Ivermectin (Systemic)


VA CLASSIFICATION
Primary: AP200

Commonly used brand name(s): Mectizan; Stromectol.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anthelmintic (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Onchocerciasis (treatment)—Ivermectin is used in the treatment of onchocerciasis (river blindness) caused by the parasite Onchocerca volvulus . {01} {02} {03} {04} {05} {06} {07} {08} {09} {11} {16} {33} {34}

[Filariasis, Bancroft"s (treatment) ]1—Ivermectin is used in the treatment of bancroftian filariasis caused by Wuchereria bancrofti . {20} {21} {22} {26}

[Scabies (treatment)]1—Ivermectin is used in the treatment of scabies caused by Sarcoptes scabiei . {38}

Strongyloidiasis (treatment)—Ivermectin is used as a secondary agent in the treatment of intestinal strongyloidiasis caused by the nematode parasite Strongyloides stercoralis . {29} {34}

Acceptance not established
Ivermectin has been used to treat cutaneous larva migrans caused by Ancylostoma braziliense or Ancylostoma caninum . However, data are limited and further study is required to define the role of ivermectin for this condition. {38}

Unaccepted
Ivermectin is not effective against flukes or protozoa. {01} {05} {06} {14}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Mechanism of action/Effect:

Microfilaricidal; ivermectin binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of the microfilaria. This binding causes an increase in the permeability of the cell membrane to chloride ions and results in hyperpolarization of the cell, leading to paralysis and death of the parasite. Ivermectin also is believed to act as an agonist of the neurotransmitter gamma-aminobutyric acid (GABA), thereby disrupting GABA-mediated central nervous system (CNS) neurosynaptic transmission. {34} {36}

Although not macrofilaricidal, ivermectin may also impair normal intrauterine development of O. volvulus microfilariae and may inhibit their release from the uteri of gravid female worms. Action on microfilariae is less abrupt but more prolonged than that of diethylcarbamazine. Ivermectin promptly decreases skin microfilarial counts, while the number of microfilariae in the cornea and anterior chamber of the eye decreases more slowly. {01} {02} {03} {04} {05} {07} {08} {09} {10} {12} {14}

Distribution:

Does not cross the blood-brain barrier in humans and most other mammals. {05} {14} In animal studies (cattle, sheep, swine, rats), highest concentrations found in the liver and fat; very little drug found in muscle or the kidneys. {23}

Apparent Vol D—46.8 liters. {25}

Plasma protein binding

High (approximately 93%). {32}

Half-life:

22 to 28 hours {25} {37}; however, some reports have shown a half-life of 12 to 16 hours for ivermectin and 3 days for its metabolites. {28} {34} {36}

Time to peak concentration:

Approximately 4 hours after a single 12-mg dose. {24} {34} {36}

Peak plasma concentration

46 nanograms per mL after a single 12-mg dose. {24}

Duration of action:

Up to 12 months. {01} {04} {07} {08} {11} {12}

Elimination:
    Ivermectin is metabolized by the liver and is excreted in the feces over an estimated period of 12 days, with less than 1% of the dose excreted in the urine. {34} {36}


Precautions to Consider

Carcinogenicity

Long-term animal studies have not been performed to evaluate the carcinogenic potential of ivermectin. {34}

Mutagenicity

Studies using the in vitro Ames microbial mutagenic assay, the mouse lymphoma cell line L5178Y, and the unscheduled DNA synthesis have not shown ivermectin to be genotoxic. {34}

Pregnancy/Reproduction
Fertility—
Studies conducted in rats using repeated doses of up to 3 times the maximum recommended human dose of 200 micrograms (mcg) per kg of body weight have shown no adverse effects on fertility. {34} Other studies in cattle, sheep, horses, swine, dogs, and rats also have not shown that ivermectin has any adverse effects on fertility. {08}

Pregnancy—
Although adequate and well-controlled studies in humans have not been done, use is not recommended in pregnant women. However, one study of 203 children born to mothers who had been treated with ivermectin during pregnancy (85% during the first trimester and 36% within the first month of pregnancy) found that use of ivermectin was not associated with any significant difference in the rate of miscarriage, stillbirth, or major congenital malformations, and was not associated with any difference in developmental status or disease patterns. {31}

When given to mice, rats, and rabbits in repeated doses of 0.2, 8.1, and 4.5 times the maximum recommended human dose, respectively, ivermectin was found to be teratogenic. Teratogenicity occurred at or near doses that were maternotoxic in these animals. Therefore, ivermectin does not appear to be selectively fetotoxic to the developing fetus in mice, rats, and rabbits. {34}

