Ivermectin

Ivermectin is an Anthelmintic Agent belonging to pharmacology class of Antiparasitic Agent Class

Ivermectin can be used in the treatment of Head lice,Onchocerciasis, Strongyloidiasis, .

Ivermectin is Well absorbed from the gastrointestinal tract (fasted state). Increased bioavailability with a high-fat meal. Time to peak plasma concentration: Approx 4 hours (oral); approx 10 hours (topical cream) with High concentration in the liver and adipose cell. Enters breast milk (small amounts). Volume of distribution: 3.1-3.5 L/kg. Plasma protein binding: Approx 93% mainly to albumin (oral); >99% (topical) and get Metabolised in the liver mainly by CYP3A4 isoenzyme and get excreted Via faeces; urine (<1%). Elimination half-life: Approx 18 hour

The common side effects associated with Ivermectin include Mazzotti reaction (e.g. lymphadenitis, oedema, arthralgia, synovitis, tachycardia, fever, pruritus, urticaria) and ophthalmic reaction particularly in patients undergoing treatment for onchocerciasis; transient aggravation of rosacea

Ivermectin is available in the form of Tablets, , Cream, Lotion.

Ivermectin is a semisynthetic anthelminthic agent; it binds selectively and with strong affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This leads to increased permeability of cell membranes to chloride ions then hyperpolarization of the nerve or muscle cell, and death of the parasite.

The Tmax of Ivermectin 10 hours post application.

Onset of Action: Most patients have response to treatment within 2 hours.

Ivermectin is available in Tablets, Cream, Lotion

Tablet: May be broken in half to achieve a smaller initial dose

Orally-disintegrating tablet: Must be taken whole; do not break, crush, or chew. Place on tongue and allow to dissolve. Administration with liquid is not required.

Ivermectin can be used in the treatment of Head lice, Onchocerciasis, Strongyloidiasis. It is also used to treat Ascariasis; Demodex folliculitis; Gnathostomiasis, cutaneous; Hookworm-related cutaneous larva migrans; Lice, refractory; Mansonella infection; Scabies; Trichuriasis.

Ivermectin is a member of the ivermectin class of broad-spectrum antiparasitic agents which have a unique mode of action. Compounds of the class bind selectively and with high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. Compounds of this class may also interact with other ligand-gated chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA).

Ivermectin is approved for use in the following clinical indications:

Head lice (Pediculus capitis) (lotion): Treatment of head lice infestations in patients 6 months and older.

Rosacea (cream): Treatment of inflammatory lesions of rosacea in adult patients.

Onchocerciasis: Treatment of onchocerciasis due to the immature form of Onchocerca volvulus.

Limitations of use: Ivermectin has no activity against adult Onchocerca volvulus parasites. The adult parasites reside in subcutaneous nodules, which are infrequently palpable. Surgical excision may be considered since removal of these nodules will eliminate the microfilariae-producing adult parasites.

Strongyloidiasis: Treatment of intestinal (eg, nondisseminated) strongyloidiasis due to Strongyloides stercoralis.

Although not approved there have been certain off labelled uses documented for Ivermectin which includes :

Ascariasis; Demodex folliculitis; Gnathostomiasis, cutaneous; Hookworm-related cutaneous larva migrans; Lice, refractory; Mansonella infection; Scabies; Trichuriasis

Head lice: Topical: Lotion: Apply sufficient amount (up to 1 tube) to completely cover dry scalp and hair; for single-dose use only.

Rosacea: Topical: Cream: Apply to each affected area (eg, forehead, chin, nose, each cheek) once daily.

• Ascariasis

Ascariasis (alternative agent) (off-label use):

Note: For patients with complications (eg, intestinal obstruction, acute cholangitis), initiate therapy after resolution of acute symptoms .

Oral: 150 to 200 mcg/kg as a single dose .

• Demodex folliculitis

Demodex folliculitis (off-label use): Oral: 200 mcg/kg once weekly for 2 doses .

• Gnathostomiasis, cutaneous (off-label use):

Note: Not recommended for CNS disease due to inflammatory response from dying larvae .

Oral: 200 mcg/kg once daily for 2 days .

• Hookworm-related cutaneous larva migrans (off-label use): Oral: 200 mcg/kg once daily for 1 or 2 days .
• Lice, refractory (off-label use):

Note: Reserve for patients with an insufficient response to topical therapy . Optimal dose, dosing interval, and frequency are uncertain .

