Ivermectin is an anti-inflammatory

Pharmacology

Pharmacodynamics

It has an anti-inflammatory effect by inhibiting the production of inflammatory cytokines induced by lipopolysaccharides. The anti-inflammatory properties of ivermectin have been observed in animal models of skin inflammation. Ivermectin also causes death of parasites, mainly through selective binding and high affinity for glutamate-regulated chlorine channels found in nerve and muscle cells of invertebrates. The mechanism of action of ivermectin in the treatment of inflammatory skin lesions in rosacea is not fully known, but may be related both to anti-inflammatory effects and to the ability to induce death of Demodex mites, which in turn may be a factor causing skin inflammation.

Pharmacokinetics

Absorption. Absorption of ivermectin was assessed in a clinical study involving adult patients with severe papulopustular rosacea using the maximum tolerated dose. At equilibrium (after 2 weeks of treatment), the highest mean (± standard deviation) plasma concentrations of ivermectin were observed within (10±8) h after administration (Cmax was (2.1±1) ng/mL, range, 0.7-4 ng/mL), and the highest mean (± standard deviation) AUC0-24 was (36±16) ng/h/mL, range, 14-75 ng/h/mL). Systemic exposure to ivermectin reached a plateau by the end of the second week of equilibrium treatment. For longer treatments in phase III studies, the systemic exposure rate of ivermectin remained the same as after two weeks of treatment. Under Css, systemic exposure levels of ivermectin (AUC0-24 (36±16) ng-h/ml) were lower than after a single oral dose of 6 mg of ivermectin in healthy volunteers (AUC0-24 (134±66) ng-h/ml).

Distribution. An in vitro study showed that the binding of ivermectin to plasma proteins (mainly to albumin) is more than 99%. Significant binding of ivermectin with erythrocytes was not observed.

Metabolism. In in vitro studies using human liver microsomes and recombinant CYP450 enzymes it was noted that ivermectin is metabolized mainly by CYP3A4.

In vitro studies have shown that ivermectin does not inhibit the CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP4A11 or CYP2E1 isoenzymes. Ivermectin does not induce the expression of the CYP1A2, CYP2B6, CYP2C9, or CYP3A4 isoenzymes) in human hepatocyte culture. Two major metabolites of ivermectin (3″-O-demethylvermectin and 4a-hydroxyvermectin) have been identified in a clinical pharmacokinetic study of the maximum tolerated dose of this agent and were studied in a phase II clinical trial. Similar to the parent compound, metabolites reached equilibrium by the end of the second week of treatment, and no evidence of accumulation was observed for up to 12 weeks. In addition, the systemic exposure of metabolites (assessed using Cmax and AUC) obtained at equilibrium was much lower than that of ivermectin after oral administration.

Excretion. The final T1/2 averaged 6 days (approximately 145 h, range 92-238 h) in patients who applied ivermectin to the skin once daily for 28 days in a clinical pharmacokinetic study at the maximum tolerated dose. Excretion depended on the degree of absorption after topical application. The pharmacokinetics of ivermectin have not been studied in patients with hepatic or renal dysfunction.

Application of the substance Ivermectin

Inflammatory skin lesions in rosacea (papulopustular form) in adult patients.

Contraindications

Hypersensitivity, pregnancy, breast-feeding, under 18 years of age (safety and effectiveness has not been studied for this age group).

Limitations on use

Impaired liver function.

Use in pregnancy and lactation

Data on the use of ivermectin in pregnant women are limited. Studies of reproductive toxicity in oral ivermectin have shown that it has teratogenic potential in rats and rabbits, but because of the low systemic effects, the risk of fetotoxicity in humans is low when administered externally at the recommended dose. The use of ivermectin during pregnancy is contraindicated.

Low concentrations of ivermectin are excreted into breast milk following oral administration. Excretion of ivermectin into breast milk has not been studied when administered externally. Pharmacokinetic and toxicological data from animal studies also indicate that ivermectin is excreted into breast milk. A risk to the infant cannot be excluded. Breastfeeding should be stopped if the use of ivermectin is necessary.

Side effects of the substance Ivermectin

The most frequent adverse reactions, such as burning sensation, skin irritation, itching and dry skin, have been reported in less than 1% of patients treated with ivermectin in clinical trials.

Skin and subcutaneous tissue: frequently (≥1/10) – burning sensation of the skin; infrequently (≥1/1000, <1/100) – skin irritation, itching, dry skin; frequency unknown – contact dermatitis, allergic reactions.

As a rule, these reactions are mild to moderate and usually subside with continued therapy.

No significant differences in the safety profile were observed in patients aged 18 to 65 years and older.

Interactions

Studies on interaction of ivermectin with other drugs have not been conducted. Concomitant use with other topical and systemic agents for the treatment of rosacea has not been studied. Caution should be exercised when concomitant use with strong CYP3A4 inhibitors, because plasma concentrations of ivermectin may increase significantly.

Overdose

No cases of ivermectin overdose have been reported.

Symptoms

When accidental or significant exposure of humans to unknown amounts of veterinary forms of ivermectin (ingestion, inhalation, parenteral administration or body surface contact), skin rash, facial edema, eyelid swelling, headache, dizziness, asthenia, nausea, vomiting and diarrhea were the most frequently reported. Other reported adverse reactions include seizures, ataxia, dyspnea, abdominal pain, paresthesia, urticaria, and contact dermatitis.

Treatment

In case of accidental ingestion, symptomatic therapy including parenteral administration of fluids and electrolytes, respiratory support (ensuring oxygen supply and, if necessary, ventilatory ventilation) and vasopressors (in case of marked BP decrease) are provided. Induction of vomiting and/or urgent gastric lavage followed by laxatives and other measures of intoxication may be indicated to prevent absorption of ingested ivermectin.

Directions for use and dosages

Externally, only on the face, once a day, treatment course – up to 4 months.

Precautions

The components of the finished dosage form ivermectin may cause local skin reactions (e.g. contact dermatitis), allergic reactions (including delayed type), skin irritation.

Wash hands after application.

After drying, cosmetic products may be applied.
Effect on the ability to drive vehicles and operate machinery. Ivermectin has no or negligible effect on the ability to drive vehicles and operate mechanisms.