FDA Pregnancy Category C. {34}

Breast-feeding

Ivermectin is distributed into breast milk. In one study, a maximum level of 23 nanograms per mL was found on the day after treatment and dropped below 0.1 nanogram per mL approximately 1 week later. {27}

Pediatrics

Appropriate studies on the relationship of age to the effects of ivermectin have not been performed in children weighing less than 15 kg. Safety and efficacy have not been established. {34}


Geriatrics


No information is available on the relationship of age to the effects of ivermectin in geriatric patients.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory values

For the treatment of onchocerciasis
Hemoglobin concentration and
White blood cell count    (may be increased {34})


For the treatment of strongyloidiasis
Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum    (may be increased {34})


Hemoglobin concentration and
White blood cell count    (may be decreased {34})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Hypersensitivity to ivermectin
Bronchial asthma    (worsening of bronchial asthma has been reported {34})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For onchocerciasis
» Ophthalmologic examinations    (ophthalmologic examinations, including examinations for visual acuity and slit-lamp examinations to determine the number of microfilariae in the cornea and anterior chamber, are recommended prior to and following treatment with ivermectin; if intraocular microfilariae are noted prior to treatment, slit-lamp examinations should be repeated 3, 6, and 12 months following treatment {02} {03} {07} {08} {09} {14})


» Skin snips    (skin snips from the lateral sides of one or both scapulae, iliac crests, or calves are recommended prior to and following treatment with ivermectin to determine the number of intradermal microfilariae; skin snips are recommended 3, 6, and 12 months following treatment {02} {03} {06} {07} {08} {09} {14})


For strongyloidiasis
» Stool examinations    (at least three stool examinations should be done over the 3 months following treatment; concentration techniques, such as a Baermann test, should be used to perform the examination. This technique can detect very low numbers of Strongyloides larvae in feces and should be used if routine stool examinations are negative and for posttherapy examinations {34} {35})




Side/Adverse Effects

Note: No major CNS toxicity has been reported since ivermectin does not cross the blood-brain barrier in humans. {06} {07} {14}
The microfilaricidal action of ivermectin is less abrupt than that of diethylcarbamazine, and no serious systemic or ocular toxicity has been reported in humans. {01} {02} {03} {04} {07} {08} However, the frequency and severity of side effects were found to be related to the degree of parasite infection. {19} Side effects usually peak around day 2 or 3. {25}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
During treatment of onchocerciasis
    
Ophthalmologic effects, including limbitis{02}{34} , punctate opacity{02}{03}{34} , conjunctivitis{34} , and eyelid edema{34} (eye or eyelid irritation, pain, redness, or swelling){34}

Note: Ophthalmologic side effects do occur as a result of the disease itself but also have been reported after treatment with ivermectin and are rarely severe or associated with loss of vision. These side effects usually resolve without corticosteroid treatment.





Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
During treatment of onchocerciasis
    
Mazzotti-like reaction, especially arthralgia or myalgia{02}{25}{34} (joint or muscle pain), but also fever{01}{02}{03}{25}{34}
lymphadenopathy{02}{03}{25}{34} (painful and tender glands in neck, armpits, or groin), pruritus{02}{03}{06}{25}{34} (itching), or skin rash{02}{03}{25}{34}
    
tachycardia{34} (rapid heartbeat)


Incidence less frequent
During treatment of onchocerciasis
    
Facial edema{34} (swelling of the face)
    
headache{03}{25}{34}
    
peripheral edema{34} (swelling of the arms, feet, hands, or legs)

During treatment of strongyloidiasis
    
Diarrhea{34}
    
dizziness{06}
    
skin rash{02}{03}{25}{34} or itching{02}{03}{06}{25}{34} —due to death of microfilariae in skin


Incidence rare
During treatment of onchocerciasis
    
Postural hypotension{25} (lightheadedness when getting up from a lying or sitting position)

During treatment of strongyloidiasis
    
Anorexia{34} (loss of appetite)
    
somnolence{34} (sleepiness)
    
tremor{34} (shaking or trembling)






Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Note: Accidental ingestion of or exposures to the veterinary formulation of ivermectin (via ingestion, inhalation, injection, or topical exposure) has occurred in humans.

