Drug-Induced Headache reports: A Comprehensive Disproportionality and Time-to-Onset Pharmacovigilance Study Using the FAERS Database (2018-2024)

Abdulaziz I Alzarea¹azfar ishaqui^2*Muhammad Bilal Maqsood³Abdullah Salah Alanazi¹Aseel Alsaidan⁴Tauqeer Hussain Mallhi⁵Narendar Kumar⁶Khalid Orayj²Sultan M. Alshahrani²Hassan Alhassan⁷Sami Alzarea⁸Omar Alsaidan⁹

• ¹Jouf University Clinical Pharmacy Department, Sakaka, Saudi Arabia
• ²Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
• ³Eastern Health Cluster, Dammam, Saudi Arabia
• ⁴Department of family and community medicine, college of medicine, Jouf University, Sakaka, Saudi Arabia
• ⁵School of Pharmacy, Faculty of Health and Medical sciences, Taylors University, Selangor, Malaysia
• ⁶University of Sindh, Jamshoro, Pakistan
• ⁷Clinical Laboratory Science, Medical Applied College, Sakaka, Saudi Arabia
• ⁸Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia
• ⁹Department of Pharmaceutics, college of pharmacy, Jouf University, Sakaka, Saudi Arabia

Background: Headache is a common adverse drug reaction (ADR) across diverse therapeutic classes, yet systematic evaluations of drug-associated headaches in real-world settings are limited. This study aimed to explore the association between various medications and the reporting of headache as an ADR using the FDA-Adverse Event Reporting System (FAERS). Methods: We conducted a retrospective disproportionality analysis using FAERS data from Q1-2018 to Q4-2024. Duplicate reports were removed per FDA guidelines. Reports with headache as an adverse event and drugs classified as Primary Suspect were included. Disproportionality metrics — Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR)—were calculated to identify signals. Drugs were classified according to the Anatomical Therapeutic Chemical(ATC) classification system, and time-to-onset analyses were performed. Results: A total of 313,166 headache-associated cases were identified. Females (66.66%) and patients aged 51–65 years (21.35%) were most commonly affected. The drugs with the highest headache risk based on ROR included glecaprevir/pibrentasvir (ROR=10.445), sofosbuvir/velpatasvir (ROR=9.729), and eptinezumab-jjmr (ROR=6.775). Top frequently reported drugs were apremilast, treprostinil, and adalimumab. Calcium homeostasis agents (ROR = 6.268) and systemic antivirals (ROR=4.259) emerged as the ATC classes with the highest headache signal strength. Early-onset headaches (≤7days) were particularly associated with ofatumumab and fingolimod. Late-onset headaches (>90days) were linked to treprostinil and infliximab-dyyb. Conclusion: This large-scale pharmacovigilance study identifies multiple drugs and therapeutic classes with significant associations to headache as an ADR. These findings highlight the need for proactive headache monitoring, particularly during early treatment phases, and warrant further prospective investigations to understand mechanisms and preventive strategies.