Date Published: February 04, 2018
Publisher: The American Society of Tropical Medicine and Hygiene
Author(s): Rebecca E. Chandler.
Serious neurological adverse events have been reported from large scale community-based ivermectin treatment campaigns against Onchocerciasis volvulus in Africa. The mechanism of these events has been debated in the literature, largely focusing on the role of concomitant infection with Loa loa versus the presence of mdr-1 gene variants in humans allowing ivermectin penetration into the central nervous system. A case series of serious neurological adverse events occurring with the use of ivermectin outside of the onchocerciasis indication has been identified in VigiBase, an international database of suspected adverse drug reactions. Forty-eight cases have been reported from multiple countries in which ivermectin has been prescribed for multiple indications; clinical review excluded 20 cases with more probable explanations or other exclusion criteria. Within the remaining 28 cases, there is supportive evidence for a causative role of ivermectin including presence of the drug in brain tissue in one case and recurrence of symptoms on repeated exposure in three cases. This series suggests that serious neurological adverse events observed with the use of ivermectin in the treatment of onchocerciasis may not be entirely explained by concomitant high burden loiasis infections. By comparison with the extensive post marketing experience with ivermectin in the successful treatment of parasitic infections, the number of reported cases suggests that such events are likely rare. However, elucidation of individual-level risk factors could contribute to therapeutic decisions that can minimize harms. Further investigation into the potential for drug–drug interactions and explorations of polymorphisms in the mdr-1 gene are recommended.
Ivermectin is a member of the class of avermectins, which are highly active broad-spectrum, anti-parasitic agents. It is indicated for use in the treatment of strongyloidiasis (Strongyloides stercoralis) and onchocerciasis (Onchocerca volvulus).1 It is also commonly used to treat scabies, although usage patterns for this indication vary between countries. In the scabies indiciation, it is approved for first-line therapy in some countries (within Europe), second-line therapy in others (such as Australia), or only recommended for special circumstances, such as immunocompromised or institutionalized patients or when topical therapy has failed (the United States).2–4 Furthermore, it has been suggested for use in the treatment of head lice given the recent increase in the burden of this condition in the developed world.5 Ivermectin is not thought to readily cross the blood-brain barrier in humans as it is excluded by a P-glycoprotein drug pump (mdr-1).6 Therefore, it has been considered to be free of the potential to cause neurological adverse drug reactions, except in situations of overdose.7,8
The data source was VigiBase, a computerized pharmacovigilance system in which reports describing adverse events are recorded in a structured, hierarchical form. Reports are received from national pharmacovigilance centers in the 125 countries participating in the WHO Program for International Drug Monitoring.13 All reports for ivermectin received into VigiBase up to November 27, 2016, were identified for use in this investigation. All analyses were performed on adverse event data using the Medical Dictionary for Regulatory Activities (MedDRA®) System Organ Class (SOC) and Preferred Term-level terminology.
A total of 1,668 reports for ivermectin were identified. The most commonly reported adverse events for ivermectin were pruritus (25.3%), headache (13.9%), and dizziness (7.5%). Under the MedDRA SOC “Neurological disorders,” there were a total of 426 reports; 156 of these were classified as “serious” according to ICH Guidance.14 Of the serious reports, 60.9% (95) originated from Africa, 20.5% (32) from the Americas, 12.2% (19) from Europe, and 6.4% (10) from Asia. One duplicate report was identified and excluded from the analysis.
From a global database of suspected adverse drug reactions we have identified a case series describing serious neurological adverse events with the use of ivermectin beyond its indication for O. volvulus. Supportive evidence for a causative role of ivermectin was found with the identification of ivermectin in brain tissue in one case and recurrence of symptoms on repeated exposure to ivermectin in three cases. This case series suggests that the serious neurological adverse events observed with the use of ivermectin in the treatment of onchocerciasis cannot be entirely explained by concomitant high burden loiasis infections.