Milbemycin Oxime
(mil-beh-my-sin) Interceptor®
Macrolide Antiparasitic
For information on the combination products with lufenuron,
see Lufenuron. For information on the combination product
with spinosad, see Spinosad. For information on the combina-
tion product with praziquantel, see Praziquantel/Praziquantel
Combination Products
Prescriber Highlights
▶ Used as a heartworm preventive and for the removal and/or
control of hookworms, roundworms, and whipworms in dogs
and puppies
▶ Available in combination with other anthelmintics or insecti-
cides
▶ Prevents heartworm disease and removes adult roundworms
and hookworms in cats and kittens
▶ No absolute contraindications
▶ Animals with a high number of circulating microfilariae may
develop a transient shock-like syndrome.
▶ Adverse effects appear unlikely at labeled dosages; at higher
doses, neurologic signs become more likely.
Uses/Indications
Milbemycin tablets for dogs and puppies are labeled as a monthly
heartworm preventive (Dirofilaria immitis), for hookworm control
(Ancylostoma caninum), and for control and removal of adult round-
worms (Toxocara canis, Toxascaris leonina) and whipworms (Trich-
uris vulpis).1 It can also be used extra-label for treatment of infes-
tations of Demodex canis, Demodex injai, and Sarcoptes scabiei var.
canis. In a systematic review of published clinical trials, the optimal
determined treatments for demodicosis were daily oral milbemycin
and weekly2,3 or monthly4–6 topical moxidectin (± imidacloprid);
Milbemycin Oxime 885
however, isoxazolines (eg, fluralaner, sarolaner) are as effective as the
moxidectin/imidacloprid combination and have supplanted macro-
lide antiparasitics for the treatment of demodicosis.3–5
In cats, milbemycin tablets are labeled as a monthly heartworm
preventive (D. immitis) and for removal of adult hookworms (Ancy-
lostoma tubaeforme) and roundworms (Toxocara cati).
Pharmacology/Actions
The primary mode of action of milbemycins is binding to gluta-
mate-gated chloride ion channels in the nervous system of nema-
todes and arthropods. Cell membrane permeability to chloride ions
is increased, inhibiting the electrical activity of nerve cells in nema-
todes and muscle cells in arthropods and causing paralysis and death
of the parasites.
Milbemycins also enhance the release of Gamma-aminobutyric
acid (GABA) at presynaptic neurons. GABA acts as an inhibitory
neurotransmitter and blocks postsynaptic stimulation of the adja-
cent neuron in nematodes or the muscle fiber in arthropods.
Milbemycins are generally not toxic to mammals, as mammals do
not have glutamate-gated chloride channels and because these com-
pounds do not readily cross the blood–brain barrier and therefore
cannot reach the mammalian GABA receptors.
Pharmacokinetics
No specific information was located. At labeled doses, milbemycin is
considered effective for at least 45 days after infection by D immitis
larvae.
Contraindications/Precautions/Warnings
Manufacturers do not list any absolute contraindications to milbemy-
cin use. Because some dogs with a high number of circulating micro-
filariae will develop a transient, shock-like syndrome after receiving
milbemycin, the manufacturer recommends testing for pre-existing
heartworm infections and treating infected dogs to remove adult
heartworms and microfilariae prior to initiating milbemycin.
If using milbemycin at doses greater than labeled in breeds sus-
ceptible to the MDR1 gene mutation (also known as ABCB1-1delta),
genetic testing is recommended before initiating milbemycin.
The manufacturer states to only use the product (Interceptor®) in
dogs 4 weeks of age or older and weighing at least 0.9 kg (2 lb) and
in cats and kittens 6 weeks of age and older and weighing at least
0.7 kg (1.5 lb). Age and weight restrictions vary slightly for combina-
tion products labelled for use in dogs and puppies; consult specific
product labels for further information.
Adverse Effects
At label dosages, adverse effects appear to be infrequent in microfi-
laria-free dogs, including breeds susceptible to neurologic toxicity
(see Overdose/Acute Toxicity). Lethargy, vomiting, ataxia, anorexia,
diarrhea, convulsions, and weakness have been reported in dogs.
