Are men or women more affected by the adverse effects of prescription drug treatments?

In a recent study published in Therapiesthe researchers presented an overview of gender-based differences in adverse drug reactions (ADRs) based on epidemiology, technique, and data on underlying mechanisms.

Study: Gender differences in adverse drug reactions: are women more affected? Image Credit: Iconic Bestiary/Shutterstock

Studies have reported increased hospitalization rates and significant economic impacts due to adverse effects, some of which are certainly preventable. Understanding the pharmacological rationale underlying potential associations between gender and drug safety profiles could guide gender-specific prescriptions and recommendations.

About the exam

In this review, the researchers provided an overview of differences in drug safety by sex. The team has chosen to present some examples of studies carried out for anti-infective drugs, cardiovascular drugs, anti-diabetics, anti-cancer drugs, psychotropics, and some drugs specifically relevant to current research.

Sources of pharmacovigilance differences by gender

Physiological differences between males and females in cardiac output and body composition affect pharmacokinetics, including drug absorption, biodistribution, metabolism, and clearance. Additionally, females have higher gastric pH, slower GI (gastrointestinal) transit, water content, plasma volumes, and blood flow to organs, leading to differential secretion of transporters and enzymes involved in drug metabolism in men and women.

In most cases, more frequent drug overexposure has been reported in women at high risk for drug concentration-related adverse reactions. Concerning the pharmacodynamics, the physiological variations in the density of the receptors (increase in Na thiazide+-Cl cotransporters in female rats) and signal transduction pathways after receptor binding (higher responses after endothelin A-mediated receptor binding in male animals), could explain the differences in drug response pattern according to sex.

Gender-based differences in microbial compositions and immunological responses (higher and stronger immune responses in females) might influence adverse effects, particularly with antineoplastic agents. Other factors affecting pharmacodynamic and pharmacokinetic interactions include medication adherence, gender-based medication use (such as oral contraceptives and hormone therapies), and the number of medications taken by individuals (higher propensity to polypharmacy in women) increase the risk of ADRs due to drug interactions.

Methods for Assessing Sex-Based Differences in Medicine Safety

To examine the impact of gender on drug safety profiles, it is essential to know the patterns of drug use in the general population and the general epidemiology of the event or condition of interest by gender. The reporting behavior of men and women must be taken into account. Studies with study designs such as randomized controlled trials (RCTs), ideally with individual participant data and meta-analyses, should be conducted to analyze data from different sources (such as clinical trials, spontaneous reporting systems and medico-administrative databases).

Data should be analyzed using pharmacovigilance disproportionality analyzes or meta-regression modeling with sex-based adjustments for safety outcomes such as hazard ratios (HR), relative risks (RR) and odds ratios (OR).

Examples of drugs with gender-based ADR differences

Drug-induced long QT syndrome (LQTS), torsades de pointes (TdP) (especially induced by sotalol), and erythromycin-associated cardiac arrhythmias occur more often in women, especially those taking oral contraceptives and IKR blockers. Peak plasma concentrations and area under the curve (AUC) of sotalol have been reported to be higher in females.

Women are at increased risk of tigecycline antimicrobial-induced acute pancreatitis and adverse effects associated with the use of antiretroviral drugs, including lactic acidosis, elevated liver enzymes, insulin resistance and dyslipidemia. Rash induced by nevirapine (a non-nucleoside reverse transcriptase inhibitor) was more common in women. Studies have reported an increased likelihood of adverse skin effects after exposure to anti-infective drugs such as cotrimoxazole, pyrimethamine-sulfadoxine, and ampicillin.

Anticholinergic and extrapyramidal reactions were reported more often in women, while sexual dysfunction was more common in men. Women reported adverse effects induced by selective serotonin reuptake inhibitor (SSRI) antidepressants such as hematoma, alopecia, blurred vision, xerostomia and palpitations, and skin adverse effects after the use of lamotrigine or carbamazepine.

Studies have reported greater 5-fluorouracil toxicity in women. In addition, female colon cancer patients consistently show significantly higher toxicity than males. In contrast, immune checkpoint inhibitor-induced Sjögren’s syndrome and toxicities due to azithromycin, hydroxychloroquine, remdesivir, or lopinavir/ritonavir use for COVID-19 have occurred more often in men. Few renal and hepatic side effects have been documented to be more common in men.

In contrast, psycho-neurological symptoms such as insomnia, headache, dizziness and blurred vision were more common in women. A higher number of female reports were observed for endocrine-related adverse reactions during treatment with ribavirin, darunavir, tocilizumab or interferon-β, and psychiatric adverse reactions with tocilizumab. An increased risk of adverse reactions after early Pfizer-BioNTech mRNA vaccinations was observed in women, while post-mRNA vaccine myocarditis occurred more frequently in young men.

To conclude, based on the results of the review, there is an increased risk in women for the majority of drugs; however, methodological, subjective and physiological points must be taken into account when interpreting the results. Additionally, clinical trials need to recruit more women for better evaluation of sex-based differences in drug efficacy and pharmacovigilance.

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