Evaluating the Equity of Female Representation for Determining the Safety and Efficacy of Ibuprofen: An Analysis of the Supporting Evidence for Canadian Ibuprofen Product Monographs

Abstract

Background:

Over-the-counter drugs such as ibuprofen are a mainstay of pain relief. Ibuprofen was introduced in 1969, contributing to the absence of reporting on female representation in the clinical trials used as evidence of its safety and efficacy. We assessed the representation of females in the product monographs informing ibuprofen products.

Methods:

Product monographs for all currently marketed ibuprofen products in Canada were retrieved from the Government of Canada Drug Product Database. A systematic process was used to screen the monograph references for human clinical trials published in English for inclusion. Studies reporting on secondary data, animal studies, pediatric studies, and studies where the full text was unavailable were excluded. Of 212 unique studies, 58 met inclusion criteria and were assessed for female representation.

Results:

Females comprised a higher proportion in 41% of the total studies examined; however, females of childbearing age and females over the age of 50 were routinely excluded from trials. Only one of the 58 studies provided sex-stratified results.

Conclusions:

Our findings demonstrate that the clinical trials used to support Canadian ibuprofen monographs consistently excluded females of childbearing age and females over the age of 50, suggesting a significant gap in our understanding of the safety and efficacy of using ibuprofen to relieve pain in women of childbearing age and women over 50 years of age.

Introduction

Policy for the inclusion of female participants in clinical trials has been evolving within research institutes globally since the 1990s.¹ While enrollment of females in clinical trials has increased, the reporting of sex-disaggregated data remains very limited.^2,3 The absence of sex-disaggregated data prevents researchers from identifying significant differences between males and females.⁴ Despite recent movements toward sex and gender representation in research, females remain underrepresented in clinical trials for common over-the-counter (OTC) medications like ibuprofen.^5,6 Underrepresentation and limited data reporting of female participants in clinical trials for medication contribute to improper dosing and⁷ poor pain control^8,9 and lead to a higher risk of adverse drug reactions.^10,11 Research has found that female bodies metabolize drugs differently than male bodies at a pharmacokinetic and pharmacodynamic level.^12–14 Yet, females use OTC medications at more regular intervals than males.^15–17 The well-documented evidence of adverse outcomes and the known biological differences in medication metabolism highlight the need for continued improvement in sex-based reporting in healthcare research.

There is currently no research specifically assessing how females have been represented or reported on in clinical trials for ibuprofen. Ibuprofen was initially approved before females were required to be included in research and has remained on the market since.¹¹ Ibuprofen is a commonly prescribed OTC pain medication for female-specific procedures^18–20 despite our limited understanding of whether supporting research is efficacious for the female sex throughout the lifespan. As product monographs are used to inform drug dosing and usage,²¹ our aim was to systematically assess female representation in the supporting literature used in Canadian ibuprofen product monographs. We analyzed the representation of female participants to provide a greater understanding of the safety and efficacy of ibuprofen for females.

Methods

As this analysis used anonymized data from previously published studies, this work does not require approval from an institutional review board or informed consent. The authors declare that all supporting data are available in the article. A systematic screening process was used in accordance with an a priori protocol. The Government of Canada Drug Product Database was searched for ibuprofen product monographs. The monographs were retrieved for all currently available marketed ibuprofen products in Canada.

This analysis included primary clinical trials conducted on adults that were published in English. We excluded studies reporting on secondary data, animal studies, pediatric studies, and studies where the full text was not available. Following the identification of relevant product monographs, duplicate monographs were removed. The references from the remaining monographs were collated, and duplicates were removed manually. The remaining citations were uploaded to Covidence to facilitate a systematic screening process. All stages of screening were performed by two independent reviewers (K.B. and J.S.), and conflicts were resolved through discussion or the involvement of a third independent reviewer.

One reviewer extracted data including study details, number of participants, ages, sex composition, whether both sexes were sufficiently represented (40%–60% of the study population), and sex stratification. The results of the study selection process are reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses with a focus on health equity (Fig. 1).^22,23

FIG. 1.

PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Results

The initial search of The Government of Canada Drug Product Database yielded 26 currently marketed ibuprofen products. Multiple ibuprofen products utilized the same monograph, and one monograph did not have a reference list, leaving 12 individual product monographs. A total of 1205 references were identified from the product monographs. After duplicates were removed, 212 studies were screened by title and abstract for eligibility. Of the remaining articles, 135 full texts were retrieved and assessed for eligibility. Seventy-four articles were excluded. The remaining 58 studies were included.

Characteristics of the included studies

The 58 included study designs included: randomized and non-randomized control trials utilizing parallel group, crossover, and comparative studies. Characteristics of the included studies are found in Table 1. The included studies were published between 1972 and 2007, in 14 reported countries, including Canada, United States of America, Chile, United Kingdom, Netherlands, Italy, Germany, Spain, India, Denmark, Sweden, France, Switzerland, and Poland. Of the included studies, 21/58 studies had exclusion criteria for females of childbearing age. Twenty-eight of the included studies were female-dominant, containing >60% females in the study population, yet even these studies excluded females of childbearing age (Fig. 2).

FIG. 2.

Sex composition diagram.

Table 1.

