Ivermectin

Introduction Overview

Generic Name

ivermectin

Brand Name

Stromectol

Dosage Form

Oral tablets; topical cream and lotion formulations

Drug Class

Anthelmintics

Pharmacokinetics

Absorption:
Ivermectin is well absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations are typically reached within 4 hours post-dose. The bioavailability can be affected by food intake, with recommendations to take ivermectin on an empty stomach (at least 1 hour before or 2 hours after a meal) to optimize absorption. Oral doses result in plasma concentrations sufficient to exert therapeutic effects against parasitic organisms. Studies have shown variable absorption depending on the formulation and patient factors such as gastrointestinal motility and integrity.

Distribution:
Ivermectin exhibits a large volume of distribution, indicating extensive tissue penetration. It is highly lipophilic and distributes preferentially into adipose tissue and organs rich in lipids. The drug binds extensively to plasma proteins, predominantly albumin, which influences its transport and bioavailability. Notably, ivermectin does not readily cross the mammalian blood-brain barrier due to the protective action of P-glycoprotein efflux pumps, thereby limiting CNS exposure and potential neurotoxicity in humans. The drug concentrates in tissues where parasites reside, contributing to its efficacy.

Metabolism:
Ivermectin undergoes extensive hepatic metabolism primarily via cytochrome P450 enzymes, especially CYP3A4. The drug is metabolized to multiple metabolites with varying activities; however, the parent compound is the major active agent. Hepatic metabolism converts ivermectin into less active or inactive metabolites, facilitating elimination. Certain patient populations with hepatic impairment may have altered metabolism, which could necessitate dosage adjustments and careful monitoring.

Elimination:
The elimination of ivermectin occurs mainly through fecal excretion, with less than 1% of the dose excreted unchanged in urine. The elimination half-life ranges from approximately 12 to 36 hours but can be longer depending on dose and individual variability. Renal clearance plays a minimal role. Complete elimination from the body may take several days. The drug's prolonged half-life contributes to its sustained antiparasitic effects, allowing for single-dose or infrequent dosing regimens.

Dosage Forms

Available Dosage Forms:
- Oral tablets: 3 mg strength for human use (Stromectol)
- Topical cream (Soolantra) for rosacea treatment
- Topical lotion (Sklice) for head lice treatment; available OTC

Dosages for Adults and Adolescents:
- Onchocerciasis: 0.15 mg/kg orally once yearly, with retreatment intervals as short as 3 months if needed
* Weight-based tablets dosing: 15–25 kg: 3 mg, 26–44 kg: 6 mg, 45–64 kg: 9 mg, 65–84 kg: 12 mg, ≥85 kg: 0.15 mg/kg
- Strongyloidiasis: 0.2 mg/kg orally once; follow-up stool exams recommended
* Weight-based tablets dosing: 15–24 kg: 3 mg, 25–35 kg: 6 mg, 36–50 kg: 9 mg, 51–65 kg: 12 mg, 66–79 kg: 15 mg, ≥80 kg: 0.2 mg/kg
- Ascariasis (off-label): 0.2 mg/kg orally once
- Cutaneous Larva Migrans (off-label): 0.2 mg/kg orally once
- Filariasis (off-label): 0.2 mg/kg orally once; mass treatment programs use 0.4 mg/kg annually combined with diethylcarbamazine
- Scabies (off-label): 0.2 mg/kg orally once, repeated in 2 weeks; may be combined with topical scabicides

Specific Patient Populations:
- Pediatric dosing for filariasis in children aged 5 years or older: 0.4 mg/kg orally once yearly
- Not recommended for children weighing less than 15 kg (33 lbs)
- Patients with weakened immune systems may require repeated or ongoing dosing
- Dosing adjustments may be necessary in hepatic impairment though specific guidelines are limited
- The tablets must be swallowed whole with water on an empty stomach to maximize absorption and clinical effect

Mechanism Of Action

Ivermectin exerts its antiparasitic activity primarily by binding selectively and with high affinity to glutamate-gated chloride channels (GluCl) located in the nerve and muscle cells of invertebrates. This binding induces an increased permeability to chloride ions, resulting in cellular hyperpolarization. Consequently, muscle paralysis occurs, leading to the immobilization and death of the parasite. The paralysis prevents the parasite from maintaining attachment or resisting host immune responses.

This mechanism is particularly selective for parasites because GluCl channels are absent in mammals or are protected by the blood-brain barrier, reducing ivermectin’s potential for toxicity in humans. Additionally, ivermectin may interact with other ligand-gated chloride channels, such as gamma-aminobutyric acid (GABA)-gated channels, in nematodes and arthropods, further contributing to neuromuscular paralysis.