Pediculus capitis: Oral: 200 mcg/kg once weekly for 2 doses ; some experts suggest 400 mcg/kg once weekly for 2 doses .

Pediculosis pubis: Oral: 200 mcg/kg once weekly for 2 doses ; some experts suggest 250 mcg/kg once, with a repeat dose in 7 to 14 days .

• Mansonella infection

Mansonella infection (off-label use):

Note: For individuals from Loa loa–endemic areas, rule out co-infection prior to ivermectin administration to avoid life-threatening encephalopathy .

Mansonella ozzardi: Oral: 150 mcg/kg as a single dose .

Mansonella streptocerca infection (alternative agent): Oral: 150 mcg/kg as a single dose .

• Onchocerciasis:

Note: For individuals from Loa loa–endemic areas, rule out co-infection prior to ivermectin administration to avoid life-threatening encephalopathy .

Oral: 150 mcg/kg once; repeat dose every 3 to 6 months until asymptomatic . For patients outside endemic areas or in areas with low transmission, doxycycline therapy is initiated 1 week after the initial ivermectin dose .

• Scabies (off-label use):

Note: For cohabitants or other individuals who have had prolonged skin-to-skin contact within the previous 6 weeks, simultaneous treatment is recommended .

Classic scabies, treatment: Oral: 200 mcg/kg once; repeat dose in 7 to 14 days .

Crusted scabies, treatment: Oral: 200 mcg/kg once daily in combination with permethrin for 3, 5, or 7 nonconsecutive days depending on infection severity (eg, for 3 days: give on days 1, 2, and 8; for 5 days: give on days 1, 2, 8, 9, and 15; for 7 days: give on days 1, 2, 8, 9, 15, 22, and 29) .

• Strongyloidiasis:

Note: For individuals from Loa loa–endemic areas, rule out co-infection prior to ivermectin administration to avoid life-threatening encephalopathy .

• Uncomplicated infection:

Patients who are immunocompetent: Oral: 200 mcg/kg once daily for 1 or 2 days .

Patients who are immunocompromised: Oral: 200 mcg/kg once daily for 2 days; repeat dosing regimen in 2 weeks .

Severe, disseminated infection: Oral: 200 mcg/kg once daily until symptoms have resolved and stool and/or sputum examination is negative for ≥2 weeks . Some experts suggest switching to an alternative approach for patients who are immunocompromised or critically ill with persistently positive (eg, ≥3 days) stool examination . For patients with persistent immunosuppression after clinical improvement, some experts use suppressive ivermectin 200 mcg/kg once monthly for ≥6 months .

Tablets, Cream, Lotion

3 mg, 0.5%, 1%

Tablet, Cream, Lotion

• Dose Adjustment in Pediatric Patient:

Head lice: Topical: Lotion 0.5%: Infants ≥6 months, Children, and Adolescents: Apply sufficient amount (up to 1 tube) to completely cover dry hair and scalp; for single use only; discard any remaining product.

Increased bioavailability with a high-fat meal.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Other warnings/precautions:

• Appropriate use:

Topical lotion: For topical use on scalp and scalp hair only; treatment of lice on eyebrows or eyelashes should only be done under the guidance of a health care provider. Avoid contact with eyes and do not use inside the nose, ears, or mouth. Wash hands after application.

Topical cream: Not for oral, ophthalmic, or vaginal use; avoid contact with eyes and lips. Wash hands after application.

There is no sufficient scientific evidence traceable regarding use and safety of Ivermectin in concurrent use with alcohol.

It is not known if ivermectin is present in breast milk following topical application.

Ivermectin is present in breast milk following oral administration. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Use of topical ivermectin for the treatment of pediculosis pubis or scabies is likely compatible with breastfeeding.

Pregnancy

Pregnancy Category (FDA): C

Ivermectin has been shown to be teratogenic in mice, rats, and rabbits when given in repeated doses of 0.2, 8.1, and 4.5 times the maximum recommended human dose, respectively (on a mg/m2/day basis). Teratogenicity was characterized in the three species tested by cleft palate; clubbed forepaws were additionally observed in rabbits. These developmental effects were found only at or near doses that were maternotoxic to the pregnant female. Therefore, Ivermectin does not appear to be selectively fetotoxic to the developing fetus. There are, however, no adequate and well-controlled studies in pregnant women. Ivermectin should not be used during pregnancy since safety in pregnancy has not been established.

