Lufenuron, Milbemycin Oxime, Praziquantel: what the FDA reviewed for dog products
2 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Lufenuron, Milbemycin Oxime, Praziquantel, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- Sentinel® Spectrum® (NADA/ANADA 141-333)
Sentinel® Spectrum® NADA 141-333, Original approval, December 08, 2011; sponsor Intervet, Inc.; species: Dogs; foi_id 891; FDA PDF
Indication
Prevention of heartworm disease (Dirofilaria immitis); prevention and control of flea populations (Ctenocephalides felis); treatment and control of adult roundworm, hookworm, whipworm and tapeworm (Taenia pisiformis, Echinococcus multilocularis, E. granulosus) infections in dogs and puppies 2 lb or more and 6 weeks of age and older.
Dose regimen
0.5 mg/kg (0.23 mg/lb) milbemycin oxime, 10 mg/kg (4.55 mg/lb) lufenuron and 5 mg/kg (2.28 mg/lb) praziquantel (minimum), oral (chewable tablet), once a month, for heartworm prevention, give monthly from within 1 month of first seasonal mosquito exposure until at least 6 months after last exposure
SENTINEL SPECTRUM is given orally, once a month, at the minimum dosage of 0.23 mg/pound body weight (0.5 mg/kg) of milbemycin oxime, 4.55 mg/pound (10 mg/kg) of lufenuron, and 2.28 mg/pound (5 mg/kg) of praziquantel.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| auc | AUC(0-t) 1125 ng/mL·h (chewable) vs 827 ng/mL·h (tablet); ratio 136% (CI 126.1-146.9) | praziquantel, single 57 mg dose, fasted, two-way crossover, 24 female Beagles (12 per sequence), geometric means | AUC(0-t) (ng/mL·h) † 1125 827 136 126.1 – 146.9 <0.0001 |
| cmax | 608 ng/mL (chewable) vs 344 ng/mL (tablet); ratio 177% (CI 152-204.9) | praziquantel, single 57 mg dose, fasted, crossover, geometric means | Cmax (ng/mL)† 608 344 177 152 – 204.9 <0.0001 |
| tmax | 1 h (median, both formulations) | praziquantel, single 57 mg dose, fasted | Tmax (h)^ 1 1 NA NA 0.3081 |
| bioavailability | praziquantel more bioavailable from the SENTINEL SPECTRUM chewable than from the tablet formulation | study NAH-09-0015, fasting | The results of this study demonstrate that the praziquantel in SENTINEL SPECTRUM is more bioavailable than the praziquantel in the milbemycin oxime, lufenuron, praziquantel tablet formulation. |
Target-animal safety
dose multiples 1X, 3X, 5X; duration every two weeks for seven treatments (90-day study) in 10-week-old Beagle puppies; doses 2.5/50.7/25.1, 7.5/152.1/75.3 and 12.5/253.5/125.5 mg/kg milbemycin/lufenuron/praziquantel; animals 20 males and 20 females.
Forty purpose-bred beagles (20 males and 20 females), approximately ten weeks of age at the time of treatment, were used in this study.
| Finding | Quote |
|---|---|
| One 5X male euthanized on Day 29 due to intussusception of the colon; all other dogs survived. | All dogs survived to termination except for one male in the 5X treated group, which was euthanized in extremis on Day 29 due to intussusception of the colon. |
| Ataxia, lethargy, tremors and salivation increased at 3X and 5X; vomiting in all groups, higher at 3X and 5X; ataxia, lethargy and tremors also seen in some 1X dogs. | The incidence of ataxia, lethargy, tremors, and salivation was increased in the 3X and 5X treatment groups. Vomiting was seen in all treatment groups but had a higher incidence in the 3X and 5X treatment groups. Ataxia was observed post- dose in two dogs administered the 1X dose. Lethargy was observed in a total of six 1X treated dogs post-dose. Tremors were observed post-treatment in two 1X treated dogs. |
| At 5X: shallow breathing in two dogs and inability to stand in one dog; mildly prolonged APTT in one 3X male and two 5X females at one month. | At the 5X dose, shallow breathing was noted in two dogs and inability to stand in one dog following two different doses. One male in the 3X group and two females in the 5X group had a mildly prolonged APTT at Month 1 or Month 2 during the study. |
| Clinical signs followed a dose-related pattern and resolved within 24 hours. | Clinical signs were noted following each dose and followed a dose-related pattern in onset, overall incidence, and duration. The percent of dogs observed with specific post-dose clinical observations in all groups is shown on Table 27 below. All clinical signs resolved within 24 hours. |
| Conclusion: signs consistent with avermectin toxicity in all treatment groups, dose-related. | SENTINEL SPECTRUM, administered at multiples of the maximum label exposure, produce clinical signs consistent with avermectin toxicity (ataxia, tremors, lethargy, vomiting and salivation) in all treatment groups that followed a dose-related pattern in onset, overall incidence, and duration. |
| Second study from 6 weeks of age (64 puppies, 4 doses): dose-dependent ataxia, decreased activity, salivation, vomiting and tremors; ataxia most common at 3X/5X. | A dose-dependent increase in the incidence of treatment associated clinical signs (ataxia, decreased activity, salivation, vomiting and tremors) was typically observed in dogs within 24 hours of test article administration. Ataxia was the most common clinical finding in the 3X and 5X treatment groups, with a greater incidence in the 5X groups overall. |
Effectiveness
Pivotal laboratory dose-confirmation study NAH-08-0008 (GCP): 16 Beagles inoculated with 50 D. immitis L3 larvae on Day -30; 8 control (multi-vitamin) and 8 SENTINEL SPECTRUM-treated dogs dosed on Days 0, 30, 60, 90, 120 and 150; adult worm counts at necropsy Day 181.; primary endpoint: Percent reduction in geometric mean adult heartworm count vs control; result: Control geometric mean 18.8 worms (range 0-39); treated 0.0; 100.0% effectiveness (p = 0.0002).