Study Characteristics and Sex Representation

Study	Country	Design	Number of participants	Age in years, range or mean (SD)	Sex composition	Adequate sex representation	Female-specific exclusions
Albert et al. 1984²⁴	USA	Latin Square Crossover Design	17	65–78	N/A	N/A	Not listed
Bombardier et al. 2000²⁵	22 unlisted countries	RCT	8076	>50, 58 (9)	Not documented	Unknown	N/A
Boureau et al. 2004²⁶	USA	Double-blind, randomized parallel group comparative clinical study	222	50–85	73% females	No	N/A
Brooks et al. 1973²⁷	USA	RCT	36	Not listed	100% males	No	Not listed
Catella-Lawson et al. 2001²⁸	USA	Randomized crossover study and randomized parallel group study	Not listed	18–65	Not documented	Unknown	N/A
Codispoti et al. 2001²⁹	USA	RCT	660	18–84	84% females	No	N/A
Cook et al. 1997³⁰	USA	Blinded randomized study	17	>56	100% females	No	Not listed
Cooper et al. 1977³¹	USA	RCT	193	16–35	56% females	Yes	Pregnancy
Cooper et al. 1989³²	Not listed	Randomized double blind	184	>16, 23.5 (0.7)	72% females	No	N/A
Corson & Bolognese 1978³³	USA	Double-blind crossover study	33	14–48	100% females	N/A	Not listed
Davies et al. 1988³⁴	United Kingdom	Double-blind, double-placebo, randomized crossover	18	37–78	83% females	No	Not listed
De Biecourt 1975³⁵	Netherlands	Double-blind crossover comparison	39	50–79	62% females	No	Not listed
Diamond 1983³⁶	USA	Double-blind, randomized, parallel trial	141	males: 43.4 females: 44.8	81% females	No	Women of “childbearing potential”
Diener et al. 2004³⁷	Italy, Germany, Spain	Threefold crossover, double-blind RCT	312	18–65	81% females	No	Pregnant, lactating, or women of childbearing age not using contraception
Doyle et al. 1999³⁸	USA	Double-blind RCT	1257	12–83	54% females	Yes	Pregnant or lactating
Fommei et al. 1987³⁹	Italy	Control trial	3	Not listed	Not documented	Unknown	Not listed
Forbes et al. 1992⁴⁰	USA	Double-blind RCT	280	15–56	58% females	Yes	Pregnant or lactating
Forbes et al. 1984⁴¹	USA	Double-blind, randomized, parallel group	109	15–44	52% females	Yes	Pregnant or lactating
Forbes et al. 1991⁴²	USA	Double-blind RCT	241	16–48	59% females	Yes	Pregnant or lactating
Forbes et al. 1990⁴³	USA	Double-blind RCT	128	16–41	58% females	Yes	Pregnant or lactating
Fricke et al. 1993⁴⁴	USA	Double-blind RCT, parallel group	201	Placebo 23.3 (5.5), naproxen 24.2 (6.8), ibuprofen 22.5 (4.5)	62% females	No	Pregnant or lactating
Gaitonde et al. 1972⁴⁵	India	Double-blind RCT	17	Not listed	100% males	No	Not listed
Gallardo and Rossi 1980⁴⁶	Chile	Double-blind clinical trial	98	Not listed	Not documented	Unknown	Pregnant
Giachetti et al. 1985⁴⁷	Italy	Control trial, not blind or randomized	4	Not listed	25% females	No	Not listed
Gontarz et al. 1987⁴⁸	USA	Randomized crossover design	8	20–30	38% females	No	N/A
Gookin et al. 1983⁴⁹	USA	Double-blind, three-way crossover design	31	18–42	100% females	N/A	Not listed
Houson et al. 1995⁵⁰	USA	Three-phase, randomized, double-blind, placebo-controlled	162	18–75	52% females	Yes	N/A
Jain et al. 1986⁵¹	USA	Double-blind, randomized, parallel trial	227	18–65	56% females	Yes	Pregnant or women of childbearing age not using approved contraception
Jorgensen et al. 1991⁵²	Denmark	Randomized trial, no control/placebo	18	51–81	44% females	Yes	Not listed
Juhl et al. 1983⁵³	USA	Two-way crossover design with control	44 patients	54.3 (10.1)	Not documented	Unknown	Not listed
Kurth et al. 2003⁵⁴	USA	Subgroup analysis Double-blind, placebo-controlled RCT	22,071	55.2 (10), 52.1 (8.8), 54.9 (9.9)	100% males	No	Not listed
Larkin et al. 1979⁵⁵	USA	Double-blind, prospective, three-way crossover design	22	18–34	100% females	N/A	Not listed
Malmstrom et al. 1999⁵⁶	USA	Randomized, double-blind, double-dummy, placebo and active comparator controlled, parallel group study	272	22.6–23.4 (4.0–4.3)	63% females	No	Pregnant or women of childbearing age not using approved contraception
Malmstrom et al. 2004⁵⁷	USA	Randomized, double-blind, placebo- and active comparator-controlled study	398	22.1	63% females	No	Pregnant or women of childbearing age not using approved contraception
Malmstrom et al. 2002⁵⁸	USA	Randomized, double-blind, placebo- and active comparator-controlled, parallel group study	483	22.1	74% females	No	Pregnant or women of childbearing age not using approved contraception
Mehlischet al. 1990⁵⁹	USA	Double-blind, randomized, parallel, placebo-controlled	697	17–64	60% females	No	Not listed
Milsom and Andersch 1984⁶⁰	Sweden	Double-blind parallel study	12	20–42	100% females	N/A	Not listed
Minuz et al. 1987⁶¹	Italy	RCT	16	25–56	100% males	No	Not listed
Misra et al. 2004⁶²	India	Placebo-controlled RCT	101	16–62	82% females	No	N/A
Misra et al. 2007⁶³	India	Placebo-controlled RCT	155	16–58	68% females	No	Pregnant, lactating and those taking oral contraceptives.
Molla and Donald 1974⁶⁴	England	Double-blind controlled crossover trial	67	18–26	100% female *Results not statistically significant for improving dysmenorrhea symptoms	N/A	Irregular menstrual cycles, fitted with intrauterine device, wishing to become pregnant or likely to require oral contraceptives within 4 months of study
Moore et al. 1999⁶⁵	France, England	Randomized, blinded, parallel group	7456	18–75	58% females	Yes	Not listed
Morrison et al. 1999⁶⁶	USA	Randomized, double-blind, placebo and active comparator controlled, parallel group study	151	16–27	50.3% females	Yes	Pregnant or women of childbearing age not using approved contraception
Morrison et al. 1980⁶⁷	USA	Triple-blind, crossover, randomized study	51	Not listed in study	100% females	N/A	Not listed
Muckle 1974⁶⁸	England	Double-blind trial	60	20–39	Not documented	Unknown	Not listed
Ngan et al. 1994⁶⁹	USA	Double-blind RCT, parallel, placebo-controlled	77	16.6 (6.8)	44% females	Yes	Not listed
Penner & Abbrecht 1975⁷⁰	USA	Double-blind RCT, placebo-controlled	36	21–60	100% males	No	Not listed
Rudy et al. 1995⁷¹	USA	Open trial	31	24–34 & 65–80	63% females	No	N/A
Ruoff et al. 1982⁷²	USA	Double-blind, parallel study	85	24–85	73% females	No	Pregnant, lactating, or women of childbearing age not using approved contraception
Saper et al. 2006⁷³	Asia, Europe, Latin America, USA	Double-blind, randomized, sponsor blinding, triple dummy, placebo and ibuprofen controlled	957	38.7–41.3 (11.5–12.0)	86% females	No	Pregnant, lactating, or women of childbearing age not using approved contraception
Schachtel et al. 1988⁷⁴	USA	Double-blind, parallel study	120	18–88	58% females	Yes	N/A
Schachtel et al. 1996⁷⁵	Canada, USA	Double-blind, randomized	455	21.1–22.3 (3.7–7.1)	63% females	No	Pregnant, lactating, or reported menstrual discomfort at the time of evaluation
Schachtel & Thoden 1988⁷⁶	Not listed	Double-blind, randomized, placebo-controlled	70	20.6	49% females	Yes	Not listed
Shapiro & Diem 1981⁷⁷	USA	Double-blind, four-way crossover study	56	24	100% females	N/A	Not listed
Schiff & Minic 2004⁷⁸	Switzerland and USA	Randomized, double-blind, placebo-controlled, parallel design	452	>25, 59–61, (12.8–13.7)	69% females	No	N/A
Szczeklik et al. 1976⁷⁹	Poland	Not listed	18	18–60	44% females	Yes	Not listed
Tyson & Glynne 1980⁸⁰	England	Double-blind, parallel trial	120	40–83	Not documented	Unknown	Not listed
Zelenaka et al. 2004⁸¹	USA	Randomized, double-blind, placebo and active controlled, parallel group	202	21.1–22.4 (4.0–6.2)	62% females	No	Women of childbearing age not using approved contraception

