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Credelio PLUS (900 mg/33.75 mg) (Canada)

This treatment applies to the following species:
Company: Elanco

(lotilaner and milbemycin oxime chewable tablets)



CREDELIO PLUS (lotilaner and milbemycin oxime) is an oral, once-a-month, flavoured chewable tablet for dogs and puppies. CREDELIO PLUS is a white to beige round biconvex chewable tablet with brownish spots, beveled edges, and the letter “I” debossed on one side of the tablet.

Therapeutic Classification

Lotilaner is a member of the isoxazoline family. Lotilaner has the chemical composition of 5 - [(5S) - 4,5 - dihydro - 5 - (3,4,5 - trichlorophenyl) - 5 - (trifluoromethyl) - 3 - isoxazolyl] - 3 - methyl - N - [2 - oxo - 2 - [(2,2,2 - trifluoroethyl)amino]ethyl] - 2-thiophenecarboxamide.

Milbemycin oxime is a macrocyclic lactone containing two major factors, A3 and A4.

Credelio PLUS (900 mg/33.75 mg) Indications

CREDELIO PLUS is for use in dogs and puppies and is indicated:

1. For the treatment and control of adult ticks [Amblyomma americanum (Lone Star tick), Dermacentor variabilis (American dog tick), Ixodes scapularis (black-legged or deer tick) and Rhipicephalus sanguineus (brown dog tick)] infestations.

2. For the treatment and prevention of flea (Ctenocephalides felis) infestations and as part of a treatment strategy for the control of flea allergy dermatitis (FAD).

3. For the treatment and control of roundworms (adult and larval L4 and L5 Toxocara canis).

4. For the prevention of heartworm disease (Dirofilaria immitis). See CAUTIONS.

CREDELIO PLUS is intended for use where treatment and/or prevention of two or more of the indications above is required concurrently.

Credelio PLUS (900 mg/33.75 mg) Dosage And Administration

CREDELIO PLUS chewable tablets are given orally once a month, at the minimum dosage of 20 - 41 mg lotilaner/kg body weight and 0.75 - 1.53 mg milbemycin oxime/kg body weight.

Use the table to find the right dose for the dog’s weight.

Dosage Schedule

Body Weight Ranges

Lotilaner Content per Tablet

Milbemycin Oxime Content per Tablet (mg)

Tablets to be Administered

1.4 to 2.8




>2.8 to 5.5




>5.5 to 11.0




>11.0 to 22.0




>22.0 to 45.0





Administer the appropriate combination of tablets

Administer CREDELIO PLUS with food or immediately after feeding.

Flea Treatment And Prevention

Treatment with CREDELIO PLUS may begin at any time of the year, preferably starting one month before fleas become active and continuing monthly through the end of flea season.

To minimize the likelihood of flea reinfestation, it is important to treat all animals within a household with an approved flea protection product.

Tick Treatment And Control

Treatment with CREDELIO PLUS may begin at any time of the year.

Heartworm Prevention

For the prevention of heartworm disease, CREDELIO PLUS must be given at regular monthly intervals during the time of the year when mosquitoes, ticks and/or fleas are present. CREDELIO PLUS should be administered at monthly intervals beginning within 1 month of the dog’s first seasonal exposure to mosquitoes and continuing until 2 months after the dog’s last seasonal exposure, based on the local epidemiological situation.

Dogs travelling to a heartworm region should start medication within a month after arrival there.

Heartworm prevention treatment should be continued monthly, with the last administration being given 2 months after the dog has left the region.

Nematode Treatment And Control

CREDELIO PLUS can be used as part of the seasonal treatment of ticks and/or fleas in dogs with diagnosed, or at risk from, concurrent gastrointestinal nematode infections. A single treatment is effective for the treatment of the indicated gastrointestinal roundworm stages.


Do not give to puppies younger than 8 weeks of age or to dogs weighing less than 1.4 kg.

Credelio PLUS (900 mg/33.75 mg) Cautions

The safe use of CREDELIO PLUS in breeding, pregnant or lactating dogs has not been evaluated.

CREDELIO PLUS is not 100% effective for the prevention of all strains of heartworm (see EFFICACY.

All dogs > 6 months of age should be tested for existing heartworm infection prior to starting treatment for the first time. Annual testing of all dogs for heartworm should be done.

Lotilaner is a member of the isoxazoline class. This class has been associated with neurological adverse reactions including tremors, ataxia, and seizures. Seizures have been reported in dogs receiving isoxazoline class drugs, even in dogs without a history of seizures. Use with caution in dogs with a history of seizures or neurological disorders.

Lotilaner and milbemycin oxime have been shown to be a substrate for P-glycoprotein (P-gp) and therefore could interact with other P-gp substrates (for example, digoxin, doxorubicin) or other macrocyclic lactones. Therefore, concomitant treatment with other P-gp substrates could lead to enhanced toxicity.

