**5.1 Ivermectin use as anti-parasitic**

Because of its broad spectrum applicability, ivermectin can be applied to treat onchocerciasis, lymphatic filariasis, strongyloidiasis, ascariasis, scabiasis, and enterobiasis. Since its discovery, ivermectin has been administered to millions of patients with the above parasitic infections around the world. Mild adverse effects of oral ivermectin therapy against certain parasites are common; many of them appear within 24-48 hours of the onset of therapy and are related to ivermectin dose as well as the microfilariae load in the skin in case of filiariasis [29, 30]. Some of these adverse effects include myalgia, skin rashes, joints swelling, limbs or face itching, fever, and chills. These effects are usually transient and do not require treatment [31, 32]. Moderate to severe effects are less common and may include skin edema with the presence of pain, arthralgia, severe dizziness, high fever, dyspnea, and hypotension (Mazzotti's Reaction). It is known that such reaction is not related to the administration of Ivermectin but with the parasite amount present in the host [30, 31]. In addition to Mazzotti's reaction, there have been cases of severe encephalopathy that can be fatal in patients with onchocerciasis and filariasis after treatment with ivermectin. The symptoms of encephalopathy include altered mental status, incontinence, and difficulty standing or walking 48 hours after ivermectin treatment [32, 33]. This effect is again probably due to the obstruction of the cerebral microcirculation due to the accumulation of paralyzed or killed parasites and not by ivermectin itself [34, 35]. Also, toxic effects have been linked to ivermectin's interaction with P-glycoprotein [8]. The absence of P-glycoprotein determines the accumulation of Ivermectin in the brain of transgenic mice who do not express it and dogs with impaired P-glycoprotein function (commonly a 4 base-pair deletion of the MDR-1 gene that produces a stop codon) have increased neurotoxicity to ivermectin [36]. **Table 2** summarizes ivermectin's adverse effects. The dose and schedules vary but human doses are standardized for approved indications within the range of 0.15 to 0.4 mg/Kg. For onchocerciasis, the recommended dose is 0.15 mg/Kg once every 12 months, though patients with heavy ocular infection may require retreatment every 3 or 6 months. Filariasis usually requires a single dose of


**Table 2.**

*Pharmacokinetic data of Ivermectin in humans infected with parasites and in healthy volunteers.*

0.4 mg/Kg. In strongyloidiasis, a single dose of 0.2 mg/Kg is recommended; however, in immunocompromised (including HIV) patients, the treatment may require repeated administration (i.e. every two weeks) and continued suppressive therapy (i.e. once a month). A single dose of 0.2 mg/Kg is also used to treat ascariasis, while the same dose repeated once at two weeks is recommended for scabiasis [37].

Recently, there has been a growing interest in newer anti-parasitic indications of ivermectin such as against soil-transmitted helminths and malaria, hence doses above 0.4 mg/Kg are being evaluated for achieving higher plasma levels [38, 39].

An example is a pharmacokinetic trial using 18 mg ivermectin tablets in 54 healthy adult volunteers to evaluate the safety of fixed regimens of 18 and 36 mg [40]. A meta-analysis to investigate the safety of higher doses of ivermectin identified four studies for inclusion, and found no differences in the number of individuals experiencing adverse events at higher doses. A descriptive analysis of these clinical trials for a variety of indications also showed no difference in the severity of the adverse events between standard (up to 0.4 mg/Kg) and higher doses of Ivermectin (0.4-0.7 mg/Kg; 0.6 mg/Kg, and 0.8 mg/Kg). Only one trial showed an increase in transient and mild to moderate subjective ocular events such as transitory blurring of vision, itching or pain of the eye, and dyschromatopsia in the higher-dose group in a trial to treat onchocerciasis. Meanwhile, severe adverse events described as life-threatening, was reported in only one out of the four studies with one case of anaphylaxis at the standard dose and another case of QTc prolongation likely due to drug-drug interaction in a higher-dose group [41]. The result of this small meta-analysis is suggestive of relatively safety of higher doses of ivermectin.
