in 25% of cases
Clinical presentation:
- High fever
- Profuse sweating
- Tachyarrhythmia
- Stiffness of extremities
- Marked elevation of creatinine phosphokinase
- Myoglobinuria
Physicians should stop neuroleptic drugs at the earliest signs and symptoms of this syndrome and administer intravenous sodium dantrolene.

Please report all serious adverse drug reactions (ADRs).

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June 2006
Safe use of energy drinks

Energy drinks are meant to supply mental and physical stimulation for a short period of time. They usually contain caffeine, but other substances can also be found, such as:

carbohydrate
taurine
glucuronolactone
various vitamins.

If these drinks are used in a manner contraindicated on the label, in excess of the recommended dose or mixed with alcohol, serious health effects can result.

Health Canada has received four reports of adverse reactions involving energy drinks, including:

nausea, vomiting and abdominal pain
dizziness and hypotension
tremor and decreased consciousness
electrolyte disturbances
dyspnea and arrhythmias.

Please report all serious adverse drug reactions (ADRs).

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May 2006
Topiramate (Topamax®)-induced metabolic acidosis

Topiramate, a carbonic anhydrase inhibitor, is an adjunctive therapy for refractory complex seizures.

Severe metabolic acidosis was reported in children treated with topiramate after starting a ketogenic diet.

Other risk factors include:

diarrhea
respiratory infections
status epilepticus
surgery
renal dysfunction.

Physicians should measure baseline and periodic serum bicarbonate during topiramate therapy.

Please report all serious adverse drug reactions (ADRs).

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April 2006
ADR detailed report forms

The Canadian Paediatric Surveillance Program reinforces the importance to include all relevant information when completing the adverse drug reactions (ADR) detailed questionnaires.

To adequately assess causality, physicians must provide the following information:

Drug name
Dose, frequency and route used
Date of suspected ADR
Date of reaction
Therapy dates
Concomitant drugs
Medical history/other conditions

Your cooperation in completing ADR forms accurately is appreciated.

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March 2006
Cefprozil (Cefzil®)

Cefprozil, a cephalosporin antibiotic, ranks ninth among the ten most commonly prescribed paediatric drug in Canada , according to IMS Health.

Suspected adverse reactions to cefprozil reported to the CPSP include:

urticarial rash;
prolonged prothrombin time with bleeding diathesis;
anaphylaxis;
Stevens-Johnson syndrome.

Please report all serious adverse drug reactions (ADRs).

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February 2006
Facts about natural health products

Many natural health products (NHPs) are available, widely used in children and regulated in Canada by the Natural Health Products Directorate. NHPs include:

Herbs
Homeopathic remedies
Probiotics
Traditional Chinese medicine
Ayurvedic medicine (used in traditional Indian healing)
Essential fatty acids not produced by humans and obtained through diet
Amino acids, vitamin and mineral supplements.

Physicians should inquire about NHP use in their patients.

Please report all serious adverse drug reactions (ADRs).

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January 2006
What is an ADR?

An ADR is any unexpected, unintended, undesired or excessive response to a drug that requires:

discontinuing the drug,
changing the drug therapy,
modifying the dose,
admission to hospital.

Physicians are reminded that ADRs can:

significantly complicate diagnosis;
negatively affect prognosis;
result in temporary or permanent harm, disability or death.

Please report all suspected adverse drug reactions (ADRs).

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December 2005
Important safety information about cold medications

Many cold medications administered orally, such as pseudoephedrine, have sympathomimetic components associated with the risk of the following adverse effects:

irritability
sleep disturbances
hallucinations
seizures
severe tachycardia and arrhythmia
severe hypertensive episodes

Physicians are reminded that:

these medications are not very effective;
"over-the-counter" cold medicines
- are contraindicated in infants < six months of age,
- should not be given to children < three years of age without close supervision.

Please report all serious adverse drug reactions (ADRs).

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November 2005
Identifying and preventing ADRs

ADRs caused by drug interaction may be due to drug effects on:

metabolic pathways,
enzyme induction ( increased metabolism), and
enzyme inhibition (decreased drug clearance).

Physicians should:

take a medication history,
have a high index of suspicion,
be aware of the toxic profile of prescribed drugs,
know that sign of drug toxicity can vary and affect any organ,
realize that ADRs
- increase with polypharmacy
- mimic other diseases.

Please report all serious adverse drug reactions (ADRs).

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October 2005
Important information about valproic acid (Depakene®, Epival®)

The CPSP has received recent reports of necrotizing pancreatitis suspected with the use of valproic acid in the treatment of convulsions in children.

Physicians should:

watch for symptoms of nausea, anorexia, abdominal pain and/or vomiting;
perform pancreatic function tests;
stop the use of valproic acid, if the diagnosis of pancreatitis is confirmed;
change the anti-convulsant medication for the patient.