Some Collies and other p-glycoprotein-deficient dogs with MDR or ABCB1-1 delta gene mutation are known to be more sensitive to the macrocyclic lactone class of medications. Such dogs may be susceptible to macrocyclic lactone toxicity with over-dosing or when used in combination with other P-gp drugs. Signs of depression, hypersalivation, tremor and ataxia have been associated with macrocyclic lactone toxicity.

Fleas and ticks need to start feeding on the dog to become exposed to lotilaner; therefore the risk of transmission of vector-borne diseases cannot be excluded.

Parasite resistance to any particular class of parasiticides may develop following the frequent, repeated use of a product of that class. Therefore, the use of this product should be based on the assessment of each individual case and on local epidemiological information about the current susceptibility of the target species in order to limit the possibility of a future selection for resistance.


Wash hands after handling the product. In case of accidental ingestion, contact a physician immediately. Keep out of reach of children.

Adverse Reactions

In clinical studies, no serious adverse reactions were reported and adverse reactions such as gastrointestinal signs (diarrhea, vomiting and colitis), anorexia, lethargy, hepatopathy, pruritus and changes in behaviour were uncommonly (more than 1 but less than 10 animals in 1,000 animals treated) reported. These occurrences were generally self-limiting and of short duration.

In a multi-centred field effectiveness and safety conducted in the USA, 159 client owned dogs received CREDELIO PLUS and 158 client owned dogs received a positive control article. The treatments were administered once monthly for up to 11 months. The table below is a Summary of the Adverse Events occurring at 1% or greater (animal rate) in the safety population.

Adverse Event



Positive Control Article



8.81% (14)

6.96% (11)


8.18% (13)

9.49% (15)


5.03% (8)

6.96% (11)


3.14% (5)

2.53% (4)

Uncoded Sign*

2.52% (4)

5.06% (8)

Hemorrhagic Diarrhea

1.89% (3)

1.27% (2)


1.89% (3)

0.63% (1)


1.26% (2)

3.16% (5)


1.26% (2)

1.90% (3)


1.26% (2)

0.63% (1)

Digestive Tract Hemorrhage not otherwise specified

1.26% (2)

0% (0)


1.26% (2)

0% (0)


0% (0)

1.27% (2)

*Dogs that had parasitic infections/infestations indicated for treatment and control by the drug the dog received.

To report suspected adverse drug events or for technical assistance, contact Elanco Canada Limited at 1-800-265-5475.




Lotilaner is an insecticide and acaricide of the isoxazoline family. It is a pure enantiomer that is active against adult ticks and fleas.

Lotilaner is a potent inhibitor of gamma-aminobutyric acid (GABA)-gated chloride channels and to a lesser extent of glutamate-gated chloride ion channels of insects and ticks, resulting in rapid death of ticks and fleas.

Milbemycin Oxime

Milbemycin oxime is a systemically active macrocyclic lactone isolated from the fermentation of Streptomyces hygroscopicus var. aureolacrimosus. It contains two major factors, A3 and A4 (ratio of A3:A4 is 20:80). Milbemycin oxime is an antiparasitic endectocide with activity against larval (L4/L5) and adult stages of nematodes, as well as larvae (L3/L4) of Dirofilaria immitis.

The activity of milbemycin oxime is related to its action on invertebrate neurotransmission. Milbemycin oxime, like avermectins and other milbemycins, increases nematode and insect membrane permeability to chloride ions via glutamate-gated chloride ion channels. This leads to hyperpolarisation of the neuromuscular membrane and flaccid paralysis and death of the parasite.



Lotilaner is readily absorbed following oral administration and peak plasma concentration is reached within 3-5 hours. Milbemycin A3 5-oxime and milbemycin A4 5-oxime are also rapidly absorbed following oral administration with a Tmax of approximately 2 - 4 hours for each drug substance. Food enhances the absorption of both lotilaner and milbemycin oxime. The bioavailability of lotilaner is 75% and that of milbemycin (A3 and A4 5-oximes) is approximately 60%.


Lotilaner and milbemycin A3 and A4 5-oximes are extensively distributed in dogs where volume of distribution after intravenous administration is 3 - 4 L/kg. Plasma protein binding is high for both lotilaner and milbemycin oxime (>95%).

Metabolism and Excretion

Lotilaner is metabolized to a small extent into more hydrophilic compounds which are observed in faeces and urine.

The major route of elimination for lotilaner is biliary excretion, with renal excretion being the minor route of elimination (less than 10% of the dose). Pharmacokinetics change as young puppies grow to adult dogs. The terminal half-life is approximately 10 days in puppies at 2 months of age. The terminal half-life is approximately 24 days in the adult dog. The long terminal half-life in the adult dog provides effective blood concentrations for the entire duration of the inter-dosing interval. With repeated monthly doses, accumulation is observed with steady state being reached after the fourth monthly dose.

