lotilaner

Credelio Quattro™ is indicated for the prevention of heartworm disease caused by Dirofilaria immitis and for the treatment and control of roundworm (immature adult and adult Toxocara canis and adult Toxascaris leonina), hookworm (fourth stage larvae, immature adult, and adult Ancylostoma caninum and adult Uncinaria stenocephala), and tapeworm (Dipylidium caninum, Taenia pisiformis, and Echinococcus granulosus) infections. Credelio Quattro™ kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) and the treatment and control of tick infestations [Amblyomma Americanum (lone star tick), Dermacentor variabilis (American dog tick), Ixodes scapularis (black-legged tick), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (longhorned tick)] for one month in dogs and puppies 8 weeks of age and older, and weighing 3.3 pounds or greater. Credelio Quattro™ is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.

Credelio Quattro™

Credelio™ kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) and the treatment and control of tick infestations [Amblyomma americanum (lone star tick), Dermacentor variabilis (American dog tick), Ixodes scapularis (black-legged tick), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (longhorned tick)] for one month in dogs and puppies 8 weeks of age and older, and weighing 4.4 pounds or greater. Credelio™ is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.

Credelio™

For the treatment of infestations caused by New World screwworm (Cochliomyia hominivorax) larvae (myiasis) in dogs and puppies 8 weeks of age and older, and weighing 3.3 pounds or greater.

Credelio Quattro™-CA1

Kills adult fleas, and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) for one month in cats and kittens 8 weeks of age and older and weighing 2.0 pounds or greater. It also indicated for the treatment and control of Ixodes scapularis (black-legged tick) infestations for one month in cats and kittens 6 months of age and older, and weighing 2.0 pounds or greater.

Credelio™ CAT

Credelio Quattro is indicated for the prevention of heartworm disease caused by Dirofilaria immitis and for the treatment and control of roundworm (immature adult and adult Toxocara canis and adult Toxascaris leonina), hookworm (fourth stage larvae, immature adult, and adult Ancylostoma caninum and adult Uncinaria stenocephala), and tapeworm (Dipylidium caninum, Taenia pisiformis, and Echinococcus granulosus) infections. Credelio Quattro kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) and the treatment and control of tick infestations [Amblyomma americanum (lone star tick), Dermacentor variabilis (American dog tick), Ixodes scapularis (black-legged tick), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (longhorned tick)] for one month in dogs and puppies 8 weeks of age and older, and weighing 3.3 pounds or greater. Credelio Quattro is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks. Credelio Quattro-CA1 is indicated for the treatment of infestations caused by New World screwworm (Cochliomyia hominivorax) larvae (myiasis) in dogs and puppies 8 weeks of age and older, and weighing 3.3 pounds or greater.

Credelio Quattro™ CredelioQuattro™-CA1(lotilaner, moxidectin, praziquantel, and pyrantel chewable tablets)

CREDELIO kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) and the treatment and control of tick infestations [Amblyomma americanum (lone star tick), Dermacentor variabilis (American dog tick), Ixodes scapularis (black-legged tick), Rhipicephalus sanguineus (brown dog tick), and Haemaphysalis longicornis (longhorned tick)] for one month in dogs and puppies 8 weeks of age and older, and weighing 4.4 pounds or greater. CREDELIO is indicated for the prevention of Borrelia burgdorferi infections as a direct result of killing Ixodes scapularis vector ticks.

Credelio™ (lotilaner)

CREDELIO CAT kills adult fleas and is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) for one month in cats and kittens 8 weeks of age and older, and weighing 2.0 pounds or greater. CREDELIO CAT is also indicated for the treatment and control of Ixodes scapularis (black-legged tick) infestations for one month in cats and kittens 6 months of age and older, and weighing 2.0 pounds or greater.