N/A, not applicable; RCT, randomized control trial; SD, standard deviation.

Sex composition of studies and stratification of data by sex

For this analysis, “Adequate Representation” of sex has been outlined as study populations with 40%–60% of either sex. Seven studies included 100% females, as the studies examined the use of ibuprofen for dysmenorrhea; 15 studies had 40%–60% female representation, and 5 studies included no female participants. Out of the 58 studies analyzed, only 1 stratified the data between male and female participants. The absence of sex stratification within the data set left the analysis of the clinical relevance of sex differences inconclusive.

Discussion

Our findings support that inadequate enrollment and disaggregation of data by sex hinders comprehensive sex‐specific assessment. Subsequently, this impacts the quality of evidence and strength of recommendations in the supporting evidence for marketed ibuprofen products in Canada. While some of the studies reported a greater proportion of female participants, females of childbearing age and over 50 years of age were routinely excluded.

Publication dates of clinical trials

The road to health equity for females in Canadian research has been unnervingly slow. To date, including females in Canadian research remains a “recommendation,” not a requirement. Considering that the studies analyzed are directly referenced as supporting evidence for currently marketed ibuprofen products in Canada, the dates of publication are concerning. Zero studies have been published in the last 10 years, and only nine (16%) have been published in the last 10–20 years. This time frame is problematic considering the history of research policies regarding the inclusion of females.

Following several catastrophic medications marketed directly to females, the U.S. Food and Drug Administration published a policy in 1977 recommending the exclusion of females of childbearing age from the early phases of drug trials.^6,82 This policy remained in place for 20 years until Health Canada put forward a guidance document, Inclusion of Women in Clinical Trials, in 1997.⁸³ The absence of recent supporting evidence in the product monographs raises questions regarding the standards used to guide pharmaceutical recommendations for ibuprofen.

Adverse drug reactions

Current research highlights an ongoing trend that females have a higher risk of adverse drug reactions,^10,11 including to ibuprofen.⁸⁴ A search of the Adverse Reaction Database through the Canada Vigilance Program shows that since 1965, 1448 adverse events from Ibuprofen have been documented on females over the age of 18 years (991 adverse events for females >50 years), compared with 801 adverse events on males over the age of 18 years (555 adverse events for males >50 years).⁸⁵ These results echo the high risk of adverse drug reactions in females but also highlight that a higher percentage of reactions occur in females and males over the age of 50 years.