Increased bioavailability with a high-fat meal.

The adverse reactions related to Ivermectin can be categorized as:

Common Adverse effects: Mazzotti reaction (e.g. lymphadenitis, oedema, arthralgia, synovitis, tachycardia, fever, pruritus, urticaria) and ophthalmic reaction particularly in patients undergoing treatment for onchocerciasis; transient aggravation of rosacea

Less Common Adverse effects: Asthenia, fatigue, Conjunctival hemorrhage (if treated for onchocerciasis); conjunctivitis, ocular hyperemia, eye irritation

Rare Adverse effects: Skin burning sensation, Irritation, Pruritus, Dry skin.

The clinically relevant drug interactions of Ivermectin is briefly summarized here

Rarely, increased INR with warfarin.

The common side of Ivermectin include the following

Mazzotti reaction (e.g. lymphadenitis, oedema, arthralgia, synovitis, tachycardia, fever, pruritus, urticaria) and ophthalmic reaction particularly in patients undergoing treatment for onchocerciasis; transient aggravation of rosacea.

Pregnancy

Pregnancy Category (FDA): C

Ivermectin has been shown to be teratogenic in mice, rats, and rabbits when given in repeated doses of 0.2, 8.1, and 4.5 times the maximum recommended human dose, respectively (on a mg/m2/day basis). Teratogenicity was characterized in the three species tested by cleft palate; clubbed forepaws were additionally observed in rabbits. These developmental effects were found only at or near doses that were maternotoxic to the pregnant female. Therefore, Ivermectin does not appear to be selectively fetotoxic to the developing fetus. There are, however, no adequate and well-controlled studies in pregnant women. Ivermectin should not be used during pregnancy since safety in pregnancy has not been established.

Labor and Delivery

There is no FDA guidance on use of Ivermectin during labor and delivery.

Nursing Mothers

Ivermectin is excreted in human milk in low concentrations. Treatment of mothers who intend to breast-feed should only be undertaken when the risk of delayed treatment to the mother outweighs the possible risk to the newborn.

Pediatric Use

Safety and effectiveness in pediatric patients weighing less than 15 kg have not been established.

Geriatric Use

Clinical studies of Ivermectin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, treatment of an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Gender

There is no FDA guidance on the use of Ivermectin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Ivermectin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Ivermectin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Ivermectin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Ivermectin in women of reproductive potentials and males.

Immunocompromised Patients

In immunocompromised (including HIV-infected) patients being treated for intestinal strongyloidiasis, repeated courses of therapy may be required. Adequate and well-controlled clinical studies have not been conducted in such patients to determine the optimal dosing regimen. Several treatments, i.e., at 2-week intervals, may be required, and cure may not be achievable. Control of extra-intestinal strongyloidiasis in these patients is difficult, and suppressive therapy, i.e., once per month, may be helpful.

Pharmacodynamics:

Ivermectin is a semisynthetic anthelmintic derived from the avermectins. It has a strong affinity and binds selectively to glutamate-gated chloride ion channels of invertebrate nerve and muscle cells resulting in increased permeability of cell membrane to chloride ions with hyperpolarisation of the nerve or muscle cell, thereby causing the death of the parasite. The mechanism of action in the treatment of rosacea is still unknown but may be associated with the anti-inflammatory effects of ivermectin and antiparasitic action that causes the death of Demodex mites reported to contribute to skin inflammation.

Pharmacokinetics:

Absorption: Well absorbed from the gastrointestinal tract (fasted state). Increased bioavailability with a high-fat meal. Time to peak plasma concentration: Approx 4 hours (oral); approx 10 hours (topical cream).

Distribution: High concentration in the liver and adipose cell. Enters breast milk (small amounts). Volume of distribution: 3.1-3.5 L/kg. Plasma protein binding: Approx 93% mainly to albumin (oral); >99% (topical).

Metabolism: Metabolised in the liver mainly by CYP3A4 isoenzyme.

Excretion: Via faeces; urine (<1%). Elimination half-life: Approx 18 hour.

1. https://www.uptodate.com/contents/Ivermectin -drug-information?search=Ivermectin &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Ivermectin _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Ivermectin ?type=full&mtype=generic#mechanism-of-action