Credelio™ CAT (lotilaner)

Mechanism of Action Credelio Quattro contains four active pharmaceutical ingredients, lotilaner, moxidectin, praziquantel, and pyrantel (as pamoate salt). Lotilaner is an ectoparasiticide belonging to the isoxazoline group. Lotilaner inhibits insect and acarine gamma-aminobutyric acid (GABA)-gated chloride channels. This inhibition blocks the transfer of chloride ions across cell membranes, which results in uncontrolled neuromuscular activity leading to death of insects and acarines. The selective toxicity of lotilaner between insects and acarines and mammals may be inferred by the differential sensitivity of the insects and acarines’ GABA receptors versus mammalian GABA receptors. Moxidectin is an endectocide in the macrocyclic lactone class. Moxidectin acts by interfering with the chloride channel-mediated neurotransmission in the parasite. This results in paralysis and death of the parasite. Praziquantel’s mode of action is not precisely known, but treated tapeworms undergo muscular paralysis accompanied by a rapid influx of calcium ions and the disruption of the tegument. Pyrantel is a nematocide belonging to the tetrahydropyrimidine class. Pyrantel acts as a depolarizing, neuromuscular-blocking agent in susceptible parasites, causing paralysis and death or expulsion of the parasite. Pharmacokinetics Due to reduced drug bioavailability of lotilaner in the fasted state, Credelio Quattro must be administered with a meal or within 30 minutes after feeding. Following a single oral administration of Credelio Quattro at the minimum labeled dose in the fed state or a single intravenous administration of 5 mg lotilaner, 0.005 mg moxidectin, 1.25 mg praziquantel, and 1.25 mg pyrantel per kg body weight to Beagle dogs (1.5 to 2.5 years old), the mean oral bioavailability for lotilaner, praziquantel, and pyrantel was 93%, 41%, and 31%, respectively. Bioavailability for moxidectin is not reported due to insufficient data to adequately describe the elimination phase following intravenous administration. For Credelio Quattro, the area under the curve from time of dosing to the time of the last measurable concentration (AUClast) was 5970, 1.75, 1.54, and 0.857 mg*h/L for lotilaner, moxidectin, praziquantel, and pyrantel, respectively. Peak concentrations (Cmax) of 9070, 15.3, 390, and 122 ng/mL were reached (Tmax) 10, 4.5, 0.75, and 2.5 h after dosing for lotilaner, moxidectin, praziquantel, and pyrantel, respectively. Mean plasma elimination half‐lives were 806, 634, 3.64, and 4.87 h for lotilaner, moxidectin, praziquantel, and pyrantel, respectively. Following nine oral administrations of Credelio Quattro at 1X, 3X, and 5X the maximum labeled dose of 40 mg/kg lotilaner, 0.04 mg/kg moxidectin, 10 mg/kg praziquantel, and 10 mg/kg pyrantel, every 28 days in 8-week-old Beagle dogs, moxidectin and lotilaner area under the curve from time of dosing to the time of the last measurable concentration (AUClast) increased approximately in a less than proportional manner, whereas praziquantel AUClast increased approximately in a more than proportional manner from 1X to 5X after most study doses. Pyrantel AUClast increased approximately in a proportional manner from 1X to 5X observed after first, sixth, and last doses. Within the 1X group, accumulation was observed between Days 0 and 224 with geometric mean accumulation ratios for AUClast of 6.2 and 7.9 for lotilaner and moxidectin, respectively. Concentrations of praziquantel and pyrantel prior to each dose were below the limit of quantification.

Credelio Quattro™ CredelioQuattro™-CA1(lotilaner, moxidectin, praziquantel, and pyrantel chewable tablets)

Following oral administration of 43 mg/kg (approximately 1X the maximum labeled dose), peak lotilaner concentrations were achieved between 6 hours and 3 days in dogs 2 months of age and between 1 and 7 days in dogs 10 months of age. Dogs 2 months of age had a shorter elimination half-life (average of 9.6 days) than at 10 months of age (average of 28.4 days). Due to reduced drug bioavailability in the fasted state, CREDELIO must be administered with a meal or within 30 minutes after feeding.

Credelio™ (lotilaner)

Following oral administration of 26 mg/kg (the maximum labeled dose), peak lotilaner concentrations were achieved in most cats at the 24-hour sampling point. Cats 3 months of age had a shorter elimination half-life (average of 7.5 days) than at 7 months of age (average of 32 days). Due to reduced drug bioavailability in the fasted state, CREDELIO CAT must be administered with a meal or within 30 minutes after feeding.