The primary fecal and urinary metabolites of milbemycin oxime in dog were identified as glucuronide conjugates of milbemycin A3 and A4 5-oximes, dealkylated milbemycin A3 or A4 5-oximes, and hydroxylated milbemycin A4 5-oxime. Hydroxymilbemycin A4 5-oxime was detected only in plasma, but not in urine or feces, suggesting predominant excretion of conjugated metabolites in the dog.

Milbemycin A4 5-oxime eliminates more slowly than milbemycin A3 5-oxime (clearance after intravenous administration was 47.0 and 106.8 mL/h/kg, respectively) resulting in exposure (AUC) to milbemycin A4 that is higher than to milbemycin A3 5-oxime. The mean elimination half-lives were 27 hours for A3 and 57 hours for A4 in the adult dog. The clearance of milbemycin oxime was higher and the terminal half-lives were shorter for milbemycin oxime in puppies. Excretion of milbemycin A3 and A4 5-oxime is primarily via faeces, and also to a lesser extent in the urine.


In a margin of safety study, CREDELIO PLUS was administered orally to 24, 8-week old Beagle puppies at average doses of 1, 3 and 5 times the recommended dose at 28-day intervals over a 9-month period. In a separate margin of safety study, CREDELIO PLUS was administered orally to 24, 11-month old Beagle puppies at average doses of 1, 3 and 5 times the recommended dose at 28-day intervals over a 7-month period.

In both studies, the dose multiples were achieved by administering the 1x dose for 1, 3 or 5 consecutive days during each dose cycle. There were also 8 control dogs that were not treated in both studies. CREDELIO PLUS was not associated with any clinically significant changes in daily observations, body weights, food consumption data, ophthalmoscopic, physical and neurological examinations, and hematology, clinical chemistry, coagulation or urinalysis parameters. Treatment with CREDELIO PLUS was not associated with any other clinically significant adverse clinical observations, gross pathology or histopathological changes.

In a third study, CREDELIO PLUS was administered orally to 36, 12-month old Beagle dogs at average doses of 1, 3 and 6 times the maximum recommended dose on a single occasion. There were also 12 control dogs that were not treated. CREDELIO PLUS was not associated with any clinically significant changes in daily observations, food consumption data, physical and neurological examinations, or adverse clinical observations.


Fleas: In a laboratory study, CREDELIO PLUS killed 100% of fleas within 24 hours through Day 30.

Ticks: In one well-controlled laboratory study, CREDELIO PLUS was effective against Rhipicephalus sanguineus (brown dog tick) with ≥99% effectiveness 48 hours post-infestation for 30 days.

Intestinal Nematode: In two additional laboratory studies, CREDELIO PLUS was ≥96.8% effective against immature (fourth stage larvae and immature adult) Toxocara canis (roundworm).

Heartworm: In well-controlled laboratory study, a single dose of CREDELIO PLUS was 100% effective against induced heartworm infections using a heartworm isolate obtained from Georgia (Georgia II isolate). In two laboratory studies using the Wildcat isolate efficacy ranged from 79.6-88.4% when CREDELIO PLUS was administered monthly for up to 6 months.

In another well-controlled laboratory study, CREDELIO PLUS was 100% effective against induced heartworm infections when administered for 2 consecutive monthly doses. This study was conducted using a heartworm isolate obtained from South Carolina (Berkeley isolate).

In a positive-controlled 11-month US field study in client owned dogs, no dogs treated with CREDELIO PLUS were positive for heartworm infection as determined by heartworm antigen testing and microfilaria testing. CREDELIO PLUS was used concurrently with other medications, such as vaccines, anthelmintics, antibiotics, steroids, NSAIDs, anesthetics, and antihistamines. No adverse reactions were attributed to the concomitant use of CREDELIO PLUS with other medications.


In the same U.S. field study with client owned dogs, 806 doses of CREDELIO PLUS were given to 159 dogs with 100% administration success by dog owners. There were no reports of unsuccessful dosing. Eighty-one percent of the doses were accepted when offered either free choice or with food; 18.2% of doses were administered by placing the tablet in the back of the dog’s mouth.

Storage Conditions

Store between 5°C and 30°C. Protect from light.


The product is available in five sizes: 56.25/2.11, 112.5/4.22, 225/8.44, 450/16.88, or 900/33.75 mg lotilaner/milbemycin oxime per tablet. Each chewable tablet size is available in colour-coded packages of 1, 3, 6 or 18 flavoured chewable tablets. Not all package sizes may be marketed.

DIN 02525674 (56.25/2.11 mg), 02525682 (112.5/4.22 mg), 02525690 (225/8.44 mg), 02525704 (450/16.88 mg), 02525712 (900/33.75 mg)


Elanco Canada Limited, 1919 Minnesota Court, Suite 401, Mississauga, Ontario L5N 0C9

DATE: March 2022

Credelio, Elanco and the diagonal bar logo are trademarks of Elanco or its affiliates.

©2022 Elanco or its affiliates.


CPN: 1231237.0

Customer Service:   800-265-5475
Fax:   519-821-7831
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