Exclusions within clinical trials

Females of childbearing age

The exclusions within the individual clinical trials revealed a concerning pattern of excluding females of childbearing potential and participants with multiple comorbidities (See Table 1). Although 21 (41%) of the non-sex-specific studies had an overrepresentation of female participants (see Fig. 2), 12 (57%) of those studies excluded females of childbearing age. This is particularly relevant as ibuprofen has been and continues to be marketed for “menstrual pain,” a type of pain confined to women of childbearing age.⁸⁶ The studies that included females of childbearing age required that participants take birth control while participating in the trials. Despite contraceptive use being a mandatory requirement for inclusion in 21 of the ibuprofen trials, the monographs fail to warn against the increased risk of thromboembolism while taking hormonal contraception and nonsteroidal anti-inflammatory medications.⁸⁷

Our findings demonstrate that there is little to no evidence to determine the effectiveness and/or safety of using ibuprofen in females of childbearing age. Despite this gap in evidence, ibuprofen remains a frontline medication recommended to female patients for pain management. Gynecological procedures like intrauterine device insertions, a very common procedure for females of childbearing age, often advise patients to take ibuprofen for pain relief.^19,88,89 Importantly, these recommendations are unsupported by current research, which provides evidence of the ineffectiveness of ibuprofen for these procedures.^90–92

Age-based representation within clinical trials

Female bodies undergo fluctuations of hormone levels over time, which can impact the pharmacodynamics of medications and can lead to an increased risk of improper medication dosing.^93,94 Our research demonstrated that participants over the age of 50 were underrepresented and more likely to be excluded due to having multiple comorbidities or taking multiple medications. Excluding aging females from studies reduces the generalizability of the findings for this population, specifically due to their increased medical complexity.^95,96 This puts aging females in a position of increased vulnerability due to poor representation in research and the consequent lack of evidence on the outcomes of commonly prescribed medications.

Sex stratification within clinical trials

Stratification of data by sex can improve our understanding of the impact of medications on females. Only one of the 58 studies provided stratification of data between female and male participants, and this stratification did not include subset analysis by age.⁹⁷ Recent research has identified that there remains a notable lack of sex-based analysis.^2,98,99 Interestingly, studies performing sex stratification are more likely to have a female first author.^100,101 Of importance, even when sex stratification has been done, it is not necessarily being done appropriately and consistently.¹⁰² There remains significant room for improvement as research practices evolve toward discernible equity.

Drug approval and product monographs

For drugs to be authorized in Canada, they must be submitted as a New Drug Submission and successfully undergo a rigorous review by the Health Products and Food Branch.¹⁰³ Product monographs are required with any New Drug Submission, and these monographs remain relatively static. There are instances in which revisions should be initiated by a product sponsor, including when newly available information alters indications for use or identifies a safety concern.²¹ A notable barrier in the identified process is that research that continues to exclude certain demographics may not produce results that would prompt monograph revisions. Further research may be required to speak to a need to update the current Ibuprofen monographs.

Limitations

Our findings may not be generalizable to other locations as we only included Canadian ibuprofen monographs. It is important to note that this study only analyzed research informing product monographs that are not a direct reflection of all current research on ibuprofen. It was beyond the scope of this project to analyze all available literature; future research may be required to identify the current state of the literature on ibuprofen efficacy and safety in females beyond what is found in product monographs. Although there remains a lack of research in this area for pediatric populations, this study focused on adults due to resource limitations. This study focused on the representation of females as a biological sex but does not include both sex- and gender-based analyses. This limitation was due to the age of the information. However, it is important to acknowledge that only providing a sex-based analysis may run the risk of sex and gender being equated.¹⁰⁴

Conclusions

Given the significant differences in how female bodies metabolize drugs compared with males at pharmacokinetic and pharmacodynamic levels, there is an ongoing need for clinicians to understand the results of pharmaceutical trials from a sex-based lens. The clinical trials used to support Canadian ibuprofen monographs consistently excluded females of childbearing age and females over the age of 50, and only 1/58 studies included stratified results between females and males, suggesting a significant gap in our understanding of the safety and efficacy of using ibuprofen to relieve pain in women of childbearing age and women over 50 years of age.

Footnotes

Authors’ Contributions

K.B.: Conceptualization, data acquisition, analysis, formal analysis, investigation, methodology, and writing—original draft. J.S.: Analysis and writing—review/editing. N.T.: Writing—review/editing. S.B.A.: Writing—review/editing C.M.N.: Conceptualization, formal analysis, resources, supervision, and writing—review/editing.

Author Disclosure Statement

The authors declare no conflict of interest.

Funding Information

This research was supported by the Cavarzan Chair in Women’s Health Research. There was no financial support for authorship or publication of this article.

Abbreviations Used

References

White

, Tannenbaum

, Klinge

, et al. The integration of sex and gender considerations into biomedical research: Lessons from international funding agencies. J Clin Endocrinol Metab, 2021; 106(10):3034–3048; doi: 10.1210/clinem/dgab434

Antequera

, Cuadrado-Conde

, Roy-Vallejo

, et al. Research for gender equity collaboration. Lack of sex-related analysis and reporting in Cochrane Reviews: A cross-sectional study. Syst Rev, 2022; 11(1):281; doi: 10.1186/s13643-021-01867-3

Phillips

, Hamberg

. Doubly blind: A systematic review of gender in randomised controlled trials. Global Health Action, 2016; 9(1); doi: 10.3402/gha.v9.29597

Foulkes

. After inclusion, information and inference: Reporting on clinical trials results after 15 years of monitoring inclusion of women. J Womens Health (Larchmt), 2011; 20(6):829–836; doi: 10.1089/jwh.2010.2527