Credelio™ CAT (lotilaner)

There are no known contraindications for the use of Credelio Quattro/Credelio Quattro-CA1.

Credelio Quattro™ CredelioQuattro™-CA1(lotilaner, moxidectin, praziquantel, and pyrantel chewable tablets)

There are no known contraindications for the use of CREDELIO CAT.

Credelio™ CAT (lotilaner)

Not for use in humans. Keep this and all drugs out of reach of children. Wash hands after handling. If accidentally ingested, seek medical attention immediately. Keep Credelio Quattro/Credelio Quattro-CA1 in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

Credelio Quattro™ CredelioQuattro™-CA1(lotilaner, moxidectin, praziquantel, and pyrantel chewable tablets)

Not for human use. Keep this and all drugs out of the reach of children. Keep CREDELIO CAT in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

Credelio™ CAT (lotilaner)

In a field safety and effectiveness study, Credelio Quattro was administered to dogs for the prevention of heartworm disease. The study included a total of 372 dogs treated once monthly for up to 11 treatments (191 treated with Credelio Quattro and 181 treated with an active control). Over the 330-day study period, all observations of potential adverse reactions were recorded. Adverse reactions seen during the field study are summarized in the table below. Dogs with Adverse Reactions in the Field Study *Four dogs administered Credelio Quattro and five dogs administered the active control had bloody diarrhea. Clinical Sign Credelio Quattro N=191 Number (Percentage) Active Control N=181 Number (Percentage) Diarrhea, with or without blood* 21 (11%) 15 (8.3%) Vomiting 18 (9.4%) 8 (4.4%) Lethargy 12 (6.3%) 1 (0.6%) Anorexia 11 (5.8%) 5 (2.8%) Dermatitis 10 (5.2%) 8 (4.4%) Weight Loss 6 (3.1%) 3 (1.7%) Pruritus (itching) 3 (1.6%) 1 (0.6%) Alopecia (hair loss) 2 (1.0%) 4 (2.2%) Seizure 1 (0.5%) 4 (2.2%) Ataxia 1 (0.5%) 1 (0.6%) Nystagmus 1 (0.5%) 0 (0.0%) Anisocoria 1 (0.5%) 1 (0.6%) One geriatric dog receiving Credelio Quattro experienced two episodes of vomiting, ataxia, and nystagmus, 11 days apart, with the first episode occurring two days after the eighth dose. The dog recovered within 24 hours after the first episode and 1 hour after the second episode and completed the study. One dog receiving Credelio Quattro was observed by the investigator to have anisocoria during scheduled physical examinations one month after the ninth dose and one month after the eleventh dose. In a second U.S. field safety and effectiveness study, Credelio Quattro was administered to 103 dogs with hookworms. Adverse reactions in dogs treated with Credelio Quattro included gastrointestinal signs (diarrhea, emesis) and lethargy. In a U.S. field study, 165 dogs received a combination of lotilaner, moxidectin, and praziquantel, three of the active ingredients at the same doses as in Credelio Quattro, monthly for up to 11 months. Two dogs with no history of seizures experienced seizures during the study. One of the dogs developed cluster seizures and was removed from the study. Ataxia was also observed in one other dog three days after the first dose. In a U.S. field study, one dog administered lotilaner alone, a component of Credelio Quattro, was observed with intermittent head tremors within 1.5 hours of administration of vaccines, an ear cleaning performed by the owner, and its first dose of lotilaner. The head tremors resolved within 24 hours without treatment. The owner elected to withdraw the dog from the study. In an Australian field study, one dog with a history of seizures experienced seizure activity (tremors and glazed eyes) six days after receiving lotilaner alone. The dog recovered without treatment and completed the study. In a U.S. field study, two dogs with a history of seizures received lotilaner alone and experienced no seizures throughout the study.