Please report all serious adverse drug reactions (ADRs).

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September 2005
Follow your instinct

More than 75% of prescribed pharmaceuticals on the market have never been tested in paediatric populations.
Post-marketing surveillance depends on the active participation of reporters.
A clinician’s index of suspicion is one of the most valuable tools in identifying an adverse drug reaction.
Next time you suspect that your patient might have experienced an adverse drug reaction…

PLEASE REPORT.

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August 2005
Ayurvedic Medicinal Products – Heavy Metal Poisoning

Ayurvedic products used in traditional Indian healing are often imported from India.

Unapproved products found on the Canadian market and analyzed by Health Canada revealed high levels of heavy metals such as arsenic, lead and mercury. Children are most susceptible to toxic effects from heavy metal poisoning.

Ayurvedic products authorized for sale in Canada will have either:

a drug identification number (DIN)
a natural product number (NPN) or
a homeopathic drug number (DIN-HM).

For more information, visit: http://www.hc-sc.gc.ca/english/protection/ warnings/2005/2005_80.html

Please report any suspected adverse drug reactions (ADRs).

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July 2005
Important safety information about DIANE®-35

All estrogen/progesterone combinations carry a risk of thrombophlebitis and thromboembolic disorders that increases with cigarette smoking.

There appears to be an elevated risk of blood clots in DIANE-35 users, compared to other combinations of oral contraceptive.
DIANE-35 should:
- not be prescribed for birth control alone,
- be reserved for women suffering from pronounced forms of acne, and
- be discontinued three or four months after signs of acne have completely resolved.

Please report any occurrences of thromboembolic disorders or other serious adverse drug reactions (ADRs) in patients receiving DIANE-35.

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June 2005
Did you know?

When a patient takes multiple medications, the likelihood of an adverse drug reaction increases.

Physicians should:

watch for any ADRs resulting from an interaction between medications;
pay particular attention to multi-ingredient medications and know all the components of such products;
favour single-ingredient medications, whenever possible.

Please report any suspected adverse drug reactions (ADRs).

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May 2005
Ibuprofen and nephrotoxicity

Fever is a physiological phenomenon.
Febrile young children have:
- increased insensible water loss;
- increased risk of dehydration.
Ibuprofen use in volume-depleted children has been associated with rare complications of acute renal failure.
Physicians should advise parents on the importance of adequate fluid intake and hydration of all febrile children, especially those taking ibuprofen.

Please report any suspected adverse drug reactions (ADRs).

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April 2005
The Power of One

A single report of a serious adverse drug reaction may lead to:

further investigation of a drug’s safety
removal of a drug from the market
better understanding of the mechanisms involved in adverse reactions.

One report can potentially save many lives.

You could make the difference.

Please report all serious ADRs.

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March 2005
Camphor and/or eucalyptus oils

Are found in over-the-counter:
- cough/cold remedies used as chest rubs or by steam inhalation;
- creams/ointments to relieve sore muscles or cold sores.
Can be toxic for children.
Are not intended for oral use.
Can cause life-threatening reactions like SEIZURES if swallowed accidentally.

Physicians should warn parents to store these products out of reach of children to prevent accidental poisoning.

Please report any suspected adverse drug reactions (ADRs).

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February 2005
Ceftriaxone (Rocephin®)-induced immune hemolytic anemia (IHA)

Rare event
- Nine paediatric cases reported
High mortality rate
- Six paediatric deaths reported
Clinical presentation
- Fever
- Back pain
- Severe hemolytic anemia
- Hemoglobinuria
- Hypotension
- Acute renal failure

Physicians should stop ceftriaxone at the earliest signs and symptoms of IHA.

Please report all serious adverse drug reactions (ADRs).

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January 2005
Important safety information about medroxyprogesterone acetate (Depo-Provera®)

New clinical studies suggest that women receiving medroxyprogesterone acetate injections may lose significant bone mineral density.

Bone loss:
- is greater with increased duration,
- may not be completely reversible.
Rare cases of osteoporosis, including osteoporotic fractures, have been reported.

Adolescence is a critical period of bone accretion to reach an adequate peak bone mass and to prevent osteoporosis in later life.

Physicians should consider this impact on peak bone mass when selecting medications for adolescents.

Please report all serious ADRs.

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December 2004
Winter brings cold and flu season

When treating, remind that:

Over-the-counter (OTC) cough medications are contraindicated in infants < six months of age.
Over 600 OTC and prescription medicines contain acetaminophen:
- pain relievers
- cough suppressants
- cold medications.
Polypharmacy increases the risk of ADRs
ASA is linked to Reye syndrome and should not be given.

Please report all severe ADRs you do see.

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November 2004
Survey - Your feedback will help the CPSP evaluate and improve these ADR Tips.

Do you read the tips?

Yes ____ No ____
__________________________________
__________________________________

Do you find them useful?