Short

, Zacher

. Women’s health: Population patterns and social determinants. Annu Rev Sociol, 2022; 48(1):277–298; doi: 10.1146/annurev-soc-030320-034200

Yakerson

. Women in clinical trials: A review of policy development and health equity in the Canadian context. Int J Equity Health, 2019; 18(1):56; doi: 10.1186/s12939-019-0954-x

Soldin

, Mattison

. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet, 2009; 48(3):143–157; doi: 10.2165/00003088-200948030-00001

Janevic

, Mathur

, Booker

, et al. Making pain research more inclusive: Why and how. J Pain, 2022; 23(5):707–728; doi: 10.1016/j.jpain.2021.10.004

Lloyd

, Paganini

, ten Brinke

. Gender stereotypes explain disparities in pain care and inform equitable policies. Policy Insights Behav Brain Sci, 2020; 7(2):198–204; doi: 10.1177/2372732220942894

10.

Liu

, DiPietro Mager

. Women’s involvement in clinical trials: Historical perspective and future implications. Pharm Pract (Granada), 2016; 14(1):708–708; doi: 10.18549/PharmPract.2016.01.708

11.

Zucker

, Prendergast

. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol Sex Differ, 2020; 11(1):32; doi: 10.1186/s13293-020-00308-5

12.

Anderson

. Chapter 1 Gender differences in pharmacological response. In: International Review of Neurobiology. Elsevier; 2008; pp. 1–10; 10.1016/S0074-7742(08)00001-9

13.

Hochmuth

, Körner

, Ott

, et al. Sex-dependent dynamics of metabolism in primary mouse hepatocytes. Arch Toxicol, 2021; 95(9):3001–3013; doi: 10.1007/s00204-021-03118-9

14.

Oi Yan Chan

, Moullet

, Williamson

, et al. Harnessing clinical trial and real-world data towards an understanding of sex effects on drug pharmacokinetics, pharmacodynamics and efficacy. Front Pharmacol, 2022; 13:874606; doi: 10.3389/fphar.2022.874606

15.

Orlando

, Mucherino

, Guarino

, et al. Gender differences in medication use: A drug utilization study based on real world data. Int J Environ Res Public Health, 2020; 17(11):3926; doi: 10.3390/ijerph17113926

16.

Osborne

, Davis

. Sex and gender differences in pain. In: International Review of Neurobiology. Elsevier; 2022; pp. 277–307; doi: 10.1016/bs.irn.2022.06.013

17.

Sánchez-Sánchez

, Fernández-Cerezo

, Díaz-Jimenez

, et al. Consumption of over-the-counter drugs: Prevalence and type of drugs. Int J Environ Res Public Health, 2021; 18(11):5530; doi: 10.3390/ijerph18115530

18.

Alberta Health Services. Intrauterine Device (IUD) Insertion. 2024.

19.

Johnson

. Insertion and removal of intrauterine devices. Academy of American Family Physicians, 2005; 71(1):95–102.

20.

The Society of Obstetricians and Gynecologists of Canada. Statement on Intrauterine Devices, Counselling and Pain Management. 2022.

21.

Government of Canada. Guidance Document—Product Monograph. 2014. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/product-monograph/product-monograph.html [Last accessed: August 30, 2024].

22.

Welch

, Petticrew

, Tugwell

, et al. PRISMA-Equity Bellagio group. PRISMA-Equity 2012 extension: Reporting guidelines for systematic reviews with a focus on health equity. PLoS Med, 2012; 9(10):e1001333; doi: 10.1371/journal.pmed.1001333

23.

Welch

, Petticrew

, Petkovic

, et al. PRISMA-Equity Bellagio group. Extending the PRISMA statement to equity-focused systematic reviews (PRISMA-E 2012): explanation and elaboration. J Clin Epidemiol, 2016; 70:68–89; doi: 10.1016/j.jclinepi.2015.09.001

24.

Albert

, Gillespie

, Wagner

, et al. Effects of age on the clinical pharmacokinetics of ibuprofen. Am J Med, 1984; 77(1A):47–50; doi: 10.1016/s0002-9343(84)80018-2

25.

Bombardier

, Laine

, Reicin

, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med, 2000; 343(21):1520–1528; doi: 10.1056/NEJM200011233432103

26.

Boureau

, Schneid

, Zeghari

, et al. The IPSO study: ibuprofen, paracetamol study in osteoarthritis. A randomised comparative clinical study comparing the efficacy and safety of ibuprofen and paracetamol analgesic treatment of osteoarthritis of the knee or hip. Ann Rheum Dis, 2004; 63(9):1028–1034; doi: 10.1136/ard.2003.011403

27.

Brooks

, Schlagel

, Sekhar

. Tolerance and Pharmacology of Ibuprofen. Therapeutic Research, 1873; 15(4):180–190.

28.

Catella-Lawson

, Reilly

, Kapoor

, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med, 2001; 345(25):1809–1817; doi: 10.1056/NEJMoa003199

29.

Codispoti

, Prior

, Fu

, et al. Efficacy of nonprescription doses of ibuprofen for treating migraine headache. a randomized controlled trial. Headache, 2001; 41(7):665–679; doi: 10.1046/j.1526-4610.2001.041007665.x

30.

Cook

, Wallin

, Kadowitz

. Comparative Effects of Nabumetone, Sulindac and Ibuprofen on Renal Function. The Journal of Rheumatology , 1997; 24(6):1137–1144.

31.

Cooper

, Needle

, Kruger

. Comparative analgesic potency of aspirin and ibuprofen. Journal of Clinical Pharmacology, 1977; 35:889–903.

32.