In a study of dog breeds susceptible to the MDR1 mutation,
milbemycin was given at dosages of 1 – 2.2 mg/kg PO daily for the
treatment of demodicosis. All MDR1 mutant/mutant dogs exhibit-
ed signs of CNS toxicity, whereas no MDR1 wild-type/wild-type or
MDR1 mutant/wild-type dogs exhibited signs of toxicity.7
Reproductive/Nursing Safety
Studies in pregnant dogs at daily doses 3 times those labeled showed
no adverse effects to offspring or bitch.1 In cats, safety in breeding,
pregnant, and lactating queens and breeding toms has not been es-
tablished.
Milbemycin enters maternal milk. At labeled doses, no adverse
effects have been noted in nursing puppies.
Because safety has not been established in animals, this drug
should only be used when the maternal benefits outweigh the poten-
tial risks to offspring.
886 Milbemycin Oxime
Overdose/Acute Toxicity
Eight-week-old puppies receiving 2.5 mg/kg (5 times the label dose)
for 3 consecutive days showed no clinical signs after the first day, but
after the second or third consecutive dose, showed some ataxia and
trembling.
Beagles have tolerated a single oral dose of 200 mg/kg (400
times the label dose). Rough-coated collies have tolerated doses of
10 mg/kg (20 times the label dose) without adversity (label informa-
tion; Interceptor®). Avermectin-sensitive collies tolerated 10 mg/kg
milbemycin when combined with 300 mg/kg spinosad.8 Toxic dos-
es can cause mydriasis, ptyalism, lethargy, ataxia, pyrexia, seizures,
coma, and death. Intravenous lipid emulsion (ILE) has been recom-
mended for management of macrocyclic lactone toxicity,9 and ILE
was used to manage milbemycin toxicity in one dog10 and one cat.11
Supportive therapy is recommended.
Safety studies were conducted in young cats and kittens and doses
of 1, 3, and 5 times the minimum recommended dose of 2 mg/kg
demonstrated no drug-related effects. Tolerability studies at 10 times
the label dose also demonstrated no drug-related adverse effects in
kittens and young adult cats.
For patients that have experienced or are suspected to have expe-
rienced an overdose, consultation with a 24-hour poison consulta-
tion center specializing in providing veterinary-specific information
is recommended. For general information related to overdose and
toxin exposures, as well as contact information for poison control
centers, refer to Appendix.
Drug Interactions
The manufacturer states that milbemycin was used safely during
testing in dogs and cats receiving other frequently used veterinary
products, including vaccines, anthelmintics, antibiotics, steroids, flea
collars, shampoos, and dips. The following drug interactions have
either been reported or are theoretical in humans or animals receiv-
ing GABA agonists and may be of significance in veterinary patients.
Unless otherwise noted, use together is not necessarily contraindi-
cated, but weigh the potential risks and perform additional monitor-
ing when appropriate.
■ Benzodiazepines: Effects may be potentiated by milbemycin;
use together not advised in humans
Caution is advised if using milbemycin with other drugs that can
inhibit p-glycoprotein, particularly in those dogs at risk for MDR1
genetic mutation (collies, Australian shepherds, shelties, long-haired
whippet, “white feet” breeds), unless tested normal. Drugs and drug
classes involved include:
■ Amiodarone
■ Carvedilol
■ Clarithromycin
■ Cyclosporine
■ Diltiazem
■ Erythromycin
■ Itraconazole
■ Ketoconazole
■ Quinidine
■ Spironolactone
■ Verapamil
Laboratory Considerations
None noted
Dosages
DOGS:
Parasiticide for labeled indications using milbemycin as a
single agent (label dosages; FDA-approved): Appropriate dose
is based on body weight and given orally, once a month, at the
recommended minimum dosage of 0.5 mg/kg (0.23 mg/lb body
weight).