Beyond direct antiparasitic effects, ivermectin has been shown to modulate the host’s immune response by inhibiting parasite-secreted proteins that usually help evade immune detection. This immunomodulatory effect may enhance host clearance of immature worms and supports the drug’s efficacy against various stages of parasitic infections.

Comparatively, ivermectin’s mechanism differs from other anthelmintics such as albendazole, which inhibits microtubule synthesis. Ivermectin’s unique GluCl mediated hyperpolarization provides a distinct and complementary approach, often used in combination therapies. Research and clinical studies confirm ivermectin’s efficacy and safety profile across a broad range of parasitic diseases, cementing its role as a cornerstone antiparasitic agent.

Pharmacological Actions

Paralysis and death of parasitic worms by activation of glutamate-gated chloride channels in invertebrate nerve and muscle cells
Selective binding to parasite-specific ion channels, sparing mammalian central nervous system due to limited blood-brain barrier penetration
Immunomodulation through suppression of parasite proteins that evade host immune defenses
Broad-spectrum anthelmintic activity against nematodes (e.g., strongyloides), arthropods (e.g., lice, scabies mites), and other parasites
Used topically to reduce inflammatory lesions associated with rosacea via anti-inflammatory properties
Exhibits minimal anticoagulant or direct antibacterial actions
Effective in mass drug administration campaigns for filariasis due to long half-life and safety
Demonstrates synergistic potential when combined with other antiparasitic agents in multi-drug regimens
Lacks significant action on mammalian voltage-gated ion channels, reducing potential adverse neurological effects
Produces a sustained antiparasitic effect allowing for single-dose or infrequent dosing schedules

Therapeutic Or Clinical Uses

FDA-approved treatment of intestinal strongyloidiasis
FDA-approved treatment of onchocerciasis (river blindness)
Topical treatment of rosacea (ivermectin cream - Soolantra)
Topical treatment of head lice (ivermectin lotion - Sklice)
Off-label treatment for scabies infestation, often combined with topical scabicides
Off-label therapy for ascariasis and cutaneous larva migrans
Used in mass drug administration programs for filariasis, especially bancroftian filariasis
Management of other parasitic infections caused by nematodes and ectoparasites
Potential investigational uses for ectoparasitic infestations resistant to standard therapy
Adjunctive therapy in immunocompromised patients requiring repeated dosing for parasitic control
Explored in clinical trials for antiviral properties, but not approved for COVID-19 treatment
Useful in controlling parasite spread in endemic tropical and subtropical regions
Employed in veterinary medicine for parasitic control in animals, though formulations differ
Investigated as part of combination regimens for broad-spectrum antiparasitic treatment

Side Or Adverse Effects

Common headache and muscle aches following oral administration
Dizziness and vertigo, with potential for light-headedness and risk of falls
Gastrointestinal disturbances including nausea, diarrhea, and mild abdominal discomfort
Mild skin rash or pruritus possibly related to immune response to dying parasites
Rare but serious allergic reactions presenting with urticaria, facial swelling, or difficulty breathing
Eye-related adverse effects such as eye pain, redness, puffiness, and vision changes
Neurological symptoms including confusion, seizures, balance problems, and altered mental status in rare overdose or sensitivity cases
Cardiovascular effects such as tachycardia and hypotension in overdose scenarios
Severe dermatologic reactions including rash with blistering or pustulation
Potential for swelling in extremities and lymphadenopathy associated with immune reaction
Bladder or bowel control loss reported in rare cases
Neck and back pain possibly linked to neurologic adverse events
Symptoms of systemic hypersensitivity such as fever and swollen glands
Risk of overdose toxicity when veterinary formulations are misused in humans
Transient dizziness necessitating caution during activities requiring alertness

Precautions

Avoid use in patients with known hypersensitivity to ivermectin or excipients
Exercise caution in patients with liver or kidney disease due to altered metabolism and elimination
Use carefully in immunocompromised individuals who may require repeated or prolonged dosing
Not recommended for use in children weighing less than 15 kg (33 pounds)
Pregnancy safety not established; consult healthcare provider before use during pregnancy
Breastfeeding mothers should weigh benefits versus risks as ivermectin passes into breast milk
Avoid activities requiring mental alertness until drug effects are known due to dizziness risk
Take on an empty stomach to maximize absorption and therapeutic efficacy
Monitor for signs of hypersensitivity or severe adverse reactions during treatment
Avoid concurrent alcohol consumption to prevent exacerbation of side effects
Patients should undergo stool examination post-treatment to confirm parasite eradication
Emphasize adherence to prescribed dose; avoid self-medication and overdose
Use with caution when combined with other CNS-active agents or P-glycoprotein inhibitors
Consider potential drug interactions in polypharmacy patients
Patients should report any unusual neurological symptoms or vision changes promptly

