The Summary Safety Review - Non-prescription fluconazole - Assessing potential risks to pregnancy outcomes

November 9, 2017

Product

Non-prescription (oral, 150 mg) fluconazole products

Potential Safety Issue

Unwanted effects in pregnancy including pregnancy loss and birth defects

Key Messages

• Non-prescription (oral, 150 mg) fluconazole products are authorized for sale in Canada to treat vaginal yeast infections (i.e., vaginal candidiasis). The consumer information for these products recommends not to use them during pregnancy.
• Health Canada reviewed the potential risk of unwanted effects in pregnancy, including pregnancy loss (i.e., miscarriage or stillbirth) or birth defects (i.e., major congenital malformations) with non-prescription fluconazole use, in part because a recently published study^{Footnote 1} suggested that such a risk may exist.
• Health Canada's review found that a link between the use of non-prescription fluconazole and the risk of unwanted effects in pregnancy cannot be made at this time based on the currently available information.
• Recently, the manufacturer of Diflucan ONE voluntarily updated the Canadian product safety information about the potential risk of pregnancy loss and birth defects. Diflucan ONE is known as the Canadian Reference Product and, as such, all the other non-prescription fluconazole products in Canada must have the same safety information. Health Canada concluded that the proposed update for Diflucan ONE is suitable and has recommended that the Canadian product information for all other non-prescription fluconazole products be updated in the same way, in order to give Canadians the most complete and up-to-date information available.
• The updated safety information for these products will make clear that they are also not recommended for use by women who are trying to become pregnant.

Overview

Health Canada reviewed the potential risk of unwanted effects in pregnancy including loss of the developing fetus (i.e., miscarriage or stillbirth), or birth defects (i.e., major congenital malformations) with the use of non-prescription fluconazole products in part because a recently published pregnancy registry study from Denmark^{Footnote 1} suggested that such a risk may exist. In a pregnancy registry study, information is collected from pregnant women taking certain medications to study the health of their pregnancies.

In Canada, the product information for consumers on oral non-prescription fluconazole currently does not recommend using the product during pregnancy; however, the risk information for healthcare professionals currently does not include the most recent information from published studies about use in pregnant patients. Currently, both the Public Health Agency of Canada and the Society of Obstetricians and Gynaecologists of Canada's practice guidelines recommend that only creams applied directly to the skin and vagina (i.e., topical antifungal therapies) be used for the treatment of vaginal yeast infections during pregnancy. They also advise that fluconazole products taken by mouth (i.e., orally) should be avoided in pregnancy, and that the safety of these products in the later stages of pregnancy (i.e. the second and third trimesters) has not been studied.

Use in Canada

• Non-prescription (oral, 150 mg) fluconazole products are authorized for sale in Canada to treat vaginal yeast infections (i.e., vaginal candidiasis) in a single dose taken by mouth. Some combination packs are available, containing the single-dose, oral fluconazole capsules along with a topical antifungal cream (e.g. clotrimazole or miconazole).
• Non-prescription fluconazole products have been marketed in Canada since 2010. There are currently 20 such products including the brand names Diflucan ONE, Canesoral, and Monicure, as well as generic versions.

Safety Review Findings

• At the time of the review, Health Canada had received 1 Canadian report^{Footnote a} and 3 international reports of miscarriage that were possibly related to non-prescription fluconazole use. Five international cases were identified in the information received from the manufacturers describing birth defects that were possibly associated with non-prescription fluconazole use; however there was not enough information in any of these reports to conclude that the fluconazole product itself caused the birth defects.
• A search in the World Health Organization's Adverse Drug Reaction Database found 360 cases including pregnancy loss or birth defects, reported in patients treated with fluconazole. There was not enough information in these reports to conclude that fluconazole caused these outcomes or to determine whether the women were taking low dose fluconazole (150 mg or less) or higher doses. Higher dose fluconazole products, available by prescription only, are known to have pregnancy-related risks and these are communicated in the product safety information.
• In the pregnancy registry study^{Footnote 1} that suggested a link between fluconazole use and unwanted effects in pregnancy, there was not enough information to conclude whether or not the fluconazole product itself was the cause. This is partly because it was not possible to know the dose of fluconazole that was used, whether it was prescription or non-prescription, the reasons for taking the drug, how long the drug was taken, and how drug exposure was measured. In general, studies on this issue are scarce, due to the ethical and safety concerns of testing drugs in pregnant women.

Conclusions and Actions

• Health Canada's review found that a link between the use of non-prescription fluconazole and the risk of unwanted effects in pregnancy cannot be made at this time based on the currently available information. Given the potential risk and the fact that there are other products to treat vaginal yeast infection during pregnancy, this risk information would still be useful to healthcare professionals.
• While Health Canada was carrying out the review, the manufacturer of Diflucan ONE voluntarily updated their Canadian product safety information to communicate this potential risk, as well as to clarify that women who are trying to become pregnant should avoid using the product as well. Diflucan ONE is known as the Canadian Reference Product and, as such, all the other non-prescription fluconazole products in Canada must have the same safety information.
• Health Canada concluded that the proposed update for Diflucan ONE is suitable and has recommended that the Canadian product safety information for all non-prescription fluconazole products be updated in the same way with this additional risk information. Women continue to be advised to avoid use of non-prescription fluconazole products while pregnant.

Additional Information

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 this drug both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.