Cooper

, Schachtel

, Goldman

, et al. Ibuprofen and acetaminophen in the relief of acute pain: a randomized, double-blind, placebo-controlled study. J Clin Pharmacol, 1989; 29(11):1026–1030; doi: 10.1002/j.1552-4604.1989.tb03273.x

33.

Corson

, Bolognese

. Ibuprofen Therapy for Dysmenorrhea. Journal of Reproductive Medicine, 1978; 20:246–252.

34.

Davies

, Rawlins

, Busson

. Effect of ibuprofen on blood pressure control by propranolol and bendrofluazide. J Int Med Res, 1988; 16(3):173–181; doi: 10.1177/030006058801600302

35.

De Biécourt

J J

. Section 1 A Comparative Study of Ibuprofen (‘Brufen’) And Indomethacin in Uncomplicated Arthrosis. Current Medical Research and Opinion, 1975; 3(8):477–480; doi: 10.1185/03007997509110577

36.

Diamond

. Ibuprofen versus aspirin and placebo in the treatment of muscle contraction headache. Headache, 1983; 23(5):206–210; doi: 10.1111/j.1526-4610.1983.hed2305206.x

37.

Diener

, Bussone

, De Liano

, et al. Placebo-controlled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks. Cephalalgia, 2004; 24(11):947–954; doi: 10.1111/j.1468-2982.2004.00783.x

38.

Doyle

, Furey

, Berlin

, et al. Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter dose. Aliment Pharmacol Ther, 1999; 13(7):897–906; doi: 10.1046/j.1365-2036.1999.00539.x

39.

Fommei

, Ghione

, Palla

. Inhibition of Prostaglandins and Antiotensin II: Effects on Renal Function in Hypetensive Patients. Agents and Actions , 1987; 22:183–189.

40.

Forbes

, Beaver

, Jones

, et al. Analgesic efficacy of bromfenac, ibuprofen, and aspirin in postoperative oral surgery pain. Clin Pharmacol Ther, 1992; 51(3):343–352; doi: 10.1038/clpt.1992.31

41.

Forbes

, Barkaszi

, Ragland

, et al. Analgesic effect of fendosal, ibuprofen and aspirin in postoperative oral surgery pain. Pharmacotherapy, 1984; 4(6):385–391; doi: 10.1002/j.1875-9114.1984.tb03401.x

42.

Forbes

, Beaver

, Edquist

. Evaluation of Bromfenac, Aspirin, and Ibuprofen in Postoperative Oral Surgery Pain. Pharmacotherapy, 1991; 11:64–70.

43.

Forbes

, Beaver

, Kehm

, et al. Evaluation of Ketorolac, Aspirin, and an Acetaminophen‐Codeine Combination in Postoperative Oral Surgery Pain. Pharmacotherapy, 1990; 10:94–105.

44.

Fricke

, Halladay

, Francisco

. Efficacy and safety of naproxen sodium and ibuprofen for pain relief after oral surgery. Current Therapeutic Research, 1993; 54(6):619–627; doi: 10.1016/S0011-393X(05)80692-7

45.

Gaitonde

, Dattani

, Morwani

. Antypyretic activity of ibuprofen (Brufen). Journal of Association of Physicians of India , 1972; 21:579–584.

46.

Gallardo

, Rossi

. Double-Blind Evaluation of Naproxen and Ibuprofen in Periodontal Surgery. Pharmacology and Therapeutics in Dentistry, 1980; 5:69–72.

47.

Giachetti

, Zanolo

, Canali

. Topical administration of ibuprofen in man. Simultaneous determination of the drug and its metabolites in urine by high resolution gas chromatography. J High Resol Chromatogr, 1985; 8(8):465–468; doi: 10.1002/jhrc.1240080822

48.

Gontarz

, Comstock

, Stalker

, et al. Effects of Antacid Suspension on the Pharmakokietics of Ibuprofen. Clinical Pharmacology, 1987; 7(5):413–416.

49.

Gookin

, Forman

, Vecchio

, et al. Comparative efficacy of ibuprofen, indomethacin, and placebo in the treatment of primary dysmenorrhea. South Med J, 1983; 76(11):1361–1362, 1367; doi: 10.1097/00007611-198311000-00008

50.

Houson

, Weir

, Ginserg

, et al. The Effects of Non-Steroidal Anti-Inflammatory Drugs on Blood Pressure of Patients with Hypertension Controlled by Verapamil. Archives of Internal Medicine, 1995; 155:1049–1054.

51.

Jain

, Ryan

, McMahon

, et al. Analgesic efficacy of low-dose ibuprofen in dental extraction pain. Pharmacotherapy, 1986; 6(6):318–322; doi: 10.1002/j.1875-9114.1986.tb03494.x

52.

Jørgensen

, Christensen

, Kampmann

. Interaction between digoxin and indomethacin or ibuprofen. Br J Clin Pharmacol, 1991; 31(1):108–110; doi: 10.1111/j.1365-2125.1991.tb03867.x

53.

Juhl

, Van Thiel

, Dittert

, et al. Ibuprofen and sulindac kinetics in alcoholic liver disease. Clin Pharmacol Ther, 1983; 34(1):104–109; doi: 10.1038/clpt.1983.137

54.

Kurth

, Glynn

, Walker

, et al. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs. Circulation, 2003; 108(10):1191–1195; doi: 10.1161/01.CIR.0000087593.07533.9B

55.

Larkin

, Van Orden

, Poulson

, et al. Dysmenorrhea: Treatment with an Antiprostaglandin. Obstetrics and Gynecology, 1979; 54(4):456–460.