Warnings

Do not use ivermectin products intended for veterinary use to avoid serious toxicity
Stool examination is necessary after treatment to ensure complete infection clearance
May cause dizziness or fainting; rise slowly from sitting or lying positions to reduce risk
Not approved or recommended for prevention or treatment of COVID-19 outside clinical trials
Use cautiously in patients with weakened immune systems; may require repeated dosing
Possible serious allergic reactions requiring emergency medical attention
Single doses may need repetition months apart for certain infections
In rare cases, ivermectin may cause severe neurological adverse events
Topical formulations approved only for specific indications (rosacea, head lice)
Overdose can result in severe symptoms including seizures, coma, and death
Abrupt discontinuation after initiation in infections with heavy parasite loads may lead to immune reactions
Pregnant and nursing women should only use under medical supervision
Avoid unregulated off-label use due to safety concerns and lack of efficacy data
Report any adverse effects to health authorities for pharmacovigilance
Impaired liver function may increase risk of adverse effects and necessitate monitoring

Contraindication

Known hypersensitivity or allergy to ivermectin or any formulation components
Children weighing less than 15 kilograms (33 pounds) due to safety concerns
Use of veterinary ivermectin products in humans due to formulation differences and toxicity risk
Patients with a history of severe allergic reactions to anthelmintic drugs
Concomitant use with drugs that significantly inhibit P-glycoprotein and CYP3A4 without monitoring
Pregnancy when risk-benefit analysis fails to justify use in absence of safer alternatives
Patients with active central nervous system disorders without strict monitoring
Concurrent treatment with other CNS depressants without supervision
Severe hepatic impairment where drug metabolism may be critically compromised
Known history of allergic dermatitis or severe skin reactions to related compounds
Use in neonates and infants under 5 years old due to limited safety data
Use caution or avoid in patients with immunological hypersensitivity syndromes
Avoid in patients with conditions predisposing to blood-brain barrier dysfunction
Known sensitivity to excipients such as benzyl alcohol in topical products
Off-label usage without medical oversight in unapproved conditions

Drug Interactions

Possible increased ivermectin plasma concentrations with CYP3A4 inhibitors such as ketoconazole or erythromycin
P-glycoprotein inhibitors may increase CNS exposure and risk of neurotoxicity
Co-administration with other CNS depressants may potentiate sedation or dizziness
No significant interaction reported with common anthelmintics but caution advised with polytherapy
No notable interactions with vitamins or herbal products reported, but clinical vigilance recommended
Interactions with anticoagulants are not significant but close monitoring advised
Limited data on interaction with immunosuppressive drugs; caution advised given patient population
Co-treatment with diethylcarbamazine in filariasis requires monitoring for enhanced adverse effects
Concomitant use with warfarin or other blood thinners appears safe but clinical judgment necessary
No dose adjustments generally needed with concomitant HIV medications, though monitoring is prudent
Interaction with P-glycoprotein inducers may reduce ivermectin efficacy
Avoid co-administration with substances that disrupt blood-brain barrier integrity
No significant pharmacokinetic interference with oral contraceptives documented
Potential for altered metabolism with liver enzyme inducers such as rifampin
Patients should inform healthcare providers of all medications, supplements, and herbal use

Preparations Of The Drug

Oral tablets (3 mg strength) suitable for weight-based dosing in parasitic infections
Topical cream (Soolantra) indicated for treatment of inflammatory lesions of rosacea
Topical lotion (Sklice) formulated for treatment of head lice, available over-the-counter
Veterinary formulations available in highly concentrated forms for large animals, contraindicated for human use
Reference commercial product: Stromectol (oral tablets by Merck Sharp & Dohme Co.)
Generic oral ivermectin tablets available from multiple manufacturers worldwide
Excipients designed to optimize oral bioavailability and gastrointestinal tolerance in oral forms
Topical formulations contain ingredients to enhance skin penetration and efficacy against ectoparasites
Packaging available in blister packs or bottles with patient instructions and dosing guidance
Storage conditions recommended at room temperature, protected from moisture and heat
Labeling includes clear warnings about off-label use and avoidance of veterinary products
Available in single-dose packaging for ease of administration in mass treatment campaigns
Formulations undergo rigorous quality control to ensure potency and safety per regulatory standards
Patient assistance programs available for access to branded or generic formulations depending on region
Combination regimens with other anthelmintics sometimes prepared extemporaneously in clinical settings