SENTINEL SPECTRUM is 100% effective against experimental infection with Dirofilaria immitis when administered once per month for 6 consecutive months after laboratory infection.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Facial swelling (field palatability/acceptability study, 117 evaluable dogs) | One dog had facial swelling one day after receiving SENTINEL SPECTRUM. The dog was treated with an antihistamine and recovered uneventfully, but was withdrawn from the study. | ||
| Vomiting within one hour and anorexia (field study) | Two dogs vomited within one hour of administration, and another dog was anorexic one day after receiving SENTINEL SPECTRUM. | ||
| Gagging and coughing (field study) | One dog exhibited gagging and coughing one hour after accepting the chewable from the owner’s hand. | ||
| Diarrhea / vomiting (bioequivalence study NAH-09-0015) | Three adverse reactions occurred in this study. One dog had diarrhea on Day 0, 8 hours after administration of SENTINEL SPECTRUM. One dog vomited on Day 7, 1.5 hours after administration of SENTINEL SPECTRUM. | ||
| Soft feces (heartworm dose confirmation study) | One dog experienced soft feces after treatment with SENTINEL SPECTRUM on Day 60; this dog recovered uneventfully without treatment. |
Extraction notes: Large summary with many laboratory studies (heartworm, flea, roundworm, hookworm, whipworm, three tapeworm species); the heartworm pivotal study is recorded as effectiveness (n_dogs null because '16' is spelled out; 8 dogs per group). The only field study (NAH-02-0054) was a palatability/acceptability study in 120 enrolled / 117 evaluable client-owned dogs (113 accepted from hand, 1 refused) with five treatment-related adverse reactions, quoted above without counts because numbers are spelled out. PK is from the praziquantel chewable-vs-tablet bioequivalence bridging study; rows quoted as flattened table rows (columns: chewable, tablet, ratio %, 90% CI, p-value). TAS design_quote is the 90-day study in 10-week-old puppies (NAH-02-0066, 10 dogs per group, 1X = 2.5 mg/kg milbemycin, i.e. multiples of maximum label exposure); Table 27 percent incidences are not reproduced.
Sentinel® Spectrum® NADA 141-333, Supplemental approval, September 28, 2017; sponsor Intervet, Inc.; species: Dogs; foi_id 2282; FDA PDF
Indication
Supplement adds treatment and control of adult tapeworm (Dipylidium caninum) infections in dogs and puppies 2 lb or more and 6 weeks of age and older.
Dose regimen
0.5 mg/kg (0.23 mg/lb) milbemycin oxime, 10 mg/kg (4.55 mg/lb) lufenuron and 5 mg/kg (2.28 mg/lb) praziquantel (minimum), oral (chewable tablet), once every month, administer immediately after or with a normal meal; for heartworm prevention give monthly for at least 6 months after mosquito exposure
SENTINEL SPECTRUM should be administered orally, once every month, at the minimum dosage of 0.23 mg/lb (0.5 mg/kg) milbemycin oxime, 4.55 mg/lb (10 mg/kg) lufenuron, and 2.28 mg/lb (5 mg/kg) praziquantel.
Effectiveness
Laboratory dose confirmation study NAH-14-093 (GLP): 16 dogs experimentally infected with US-derived D. caninum via infected fleas; 8 treated once with SENTINEL SPECTRUM (minimum 5 mg/kg praziquantel) on Day 82 and 8 untreated controls; necropsy Day 92. Supported by non-interference study NAH-02-0032 (29 naturally infected dogs, non-final tablet formulation, 100% effective).; n = 8; primary endpoint: Percent reduction in geometric mean tapeworm count vs control; result: 100% effective (treated geometric mean 0.0 vs control 30.7, range 8-124; p < 0.0001).
SENTINEL® SPECTRUM® 8 0.0 (NA) 100% Control (untreated) 8 30.7 (8-124) NA
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Diarrhea (study NAH-02-0032; control vs 3-way tablet group) | Diarrhea was observed in two dogs in the control group and four dogs in the milbemycin oxime, lufenuron, praziquantel tablet group, including one dog with bloody stool noted on Day 6. None of the dogs required treatment. | ||
| Vomiting (study NAH-14-093) | Vomiting was observed in one dog, several hours after receiving SENTINEL® SPECTRUM®. No treatment was needed. |
Extraction notes: Supplemental approval; no new TAS studies (CVM did not require them) and no PK; dosage unchanged. Effectiveness quote is the flattened Table 4 rows (columns: treatment group, number of dogs, geometric mean (range), percent effectiveness). Adverse-reaction counts are spelled out in words so treated/control are left null.
Reproduce: foi_structured_search(query="Lufenuron, Milbemycin Oxime, Praziquantel") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).