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Ivermectin: Side Effects

Ivermectin, a dihydroavermectin B1, is an effective microfilaricide used in the treatment of strongyloides, scabies, and all types of filariasis except Dipalonema (Mansonella) perstans infections.

Over a number of years, ivermectin has shown excellent results in the treatment of onchocerciasis, both in controlled studies and in the field, including use in the WHO-sponsored program of treatment. This experience has provided a thorough picture of its adverse effects. The effective dosage is of the order of 50-200 micrograms/kg. After a single oral dose, skin microfilariae remain at low levels for up to 9 months.

As antihelminthic drugs go, ivermectin can be considered a reasonably safe drug, and it is generally better tolerated than diethylcarbamazine. Clinical experience has often shown relatively little toxicity, although mild adverse effects, presumably due to the killing of the microfilariae, involve at least one-third of patients; some work has suggested that neutrophil activation may play a role in the development of these reactions. It has also been well tolerated in combinations, for example when given with albendazole in order to kill adult worms (which cannot be achieved with ivermectin alone) or with diethylcarbamazine for bancroftian filariasis.

The principal reservation from the start was that ivermectin has a long half-life and that some late effects might occur in certain individuals. During the early phases it was recommended that in areas where the drug had been widely used the health workers involved should continue to observe patients for a time, in case problems did arise, but no late complications have in fact been documented.

Mode of action

The mode of action of ivermectin has been reviewed. It has tentatively been identified as agonism at GABA receptors, with inhibition of ion channels that control specific nerve cell connections. The functioning of chloride channels should thus be altered in most organisms, leading to paralysis and death of parasites. Several sites of action have been proposed:

• a postsynaptic agonist site either on the receptor or in its immediate neighborhood;
• a presynaptic site of activation of GABA release;
• potentiation of GABA binding to its receptor.

Another mechanism of action involves the binding of ivermectin to P glycoprotein.

Ivermectin: Observational studies

Comparative studies

Sarcoptes scabiei

In a randomized trial a single oral dose of ivermectin (200 micrograms/kg) has been compared with 1% gamma-benzene hexachloride lotion for topical application overnight in 200 patients with scabies. The patients were assessed after 48 hours, 2 weeks, and 4 weeks. After 4 weeks, 83% showed marked improvement with ivermectin, compared with 44% of those treated with gamma-benzene hexachloride. There were no adverse events reported with gamma-benzene hexachloride. Headache was reported only once with ivermectin.

In 80 children aged 6 months to 14 years a single dose of ivermectin 200 micrograms/kg was compared with topical benzyl benzoate for the treatment of pediatric scabies in a randomized, controlled trial. Ivermectin cured 24 of 43 patients and topical benzyl benzoate cured 19 of 37 patients at 3 weeks after treatment. There were no serious adverse effects with either treatment, although benzyl benzoate was more likely to produce local skin reactions. These results are in line with those of another study, in which 18 children aged 14 months to 17 years with either scabies or cutaneous larva migrans were treated with a single dose of ivermectin 150-200 micro-grams/kg. A single oral dose cured 15 patients, and three patients with crusted scabies required a second dose. None had significant adverse reactions.

Wuchereria bancrofti

In a study in which doses of 200 or 400 micrograms were used, with or without diethylcarbamazine, for Wuchereria bancrofti infection, there was a higher than average incidence of reactions (and a higher incidence with ivermectin than with diethylcarbamazine), but this perhaps reflected an unusually high success rate or the severity of the original infection. For similar reasons, repeated courses of treatment tend to show a falling incidence of adverse effects. Normally, such general symptoms as fever, weakness, anorexia, malaise, and chills occur in a substantial minority of patients on a first course, while at least one-third have muscle and/or joint pains. Vertigo, dyspnea, diarrhea and abdominal disturbances affect a few patients. The severity of adverse effects is not related to serum concentrations of the drug, which again reflects the fact that they are largely a consequence of the parasitic breakdown, rather than toxic effects of ivermectin.

Ivermectin: Placebo-controlled studies

General adverse effects

Acute symptoms, often flu-like or affecting the skin, are related almost entirely to the release of toxic products and allergens from the killed filariae, and can affect two-thirds of patients; in conditions in which this type of reaction does not occur one may suspect that the drug is ineffective. The mechanism of the effects also explains why they tend to occur early and sometimes briefly, that is immediately after the microfilariae die. For similar reasons, these effects are most severe in patients with a high microfilaria count.

Despite the sometimes transient and apparently tolerable nature of the skin effects, they can persist in patients requiring long-term treatment, for example for onchocerciasis, and under these conditions they are sufficient to impair compliance with treatment.

The effects of age, sex, dosing round, time of day, and distance from the nurse monitor on adverse event reporting during mass ivermectin administration in Achi in South-East Nigeria have been examined. There was a significant increase in adverse reporting with age, but not sex. Fewer adverse effects were reported after starting at night than after starting by day. There was no significant effect of distances up to 1 km on adverse events reporting. Both compliance and adverse reporting were less after the second dosing round than after the first. These variables should be included in the standardization of adverse events reporting.

Onchocerciasis

Although adverse reactions after ivermectin in onchocerciasis are usually less severe than after diethylcarbamazine, they still affect a significant number of patients with onchocerciasis after the first dose. With subsequent treatments, these reactions become less frequent and severe. The so-called Mazzotti reaction, which is often seen after treatment of Onchocerca volvulus with diethyl-carbamazine or ivermectin, is characterized by fever, tachycardia, hypotension, adenitis, pruritus, arthralgia, a papular or urticarial rash, and lymphedema. It is ascribed to an inflammatory host response to microfilarial killing and tends to be more severe in those who have greater numbers of parasites. The roles of chemoattractants, such as eotaxin, RANTES, and MCP-3, in the recruitment of eosinophils to the site of parasite killing has been studied in 13 patients with onchocerciasis and two control subjects before and after ivermectin. There were adverse reactions in eight patients, but none were severe. The reactions were fever (54%), pruritus (62%), rash (46%), and lymphedema (46%). There was no significant postural hypotension. There was endothelial expression of both RANTES and eotaxin after ivermectin, suggesting that these chemoattractants have an important role in eosinophil recruitment into the skin during killing or degeneration of parasites after ivermectin.

A role for the release of Wolbachia bacterial endosymbionts has been suggested in the pathogenesis of the Mazzotti reaction. There was a good correlation between Wolbachia DNA, serum TNF-alfa, and the antibacterial peptides calprotectin and calgranulin after treatment with ivermectin or diethylcarbamazine, supporting a role for Wolbachia products in mediating these inflammatory responses.

There has been an epidemiological survey of the endemicity of human onchocerciasis and the effects of subsequent mass distribution of ivermectin in villages of the Nzerem-Ikpem community in Nigeria. Of 1126 people studied, 527 were positive for skin microfilariae, 329 had a leopard skin (characterized by focal skin depig-mentation), 385 had nodules, and 167 had onchodermatitis. There were adverse effects in 362 patients (19%): pruritus in 13%, limb swelling in 8.5%, facial swelling in 2%, weakness in 4.8%, nausea and vomiting in 3.4%, headache in 5.8%, diarrhea in 3.4%, and rheumatism in 3.5%. There were no severe reactions.

Ivermectin: Organs and Systems

Second-Generation Effects Teratogenicity

There is no evidence of second-generation injury from ivermectin, but it is prudent to avoid it in pregnant women.

Lactation

Only a small amount of ivermectin is excreted in the breast milk and it has been suggested that it is unnecessary to exclude lactating mothers from mass chemotherapy with ivermectin.