What are the documented drug interactions and serious adverse effects associated with ivermectin?
Executive summary
Ivermectin’s documented serious adverse effects center on rare but potentially severe neurotoxicity, hepatotoxicity and dermatologic reactions, and clinically meaningful drug–drug interactions driven largely by CYP3A4 metabolism and P‑glycoprotein (P‑gp/MDR1) transport; concomitant use with anticoagulants (notably warfarin), CYP3A4/P‑gp inhibitors or other central nervous system (CNS) depressants raises particular concern [1] [2] [3] [4]. Most authorities and post‑marketing data characterize these events as uncommon relative to decades of antiparasitic use, but case reports and interaction databases document concrete scenarios where serious harm occurred or is plausible [1] [5] [3].
1. Neurotoxicity: rare but well‑documented and sometimes fatal
Multiple case series and drug prescribing information describe neurotoxic syndromes after ivermectin that include somnolence, confusion, stupor, seizures and coma, with rare deaths reported; these syndromes have occurred both in patients with and without onchocerciasis and often resolved after stopping the drug and providing supportive care [5] [6] [1]. The PMC case series highlights instances of serious neurological adverse events and notes positive rechallenge in several patients — meaning symptoms recurred on re‑exposure — strengthening a causal signal in at least some individual cases [1].
2. Drug–drug interactions: CYP3A4 and P‑glycoprotein are the mechanisms to watch
Ivermectin is metabolized by hepatic enzymes and handled by drug transporters, so interactions that inhibit CYP3A4 or P‑gp can raise systemic and central nervous system levels of ivermectin and increase toxicity risk; the literature and reviews explicitly flag co‑administration with CYP3A4/P‑gp substrates or inhibitors (statins, HIV protease inhibitors, certain calcium‑channel blockers, ketoconazole, ritonavir) as situations of concern [2] [1] [3]. Drugs.com lists over 100 potential interacting medications, naming warfarin, ketoconazole and erythromycin among them, underscoring the broad interaction footprint clinicians must consider [3].
3. Anticoagulants, liver injury and laboratory signals
Post‑marketing reports and drug information note rare increases in INR and bleeding when ivermectin is used with warfarin, and cases of hepatitis or elevations in liver enzymes have been reported, requiring monitoring and caution in patients on blood thinners or with liver disease [4] [6] [3]. The prescribing literature and monitoring advisories recommend awareness that ivermectin’s hepatic metabolism could be altered by co‑medications and that liver impairment may change risk [7] [2].
4. Dermatologic and hypersensitivity reactions, and other systemic effects
Serious cutaneous reactions including Stevens‑Johnson syndrome and toxic epidermal necrolysis have been reported post‑marketing, alongside hypotension (mainly orthostatic), worsening asthma and allergic‑type reactions; many of these reports derive from global pharmacovigilance rather than randomized trials, so incidence estimates are low but severity is high when they occur [4] [6]. In the context of parasitic infections, some adverse effects overlap with host inflammatory reactions to dying worms (e.g., Mazzotti reactions), which complicates attribution to the drug alone [6].
5. Clinical context, uncertainties and practical implications
Authors of pharmacokinetic and case‑series reviews stress that serious adverse events are uncommon given ivermectin’s extensive use for parasitic diseases, but individual factors — co‑medications that inhibit CYP3A4 or P‑gp, genetic variants in transporters (mdr‑1), high or veterinary dosing, pregnancy and pediatric use below 15 kg — create pockets of elevated risk and evidence gaps remain about exact frequencies and mechanisms [8] [2] [1]. Regulatory labels and clinical references therefore advise caution with specific drug combinations (notably warfarin and strong CYP3A4/P‑gp inhibitors), vigilance for neurologic or hepatic signs, and avoidance of unapproved high‑dose or animal formulations; where the sources do not provide precise risk numerators, that limitation is acknowledged [5] [4] [3].