    
Asthenia
    
dizziness
    
edema
    
headache
    
rash
    
seizures


Treatment of overdose
To decrease absorption—Induction of emesis and/or gastric lavage as soon as possible, followed by administration of purgatives and other routine overdose measures. {34}

Supportive care—If indicated, should include parenteral fluids and electrolytes, respiratory support, and pressor agents if clinically significant hypotension is present. {34}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ivermectin (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Use not recommended during pregnancy





Breast-feeding—Ivermectin is distributed into breast milk

Proper use of this medication
Taking as a single dose, with water, on an empty stomach (1 hour before breakfast)

» Compliance with therapy; for onchocerciasis, dose may be repeated every 3 to 12 months

Systemic corticosteroids taken concurrently may be indicated in patients with advanced disease and high microfilariae counts in the eye in order to reduce inflammatory reactions due to death of O. volvulus microfilariae

» Proper dosing

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress, as well as ophthalmologic and/or stool examinations

Checking with physician if symptoms worsen

» Caution if lightheadedness occurs

Caution if any laboratory test required; ivermectin may cause an increase in alanine aminotransferase (ALT [SGPT]) and aspartate aminotransferase (AST [SGOT]) serum values, may cause a decrease in white blood cells, or may cause anemia



Side/adverse effects
During treatment of onchocerciasis—signs of potential side effects, especially ophthalmologic effects including limbitis, punctate opacity, conjuctivitis, and eyelid edema


General Dosing Information
Ivermectin should be administered as a single dose with a full glass (240 mL) of water on an empty stomach (1 hour before breakfast). {08} {09} {34}

Single doses as low as 50 mcg per kg of body weight have shown significant microfilaricidal activity. {04} {06} {07} {12} In addition, a single oral dose (approximately 150 mcg per kg of body weight) usually reduces the dermal microfilarial count to very low levels and maintains them for up to 12 months. {01} {07}

Systemic corticosteroids, although rarely required, may be helpful when administered concurrently to suppress the inflammatory response to the death of microfilariae caused by ivermectin in patients with advanced disease and high microfilariae counts in the eye. {01} {03} {08} {14}

For onchocerciasis—
Ivermectin does not kill the adult Onchocerca parasite; treatment may need to be repeated for killing the new batch of larvae. {34}

For strongyloidiasis—
Examination of stool should be repeated at least two times, 3 to 4 weeks post-therapy, to document the clearance of the strongyloidiasis infection. {34}

For treatment of adverse effects
Recommended treatment consists of the following: {01} {03} {08} {09}

   • Systemic corticosteroids for severe allergic reactions.
   • Antihistamines.
   • Analgesics.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

IVERMECTIN TABLETS

Usual adult and adolescent dose
Onchocerciasis
Oral, 150 mcg per kg of body weight as a single dose; may be repeated every three to twelve months, depending on the recurrence of symptoms and/or microfilariae. {01} {02} {03} {04} {05} {06} {07} {08} {09} {10} {11} {12} {14} {34}.

Strongyloidiasis
Oral, 200 mcg per kg of body weight as a single dose. {34} In general, additional doses are not necessary. Follow-up stool examination should be performed to verify clearance of the infection.

[Bancroftian filariasis]1
Oral, 20 to 200 mcg per kg of body weight as a single dose have been used. {29}

[Scabies]1
Oral, 150 mcg per kg of body weight as a single dose for one treatment. {38}

[Scabies, immunocompromised]1
Oral, 150 mcg per kg of body weight as a single dose. Treatment may be repeated two weeks after the first treatment. {38}


Usual pediatric dose
Onchocerciasis
Infants and children weighing less than 15 kg: Safety and efficacy have not been established.

Children weighing 15 kg or more: See Usual adult and adolescent dose. {13} {14}

Strongyloidiasis
Infants and children weighing less than 15 kg: Safety and efficacy have not been established.

Children weighing 15 kg or more: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


6 mg (Rx) [Stromectol (butylated hydroxyanisole) (citric acid powder, anydrous) (magnesium stearate) (microcrystalline cellulose) ( pregelatinized starch)]{34}

Canada—


6mg (Rx) [Mectizan]

Africa—


6 mg (Rx) [Mectizan]

Europe—


6mg (Rx) [Mectizan]

South America—


6mg (Rx) [Mectizan]

Packaging and storage:
Store below 30 °C (86 °F). {34}

Auxiliary labeling:
   • Take with a full glass of water. {34}
   • Take 1 hour before breakfast.
   • May cause lightheadedness.



Revised: 5/20/1999



References
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