Recommended Dosage Schedule for Dogs
Body weight INTERCEPTOR® Flavor Tabs
0.9-4.5 kg (2-10 lb) One tablet (2.3 mg)
5-11.3 kg (11-25 lb) One tablet (5.75 mg)
11.8-22.7 kg (26-50 lb) One tablet (11.5 mg)
23.2-45.5kg (51-100 lb) One tablet (23.0 mg)
Dogs over 45.5 kg (100 lb) are provided the appropriate combina-
tion of tablets (Label information; Interceptor®)
Treatment of canine demodicosis (extra-label):
a) 0.5 – 1.6 mg/kg/day (mean dose 0.75 mg/kg/d) PO for 1 to 6
months and/or until skin scrape is negative. Cure more likely
with juvenile-onset patients12
b) 1 – 2 mg/kg/day PO13,14
Treatment of canine sarcoptic mange (extra-label):
a) 0.75 mg/kg/day PO for 30 days15
b) 2 mg/kg PO once weekly for 3 treatments16
Prevention of Angiostrongylus vasorum infection (extra-label):
milbemycin oxime/spinosad combination tablet at 0.75 – 1 mg/kg
and 45 – 60 mg/kg PO, respectively. From a laboratory study,
monthly doses would be expected to be effective.17
CATS:
Parasiticide for labeled indications using milbemycin as a sin-
gle agent (label dosages; FDA-approved): Appropriate dose is
based on body weight and given orally, once a month, at the rec-
ommended minimum dosage of 2 mg/kg (0.9 mg/lb body weight).
Recommended Dosage Schedule for Cats
Body weight INTERCEPTOR® Flavor Tabs
0.7-2.7 kg (1.5-6 lb) One tablet (5.75 mg)
2.8-5.5 kg (6.1-12 lb) One tablet (11.5 mg)
5.4-11.4 kg (12.1-25 lb) One tablet (23.0 mg)
Cats over 11.4 kg (25 lb) are provided the appropriate combina-
tion of tablets. (Label information; Interceptor®)
Treatment of Lungworm infections (extra-label): milbemycin
2 mg/kg with praziquantel 5 mg/kg PO every 15 days for 3 doses18
Monitoring
■ Efficacy based on clinical signs and diagnostic testing (eg, fecal
flotation, heartworm antigen testing, external parasite elimina-
tion)
■ For demodicosis, clinical signs and monthly skin scraping; con-
tinue treatment for 4 weeks beyond 2 negative monthly skin
scrapings.14
■ Adverse effects
Client Information
■ Used monthly in dogs to control heartworm and hookworms and
to control and remove roundworms and whipworms.
■ Used monthly in cats to control heartworm and to control and
remove hookworms.
■ Appears very safe when used at recommended dosages for preven-
tion of heartworm, even in dogs with the MDR1 genetic mutation.
■ Store flavored tablets out of reach of children and animals. This
medicine may be toxic to wildlife so dispose of unused tablets re-
sponsibly.
■ When using milbemycin for heartworm prevention it is important
to administer each monthly dose on schedule, as a late or missed
dose may allow a heartworm infection to become established. Be
certain that your pet fully consumes each dose.
■ It is recommended to administer heartworm preventives year-
round. If being administered seasonally, the first dose should be
given within one month of the first mosquito exposure and con-
tinued monthly thereafter until the end of the mosquito season.
Chemistry/Synonyms
Milbemycin oxime consists of ≈80% of the A4 derivatives and 20%
of the A3 derivatives of 5-didehydromilbemycin. Milbemycin is con-
sidered to be a macrolide antibiotic structurally. Milbemycin oxime
occurs as a white to yellow powder.
Milbemycin may also be known as CGA-179246, Interceptor®,
Milbeguard®, and Milbehart®.
Storage/Stability
Store milbemycin oxime tablets at room temperature between 15°C
and 25°C (59°F-77°F).
