Health Canada has published new drug safety information to raise awareness to health care professionals and public about the below safety concern which recently made safety labelling changes for the product monograph. –Health Product Info Watch –July 2020. The safety topics discussed below in brief.

Risk of cerebrovascular accidents with ibrutinib

Severe 6-mercaptopurine toxicity associated with azathioprine

New contraindication: Propafenone hydrochloride use in patients with severe obstructive pulmonary disease


Risk of cerebrovascular accidents with ibrutinib

Ibrutinib is an anticancer medicine used in the treatment of certain types of cancers like mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia. Ibrutinib comes under the class of kinase inhibitor which inhibits bruton’s tyrosine kinase (BTK), thereby slowing or stopping the growth of cancer cells.

Health Canada has received case reports with the use of Imbruvica (brand medicine for ibrutinib molecule) associated with safety concerns such as cerebrovascular accident, transient ischemic attack, and ischemic stroke. Some of the cases included fatal outcome (death case reports).

Some of the cases were reported with underlying medical conditions such as atrial fibrillation and/or hypertension (high blood pressure) and the causal relationship with ibrutinib has not been established.

Health Canada advised health are professionals to regularly monitor and provide appropriate treatment of conditions which can contribute to the occurrence of these safety findings.

Health Canada has updated the product monograph for Imbruvica by including this new safety information- “risk of cerebrovascular accidents” in the Warnings and Precautions, Adverse Reactions and Patient Medication Information sections.

Severe 6-mercaptopurine toxicity associated with azathioprine

Azathioprine is an immunosuppressant medicine (weakens the immune system of body) used in the prevention of organ rejection in kidney transplant patients. It is used along with other medications to allow acceptance and functioning of new kidney in the patient’s body. Azathioprine is also used in the treatment of rheumatoid arthritis.

Health Canada identified a new safety finding- “severe 6-mercaptopurine toxicity” associated with the normal doses of azathioprine in patients with inherited mutated NUDT15 gene. 6-mercaptopurine toxicity could lead to leukopenia (reduced WBC count) and alopecia (loss of hair).

Risk minimizing measures:

Health Canada provided following advice to healthcare professionals to prevent the occurrence of this toxicity risk in susceptible patients.

To be aware of increased risk for severe 6-mercaptopurine toxicity in patients having inherited mutated NUDT15 gene with conventional doses of thiopurine therapy.

Dose Adjustment for minimizing the risk: Patients with this genetic mutation (NUDT15 variant homozygotes) generally require reduction of thiopurine dose to prevent occurrence of toxicity.

To perform close monitoring of patient’s blood count

Preliminary genotypic testing of NUDT15 variants before initiating thiopurine therapy.

It was reported that frequency of the NUDT15 variant NUDT15 c.415C>T has an ethnic variability of approximately 10 % in East Asians, 4 % in Hispanics, 0.2 % in Europeans and 0 % in Africans.

Health Canada updated Canadian product monograph for Imuran by including the risk of risk for severe 6-mercaptopurine toxicity in patients with inherited mutated NUDT15 gene under the sections of Dosage and Administration, Warnings and Precautions, Action and Clinical Pharmacology and Patient Medication Information.

New contraindication: Propafenone hydrochloride use in patients with severe obstructive pulmonary disease

Propafenone is a class 1C anti-arrhythmic medication used in the treatment of certain types of atrial and ventricular arrhythmias (serious irregular heartbeats) which included paroxysmal supraventricular tachycardia and atrial fibrillation.

Based on the clinical evidence of safety and efficacy, propafenone is considered having unfavorable benefit risk profile for patients with the condition of severe obstructive pulmonary disease.

Health Canada updated the Canadian product monograph for Rythmol (brand medicine for propafenone) by including this safety information (a new contraindicated use of propafenone) has under the sections of Contraindications and Consumer Information.

Voluntary ADR reporting:

Every medicine has its own benefits and risks (known & unknown). The medicine is prescribed to patient considering the positive benefit risk (known) profile with respect to individual patient (considering ongoing concurrent illness/disease). If any unanticipated adverse events (both expected and unexpected) are experienced by patient. It is advisable to report the same to health regulatory bodies of that nation.

Health care professionals and consumers are advised to report these new safety observations to Canada’s post-market surveillance program by submitting the voluntary reporting form online under drug health products.

For more information on other product safety updates- Product monograph brand safety updates

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