56.

Malmstrom

, Daniels

, Kotey

, et al. Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther, 1999; 21(10):1653–1663; doi: 10.1016/S0149-2918(99)80045-9

57.

Malmstrom

, Sapre

, Couglin

, et al. Etoricoxib in acute pain associated with dental surgery: a randomized, double-blind, placebo- and active comparator-controlled dose-ranging study. Clin Ther, 2004; 26(5):667–679; doi: 10.1016/s0149-2918(04)90067-7

58.

Malmstrom

, Fricke

, Kotey

, et al. A comparison of rofecoxib versus celecoxib in treating pain after dental surgery: a single-center, randomized, double-blind, placebo- and active-comparator-controlled, parallel-group, single-dose study using the dental impaction pain model. Clin Ther, 2002; 24(10):1549–1560; doi: 10.1016/s0149-2918(02)80059-5

59.

Mehlisch

, Sollecito

, Helfrick

, et al. Multicenter clinical trial of ibuprofen and acetaminophen in the treatment of postoperative dental pain. J Am Dent Assoc, 1990; 121(2):257–263; doi: 10.14219/jada.archive.1990.0237

60.

Milsom

, Andersch

. Effect of ibuprofen, naproxen sodium and paracetamol on intrauterine pressure and menstrual pain in dysmenorrhoea. Br J Obstet Gynaecol, 1984; 91(11):1129–1135; doi: 10.1111/j.1471-0528.1984.tb15089.x

61.

Minuz

, Lechi

, Arosio

, et al. Antihypertensive Activity of Enalapril. Effect of Ibuprofen and Different Salt Intakes. Journal of Clinical Hypertension, 1987; 3:645–653.

62.

Misra

, Jose

, Kalita

. Rofecoxib versus ibuprofen for acute treatment of migraine: a randomised placebo controlled trial. Postgrad Med J, 2004; 80(950):720–723; doi: 10.1136/pgmj.2003.012393

63.

Misra

, Kalita

, Yadav

. Rizatriptan vs. ibuprofen in migraine: a randomised placebo-controlled trial. J Headache Pain, 2007; 8(3):175–179; doi: 10.1007/s10194-007-0386-7

64.

Molla

, Donald

. A Comparative Study of Ibuprofen and Paracetamol in Primary Dysmenorrhoea. J Int Med Res, 1974; 395–399.

65.

Moore

, Vanganse

, Leparc

J-M

, et al. The PAIN Study: Paracetamol, Aspirin and Ibuprofen New Tolerability Study. Clinical Drug Investigation, 1999; 18(2):89–98; doi: 10.2165/00044011-199918020-00001

66.

Morrison

, Christensen

, Yuan

, et al. Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: a randomized, controlled trial. Clin Ther, 1999; 21(6):943–953; doi: 10.1016/S0149-2918(99)80016-2

67.

Morrison

, Ling

, Forman

, et al. Analgesic efficacy of ibuprofen for treatment of primary dysmenorrhea. South Med J, 1980; 73(8):999–1002; doi: 10.1097/00007611-198008000-00014

68.

Muckle

. Comparative study of ibuprofen and aspirin in soft-tissue injuries. Rheumatol Rehabil, 1974; 13(3):141–147; doi: 10.1093/rheumatology/13.3.141

69.

Ngan

, Wilson

, Shanfeld

, et al. The effect of ibuprofen on the level of discomfort in patients undergoing orthodontic treatment. Am J Orthod Dentofacial Orthop, 1994; 106(1):88–95; doi: 10.1016/S0889-5406(94)70025-7

70.

Penner

, Abbrecht

. Lack of interaction between ibuprofen and warfarin. Curr Ther Res Clin Exp, 1975; 18(6):862–871.

71.

Rudy

, Knight

, Brater

, et al. Enantioselective Disposition of Ibuprofen in Elderly Persons With and Without Renal Impairment. The Journal of Pharmacology and Experimental Therapeutics, 1995; 273(1):88–93.

72.

Ruoff

, Williams

, Cooper

, et al. Aspirin-Acetaminophen vs ibuprofen in a controlled multicenter double-blind study with patients experiencing pain associated with osteoarthritis. Current Therapeutic Research, 1982; 31(5):821–831.

73.

Saper

, Dahlof

, So

, et al. Rofecoxib in the acute treatment of migraine: a randomized controlled clinical trial. Headache, 2006; 46(2):264–275; doi: 10.1111/j.1526-4610.2006.00334.x

74.

Schachtel

, Fillingim

, Thoden

, et al. Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther, 1988; 44(6):704–711; doi: 10.1038/clpt.1988.215

75.

Schachtel

, Furey

, Thoden

. Nonprescription ibuprofen and acetaminophen in the treatment of tension-type headache. J Clin Pharmacol, 1996; 36(12):1120–1125; doi: 10.1002/j.1552-4604.1996.tb04165.x

76.

Schachtel

, Thoden

. Onset of action of ibuprofen in the treatment of muscle-contraction headache. Headache, 1988; 28(7):471–474; doi: 10.1111/j.1526-4610.1988.hed2807471.x

77.

Shapiro

, Diem

. The Effect of Ibuprofen in the Treatment of Dysmenorrhea. Current Therapeutic Research, 1981; 30(3):327–334.

78.

Schiff

, Minic

. Comparison of the analgesic efficacy and safety of nonprescription doses of naproxen sodium and Ibuprofen in the treatment of osteoarthritis of the knee. The Journal of Rheumatology, 2004; 31(7):1373–1383.

79.

