Summary Safety Review - Olanzapine - Assessing the Potential Risks of Syndrome of Inappropriate Secretion of Antidiuretic Hormone and Hyponatremia

Olanzapine-containing products

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH), a condition in which the body makes too much antidiuretic hormone leading to more water being held in the body, and hyponatremia, a condition in which blood sodium levels are low

• Health Canada’s safety review concluded that a link between olanzapine and the risks of SIADH and hyponatremia could not be ruled out.

• As a precautionary measure, Health Canada will work with the manufacturers to update the product safety information in the Canadian product monograph (CPM) for all olanzapine-containing products to include the potential risks of SIADH and hyponatremia.

Health Canada reviewed the potential risks of SIADH and hyponatremia with the use of olanzapine. The safety review was triggered by a safety report completed by a manufacturer of olanzapine-containing products on the risk of hyponatremia secondary to SIADH, which was prepared following the identification of a published case report during routine surveillance.

Syndrome of inappropriate secretion of antidiuretic hormone is a condition in which the body makes too much antidiuretic hormone, a hormone that helps regulate the water balance in the body. Too much antidiuretic hormone causes more water to be held in the body and commonly leads to hyponatremia, which is low blood sodium levels.

Symptoms of hyponatremia include muscle cramps, tremor, headache, nausea, and vomiting. If blood sodium levels become too low or if sodium levels drop too quickly, symptoms may progress to seizures, coma and respiratory arrest (absence of breathing), with life-threatening or fatal consequences.

• Olanzapine is a prescription drug authorized for sale in Canada for the treatment of schizophrenia and related psychotic disorders, and bipolar disorder. When administered intramuscularly, it may also be used for the rapid control of agitation in these patient populations.

• Olanzapine has been marketed in Canada since 1996 under the brand name Zyprexa. Generic versions are also available in Canada. Olanzapine is currently available as tablets, orally disintegrating tablets and a solution for injection into the muscle.

• Approximately 3.4 million prescriptions were dispensed for olanzapine in Canada in 2023.

• Health Canada reviewed the available information provided by manufacturers, and from searches of the Canada Vigilance^a database and the scientific literature.

• Health Canada reviewed 15 cases (1 Canadian and 14 international) of SIADH or hyponatremia in patients taking olanzapine. Twelve of those cases (1 Canadian) reported SIADH and 3 reported hyponatremia only.

• Of the 15 cases, 13 (11 SIADH [1 Canadian], 2 hyponatremia) were found to be possibly linked to the use of olanzapine and 2 (1 SIADH, 1 hyponatremia) could not be assessed due to missing or contradictory information. Overall, these cases provided limited evidence for a link between the use of olanzapine and the development of SIADH and hyponatremia due to the presence of confounders (other factors that may have contributed to the occurrence of SIADH or hyponatremia) and missing clinical information.

• Health Canada also reviewed 30 articles published in the scientific literature that investigated or summarized existing evidence for the association between antipsychotics (including olanzapine) and the development of SIADH and hyponatremia. Due to study limitations, including the presence of confounders, there was limited evidence to support a link between the use of olanzapine and the development of SIADH and hyponatremia.

• Health Canada’s review could not confirm a definitive link between the use of olanzapine and the development of SIADH and hyponatremia. However, a possible link could not be ruled out.

• While a definitive link could not be confirmed, Health Canada’s review of the available information could not rule out a possible link between olanzapine and the risks of SIADH and hyponatremia. Despite the limited available evidence, the extensive use of olanzapine in Canada and vulnerability of the patient population who could be prescribed the drug warranted a precautionary approach for these risks.

• Health Canada will work with the manufacturers to update the CPM for all olanzapine-containing products to include the potential risks of SIADH and hyponatremia.

• Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of olanzapine, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving olanzapine, 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 should new health risks be identified.

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

For additional information, contact the Marketed Health Products Directorate.

1. Canadian reports can be accessed through the Canada Vigilance Online Database.