Yes ____ No ____
__________________________________
__________________________________

How could they be improved?
__________________________________
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__________________________________

Any suggestions
__________________________________
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Please return with your monthly report form.
Thank you for your participation.

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October 2004
New safety information about lamotrigine (Lamictal®)

Concomitant use of lamotrigine with hormonal contraceptives has been associated with limited reports of seizures, breakthrough bleeding, and unexpected pregnancies.

Significant adjustments in the maintenance dose of lamotrigine may be required in some patients.

Physicians should:

advise patients using these drugs to:
- be aware of these interactions,
- promptly report any changes in their menstrual pattern, especially breakthrough bleeding,
- seek appropriate consultation before stopping or restarting their oral contraceptives.
monitor serum lamotrigine levels closely and adjust the maintenance dose accordingly.

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September 2004
Transdermal fentanyl (Duragesic): respiratory arrests in adolescents

Two cases of respiratory arrest in adolescents using transdermal fentanyl showed the following:

In each case, this was a first-time opioid use.
The fatal outcome occurred at 14 and 21 hours after application of Duragesic 25.
Transdermal fentanyl is not suitable for acute pain management or for opioid naive patients.
Signs of serious opioid-related toxicity include hypoventilation and cognitive impairment and should be recognized early and acted upon rapidly.

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August 2004
Adverse drug reactions (ADRs) can take many different forms

Your patient presents with serious or life-threatening

haematological or biochemical laboratory results and/or
symptoms of undetermined etiology.

Have you considered an adverse drug reaction?

All these cases are vital to ADR surveillance.

PLEASE REPORT.

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July 2004
Important safety information about SSRIs (selective serotonin reuptake inhibitors) and other newer antidepressants

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

If discontinuing these drugs, a gradual reduction in the dose rather than an abrupt cessation is recommended to prevent discontinuation symptoms.

PLEASE REPORT ANY SUSPECTED ADRs

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June 2004
True or False

All serious ADRs are documented by the time a drug is marketed.
It is difficult to determine if a drug is responsible.
ADRs should only be reported if absolutely certain.
One reported case can’t make a difference.

All of the above are common misconceptions about ADR reporting.

Help us address these issues with your active participation.

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May 2004
Good decisions are based on good data

Increased knowledge will improve the safe use of medications in children.

Establishing the time sequence from drug exposure to the adverse reaction is critical in determining causality.

If available, please provide dates for:

start of medication(s)
onset of the reaction.

If unavailable, indicate a general time frame; e.g., onset of reaction was five days after the start of therapy.

Improved ADR reporting will help detect product safety signals in this paediatric population.

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April 2004
Feasibility study of active surveillance of adverse reactions in children

(Excerpt from the Canadian Adverse Reaction Newsletter, Volume 14, Issue 2, April 2004, Health Products and Food Branch, Marketed Health Products Directorate, Health Canada)

In January 2004, the Marketed Health Products Directorate (MHPD) of Health Canada, in collaboration with the Canadian Paediatric Society and the Pharmaceutical Outcomes Programme of the Children’s and Women’s Health Centre of British Columbia, initiated a 3-year study to investigate the feasibility of using active surveillance methods to generate additional data on serious and life-threatening adverse reactions (ARs) in Canadian children under 18 years of age.

Data will be collected through the Canadian Paediatric Surveillance Program (CPSP), an established active surveillance network that reaches over 2300 pediatricians and pediatric subspecialists monthly. These physicians provide health care to a geographically diverse pediatric population of over 6 million.

Health Canada continues to monitor and collect AR and medication incident reports, including those generated through the CPSP. All these data are also maintained in the national computerized database. This database is a major tool in the continuing assessment of marketed health products. The information from suspected AR and medication incident reports is analyzed to detect potential health product safety signals. A signal is considered to be the preliminary indication of a product-related issue. The identification of a signal is not by itself proof of an association between an AR and a health product; rather, it triggers the need to investigate a potential association further.

CPSP’s study investigators are responsible for the review and analysis of data derived from the active surveillance study, both during and upon completion of data collection, which may result in the development of practice guidelines, published articles and presentations. MHPD of Health Canada is responsible for the coordination of consistency of post-marketing surveillance and the assessment of signals and safety trends concerning all marketed health products.

For more information on this study, visit the Canadian Paediatric Society’s Web site
(http://www.cps.ca/english/Surveillance/CPSP/Studies/drugreactions.htm).

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March 2004
Why do surveillance for adverse drug reactions (ADR)?

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.
ADRs are a major cause of childhood morbidity and mortality, yet alarmingly less than 5% are ever reported to regulators.

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February 2004
Important safety information about Tamiflu® (oseltamivir phosphate)

Based on new preclinical data with juvenile rats, the labelled indication of Tamiflu should be followed.
Tamiflu should not be used in children less than one year of age.

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