Szczeklik

, Gryglewski

, Czerniawska-Mysik

, et al. Aspirin-induced asthma. Hypersensitivity to fenoprofen and ibuprofen in relation to their inhibitory action on prostaglandin generation by different microsomal enzymic preparations. J Allergy Clin Immunol, 1976; 58(1 PT 1):10–18; doi: 10.1016/0091-6749(76)90102-0

80.

Tyson

, Glynne

. A Comparative Study of Benoxaprofen and Ibuprofen in Osteoarthritis in General Practice. The Journal of Rheumatology Supplement, 1980; 7:132–138.

81.

Zelenakas

, Fricke

, Jayawardene

, et al. Analgesic efficacy of single oral doses of lumiracoxib and ibuprofen in patients with postoperative dental pain. Int J Clin Pract, 2004; 58(3):251–256; doi: 10.1111/j.1368-5031.2004.00156.x

82.

Government of Canada. Health portfolio sex- and gender-based analysis plus policy: Advancing equity, Diversity and Inclusion. 2023.

83.

Federal Register. Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs; Notice. 1993.

84.

Health Canada. Inclusion of Women in Clinical Trials. 1997.

85.

Farkouh

, Riedl

, Gottardi

, et al. Sex-related differences in pharmacokinetics and pharmacodynamics of frequently prescribed drugs: A review of the literature. Adv Ther, 2020; 37(2):644–655; doi: 10.1007/s12325-019-01201-3

86.

Government of Canada. Canada Vigilance Adverse Reaction Online Database. 2024. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/adverse-reaction-database.html [Last accessed: September 2, 2024].

87.

Mayo Clinic. Menstrual Cramps. 2022. Available from: https://www.mayoclinic.org/diseases-conditions/menstrual-cramps/diagnosis-treatment/drc-20374944#

88.

Meaidi

, Mascolo

, Sessa

, et al. Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: Nationwide Cohort Study. BMJ, 2023:e074450; doi: 10.1136/bmj-2022-074450

89.

Alberta Health Services. Intrauterine Device (IUD) Insertion. 2023.

90.

Allen

, Micks

, Edelman

. Pain relief for obstetric and gynecologic ambulatory procedures. Obstet Gynecol Clin North Am, 2013; 40(4):625–645; doi: 10.1016/j.ogc.2013.08.005

91.

Ahmad

, Attarbashi

, O’Flynn

, et al. Pain relief in office gynaecology: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol, 2011; 155(1):3–13; doi: 10.1016/j.ejogrb.2010.11.018

92.

Allen

, Bartz

, Grimes

, et al. Interventions for pain with intrauterine device insertion. In: Cochrane Database of Systematic Reviews. (The Cochrane Collaboration. eds.) John Wiley & Sons, Ltd: Chichester, UK; 2009; p. CD007373.pub2; doi: 10.1002/14651858.CD007373.pub2

93.

Bednarek

, Creinin

, Reeves

, et al. Post-Aspiration IUD Randomization (PAIR) Study Trial Group. Prophylactic ibuprofen does not improve pain with IUD insertion: A randomized trial. Contraception, 2015; 91(3):193–197; doi: 10.1016/j.contraception.2014.11.012

94.

Becher

, Oertelt-Prigione

. The impact of sex and gender in medicine and pharmacology. In: Handbook of Experimental Pharmacology. Springer Berlin Heidelberg: Berlin, Heidelberg; 2023; pp. 3–23; 10.1007/164_2023_688

95.

Mitchell

, Smith

, Waring

. The menstrual cycle and drug metabolism. Curr Drug Metab, 2009; 10(5):499–507; doi: 10.2174/138920009788897966

96.

Konrat

, Boutron

, Trinquart

, et al. Underrepresentation of elderly people in randomised controlled trials. The example of trials of 4 widely prescribed drugs. Scherer RW. ed. PLoS One, 2012; 7(3):e33559; doi: 10.1371/journal.pone.0033559

97.

Shah

, Nagi

, Khare

, et al. Limiting factors in implementing pharmacovigilance principles in the elderly. Cureus, 2023; 15(3):e36899; doi: 10.7759/cureus.36899

98.

Brady

, Nielsen

, Andersen

, et al. Lack of consideration of sex and gender in COVID-19 clinical studies. Nat Commun, 2021; 12(1); doi: 10.1038/s41467-021-24265-8

99.

Plumb

, Lesnak

, Berardi

, et al. Standing on the shoulders of bias: Lack of transparency and reporting of critical rigor characteristics in pain research. Pain, 2023; 164(8):1775–1782; doi: 10.1097/j.pain.0000000000002874

100.

Carrillo

, Martín

, Bacigalupe

. Gender inequalities in publications about COVID-19 in Spain: Authorship and sex-disaggregated data. Int J Environ Res Public Health, 2023; 20(3):2025; doi: 10.3390/ijerph20032025

101.

Sugimoto

, Ahn

Y-Y

, Smith

, et al. Factors affecting sex-related reporting in medical research: A cross-disciplinary bibliometric analysis. Lancet, 2019; 393(10171):550–559; doi: 10.1016/S0140-6736(18)32995-7

102.

Garcia-Sifuentes

, Maney

. Reporting and misreporting of sex differences in the biological sciences. Elife, 2021; 10:e70817; doi: 10.7554/eLife.70817

103.

Government of Canada. How Drugs Are Reviewed in Canada. 2015. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/fact-sheets/drugs-reviewed-canada.html [Last accessed: September 3, 2024].

104.

Nowatzki

, Grant

. Sex is not enough: The need for gender-based analysis in health research. Health Care Women Int, 2011; 32(4):263–277; doi: 10.1080/07399332.2010.519838