Credelio Quattro™ CredelioQuattro™-CA1(lotilaner, moxidectin, praziquantel, and pyrantel chewable tablets)

In a well-controlled U.S. field study, which included 284 dogs (198 dogs treated with CREDELIO and 86 dogs treated with an oral active control), there were no serious adverse reactions. Over the 90-day study period, all observations of potential adverse reactions were recorded. Reactions that occurred at an incidence of 1% or greater are presented in the following table. Dogs with Adverse Reactions in the Field Study *Two geriatric dogs developed mildly elevated BUN (34 to 54 mg/dL; reference range: 6 to 31 mg/dL) during the study. One of these dogs also developed polyuria and a mildly elevated potassium (6.5 mEq/L; reference range: 3.6 to 5.5 mEq/L) and phosphorous (6.4 mg/dL; reference range: 2.5 to 6.0 mg/dL). The other dog also developed a mildly elevated creatinine (1.7 to 2.0 mg/dL; reference range: 0.5 to 1.6 mg/dL) and weight loss. Adverse Reaction (AR) CREDELIO Group: Number (and Percent) of Dogs with the AR (n=198) Active Control Group: Number (and Percent) of Dogs with the AR (n=86) Weight Loss 3 (1.5%) 2 (2.3%) Elevated Blood Urea Nitrogen (BUN) 2 (1.0%)* 0 (0.0%) Polyuria 2 (1.0%)* 0 (0.0%) Diarrhea 2 (1.0%) 2 (2.3%) In addition, one dog experienced intermittent head tremors within 1.5 hours of administration of vaccines, an ear cleaning performed by the owner, and its first dose of CREDELIO. The head tremors resolved within 24 hours without treatment. The owner elected to withdraw the dog from the study. In an Australian field study, one dog with a history of seizures experienced seizure activity (tremors and glazed eyes) six days after receiving CREDELIO. The dog recovered without treatment and completed the study. In the U.S. field study, two dogs with a history of seizures received CREDELIO and experienced no seizures throughout the study. In three well-controlled European field studies and one U.S. laboratory study, seven dogs experienced episodes of vomiting and four dogs experienced episodes of diarrhea between 6 hours and 3 days after receiving CREDELIO.

Credelio™ (lotilaner)

In a well-controlled U.S. field study, which included 341 cats (228 cats treated with CREDELIO CAT and 113 cats treated with a topical active control), there were no serious adverse reactions. Cats with Adverse Reactions in the Field Study *Two geriatric cats developed mildly elevated blood urea nitrogen (BUN) (42 to 58 mg/dL; reference range: 14 to 36 mg/dL) during the study. One of these cats, which had suspected pre-existing kidney disease, also developed a mildly elevated serum creatinine (2.5 mg/dL; reference range: 0.6 to 2.4 mg/dL) during the study. Adverse Reaction (AR) CREDELIO CAT Group: Number (and Percent) of Cats with the AR (n=228) Active Control Group: Number (and Percent) of Cats with the AR (n=113) Weight Loss 5 (2.2%) 2 (1.8%) Tachypnea 3 (1.3%) 0 (0.0%) Vomiting 3 (1.3%) 1 (0.9%) Diarrhea 2 (0.9%) 0 (0.0%) Anorexia 2 (0.9%) 0 (0.0%) Elevated blood urea nitrogen (BUN)* 2 (0.9%) 0 (0.0%)

Credelio™ CAT (lotilaner)

Administer orally once a month, at the minimum dosage of 9 mg/lb (20 mg/kg) lotilaner, 0.009 mg/lb (0.02 mg/kg) moxidectin, 2.28 mg/lb (5 mg/kg) praziquantel, and 2.28 mg/lb (5 mg/kg) pyrantel (as pamoate salt).

Oral

Credelio Quattro™

Credelio™ chewable tablets are given orally once a month at the recommended minimum dosage of 9 mg/lb (20 mg/kg). Credelio™ must be administered with food.

Oral

Credelio™

Administer orally once a month at the minimum dosage of 2.7 mg/lb (6 mg/kg). Must be administered with food.