Compatibility/Compounding Considerations
An analysis of aqueous milbemycin suspensions compounded by
two national compounding pharmacies found that potency varied
from 67.5% to 135% of labeled strength, and that potency decreased
by ≈20% over the 3-week study period.19
Dosage Forms/Regulatory Status
VETERINARY-LABELED PRODUCTS:
Milbemycin Oxime Oral Tablets for dogs: 0.9 to 4.5 kg (2 to 10 lb):
2.3 mg; 5 to 11.4 kg (11 to 25 lb): 5.75 mg; 11.8 to 22.7 kg (26 to 50
lb): 11.5 mg; 23.2 to 45.5 kg (51 to 100 lb): 23 mg; dogs more than
45.5 kg (100 lb) are provided the appropriate combination of tablets;
Interceptor® Flavor Tabs, generic (Rx). FDA-approved for use in dogs
and puppies older than 4 weeks of age and at least 0.9 kg (2 lb).
Milbemycin Oxime Oral Tablets for cats: 0.7 to 2.7 kg (1.5 to 6 lb):
5.75 mg; 2.8 to 5.5 kg (6.1 to 12 lb): 11.5 mg; 5.5 to 11.4 kg (12.1 to 25
lb): 23 mg; Interceptor® Flavor Tabs, generic; (Rx). FDA-approved for
cats and kittens older than 6 weeks of age and at least 0.7 kg (1.5 lb).
Milbemycin/Lufenuron Oral Tablets for dogs: 0.9 to 4.5 kg (2 to 10
lb): 2.3 mg/46 mg; 5 to 11.4 kg (11 to 25 lb): 5.75 mg/115 mg; 11.8 to
22.7 kg (26 to 50 lb): 11.5 mg/230 mg; 23.2 to 45.5 kg (51 to 100 lb):
23 mg/460 mg milbemycin/lufenuron; Sentinel® Flavor Tabs; (Rx).
FDA-approved for use in dogs and puppies older than 4 weeks of age
and at least 0.9 kg (2 lb). Also available with nitenpyram (Capstar®).
Milbemycin/Praziquantel Chewable Oral Tablets for dogs: 0.9 to
3.6 kg (2 to 8 lb): 2.3 mg/22.8 mg; 3.7 to 11.4 kg (8.1 to 25 lb):
5.75 mg/57 mg; 11.4 to 22.7 kg (25.1 to 50 lb): 11.5 mg/114 mg; 22.7
to 45.5 kg (50.1 to 100 lb): 23 mg/228 mg; Interceptor® Plus (Rx).
FDA-approved for use in dogs and puppies 6 weeks of age or older
and at least 0.9 kg (2 lb).
Milbemycin/Lufenuron/Praziquantel Chewable Oral Tablets for
dogs: 0.9 to 3.6 kg (2 to 8 lb): 2.3 mg/46 mg/22.8 mg; 3.7 to 11.4 kg
(8.1 to 25 lb): 5.75 mg/115 mg/57 mg; 11.4 to 22.7 kg (25.1 to 50
lb): 11.5 mg/230 mg/114 mg; 22.7 to 45.5 kg (50.1 to 100 lb):
23 mg/460 mg/228 mg; Sentinel® Spectrum®; (Rx). FDA-approved for
use in dogs and puppies older than 6 weeks of age and at least 0.9 kg
(2 lb).
Milbemycin/Spinosad Chewable Oral Tablets for dogs: 2.3 to
4.5 kg (5 to 10 lb): 2.3 mg/140 mg; 4.5 to 9.1 kg (10.1 to 20 lb):
4.5 mg/270 mg; 9.1 to 18.2 kg (20.1 to 40 lb): 9.3 mg/560 mg; 18.2 to
27.3 kg (40.1 to 60 lb): 13.5 mg/810 mg; 27.3 to 54.5 kg (60.1 to 120 lb):
27 mg/1620 mg; Trifexis®, Comboguard®; (Rx). FDA-approved for use
in dogs and puppies 8 weeks of age or older and at least 2.2 kg (5 lb).
Milbemycin 0.1% otic solution (Milbemite®) available for treatment
of ear mite (Otodectes cynotis) infestations in cats and kittens 4 weeks
of age and older.
HUMAN-LABELED PRODUCTS: NONE
References
For the complete list of references, see wiley.com/go/budde/plumb
