Summary Safety Review - Hydroxyzine (ATARAX and generics) - Assessing the Potential Risk of Abnormal Heart Rhythm

June 6, 2016

Product

Hydroxyzine (Atarax and generics)

Potential Safety Issue

Abnormal heart rhythm (QT interval prolongation)

Key Messages

• Hydroxyzine is a first-generation antihistamine used as part of treatment of anxiety; for itching (pruritus) due to allergic skin reactions; as a pre-surgical medication, such as for dental procedures; and for nausea and vomiting.
• Health Canada carried out a safety review following an action taken by the European Medicines Agency to limit the use of this medicine, partly by reducing the dose. This was brought on because slight changes in the heart rhythm were seen in a study of patients using this medicine.
• Health Canada is working with the manufacturers of Atarax to update the product information to better reflect the risk of changes in the heart rhythm, especially in patients with factors that would increase the risk of this side effect. Manufacturers of generic hydroxyzine products will also update their product information.

Overview

A safety review was undertaken soon after the European Medicines Agency notified Health Canada of the possibility that the use of hydroxyzine products could be associated with abnormal changes in the electrical activity of the heart, such as QT interval prolongation. These changes can lead to an abnormal heart rhythm (such as what is known as torsades de pointes). An abnormal heart rhythm refers to the heart beating too fast, too slow or irregularly. In some rare cases, abnormal heart rhythm can cause death.

Use in Canada

• Hydroxyzine has been marketed in Canada since 1956.
• Hydroxyzine is an anti-histamine that works in the skin to alleviate allergic reactions (e.g. swelling, itching) and in the brain to cause a sedative effect.
• With approximately 750,000 prescriptions and refills in Canada for 2013, 9 out of every 10 were written for adult patients - primarily to treat allergic reactions.
• Hydroxyzine is available in 3 different formulations: tablets, syrup, and as an injection into a muscle. These medicines are available only by prescription. It is known under the brand name Atarax and generic products are available.

Safety Review Findings

• At the time of Health Canada's review, cases of QT interval prolongation or torsades de pointes (QTP/TdP) associated with the use of hydroxyzine were reported in 35 Canadian ^{Footnote _a} and 26 international patients since the products were introduced to the market. In the majority of those cases, the patients had additional characteristics that would place them at a higher risk of experiencing these side effects. These factors included taking additional medicines known to be associated with QTP/TdP, having an imbalanced body chemistry (electrolyte imbalance), family history (such as congenital long QT syndrome), consuming daily doses of hydoxyzine that are over 100 mg, and/or using drugs that prevent the breakdown of hydroxyzine in the body.
• Of these reports, only three cases (all international) provided enough information for a more detailed medical review. Hydroxyzine was found to have had a "possible" or "probable" contribution to QTP/TdP. It was observed in these reports that at least one of the risk factors above could also have played a role in the adverse events. No cases of QTP/TdP without risk factors were identified by the medical evaluator. This made it difficult to conclude that hydroxyzine was the sole cause of the effects on the heart.
• During a review of the published medical literature, a slight QT interval prolongation was observed after a single 100 mg dose of hydroxyzine in a recent clinical study, and with even higher doses in older clinical studies.
• Studies in animals and human cells have showed that the doses of hydroxyzine typically used in therapy can cause QT interval prolongation. The size of the effect depended on the dose.

Conclusions and Actions

• Health Canada's safety review concluded that there is evidence that hydroxyzine may contribute, along with other risk factors, to changes in the electrical activity of the heart and adversely affect heart rhythm.
• After reviewing the available evidence, Health Canada is working with manufacturers to update:
  • the dosing information to recommend that duration of dosing be as short as a possible, and also a new lower maximum daily dose (in divided doses) for:
    • adults, as well as children and adolescents over 40 kg: 100 mg
    • children and adolescents up to 40 kg: 2 mg/kg
    • the elderly: 50 mg
  • the reasons for use (i.e. the indications) to be more clearly outlined, and to limit the use in the management of anxiety to adults only.
• In addition, Health Canada is working with the manufacturer of Atarax to update the product information to better reflect the risk of experiencing abnormal heart rhythm, especially in patients with a known personal or family history as well as other potential risk factors such as taking various medications along with Atarax. Manufacturers of generic hydroxyzine products will also update their product information.
• Health Canada will also issue a Health Product Risk Communication to inform health care professionals once the above recommendations have been implemented.
• Health Canada will continue to monitor side effect information involving hydoxyzine, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action if and when any new health risks are identified.

Additional Information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international adverse reaction reports and what is known about the use of this drug both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.