Oral

Credelio™ CAT

Credelio Quattro/Credelio Quattro-CA1 is given orally at the minimum dosage of 9 mg/lb (20 mg/kg) lotilaner, 0.009 mg/lb (0.02 mg/kg) moxidectin, 2.28 mg/lb (5 mg/kg) praziquantel, and 2.28 mg/lb (5 mg/kg) pyrantel (as pamoate salt). Credelio Quattro/Credelio Quattro-CA1 must be administered with food (see Clinical Pharmacology ). Care should be taken to ensure that the dog consumes the complete dose and that part of the dose is not lost or refused. If vomiting occurs within an hour after administration, readminister a new dose of Credelio Quattro/Credelio Quattro-CA1. Credelio Quattro: Credelio Quattro is given once a month. If a dose is missed, give Credelio Quattro immediately and resume a monthly dosing schedule. Dosing Schedule: *As pamoate salt Body Weight (lbs) Tablets to Administer Lotilaner per Tablet (mg) Moxidectin per Tablet (mg) Praziquantel per Tablet (mg) Pyrantel* per Tablet (mg) 3.3 – 6 1 56.25 0.056 14.25 14.25 6.1 – 12 1 112.5 0.113 28.5 28.5 12.1 – 25 1 225 0.225 57 57 25.1 – 50 1 450 0.45 114 114 50.1 – 100 1 900 0.9 228 228 > 100 Administer the appropriate combination of tablets Heartworm Prevention Credelio Quattro should be administered year-round at monthly intervals or at least within 1 month of the animal’s first seasonal exposure to mosquitoes and continuing until at least 1 month after the dog’s last seasonal exposure. If a dose is missed, give Credelio Quattro immediately and resume monthly dosing. When replacing a monthly heartworm preventive product, Credelio Quattro should be given within 1 month of the last dose of the former medication. Intestinal Nematode and Cestode Treatment and Control Credelio Quattro should be administered as a single dose for the treatment of roundworm, hookworm, and tapeworm infections. Monthly use of Credelio Quattro will control any subsequent infections. Dogs may be exposed to and can become infected with gastrointestinal worms throughout the year, regardless of season or climate. Clients should be advised of appropriate measures to prevent reinfection of their dog with intestinal parasites. Flea Treatment and Prevention Treatment with Credelio Quattro should be administered year-round at monthly intervals or started at least 1 month before fleas become active. To minimize the likelihood of flea re-infestation, it is important to treat all dogs and cats within a household with a flea control product. Tick Treatment and Control Treatment with Credelio Quattro can begin at any time of the year. Credelio Quattro should be administered year-round at monthly intervals or started at least 1 month before ticks become active. Credelio Quattro-CA1: New World Screwworm (NWS) Myiasis Treatment A single dose of Credelio Quattro-CA1 is reasonably expected to treat C. hominivorax present at the time of treatment. Re-infestation with C. hominivorax may occur sooner than one month. Treatment should be used in conjunction with the mechanical removal of larvae (live and dead) remaining in the wound after treatment (see PRECAUTIONS ).

ORAL

Credelio Quattro™ CredelioQuattro™-CA1(lotilaner, moxidectin, praziquantel, and pyrantel chewable tablets)

CREDELIO is given orally once a month, at the minimum dosage of 9 mg/lb (20 mg/kg). Dosage Schedule: Body Weight Lotilaner Per Chewable Tablet (mg) Chewable Tablets Administered 4.4 to 6.0 lbs 56.25 One 6.1 to 12.0 lbs 112.5 One 12.1 to 25.0 lbs 225 One 25.1 to 50.0 lbs 450 One 50.1 to 100.0 lbs 900 One Over 100.0 lbs Administer the appropriate combination of chewable tablets CREDELIO must be administered with food (see Clinical Pharmacology ). Treatment with CREDELIO can begin at any time of the year and can continue year-round without interruption.

ORAL

Credelio™ (lotilaner)

CREDELIO CAT is given orally once a month, at the minimum dosage of 2.7 mg/lb (6 mg/kg). Dosage Schedule: NA = not applicable. Body Weight Lotilaner Per Chewable Tablet (mg) Chewable Tablets Administered 2.0 to 4.0 lbs 12 One 4.1 to 17.0 lbs 48 One Over 17.0 lbs NA Administer the appropriate combination of chewable tablets CREDELIO CAT must be administered with food (see Clinical Pharmacology ). Treatment with CREDELIO CAT can begin at any time of the year and can continue year-round without interruption.

ORAL

Credelio™ CAT (lotilaner)