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 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
- INTERCEPTOR™ PLUS (NADA/ANADA 141-338)
INTERCEPTOR™ PLUS NADA 141-338, Original approval, June 16, 2012; sponsor Elanco US Inc.; species: Dogs; foi_id 895; FDA PDF
Indication
Prevention of heartworm disease (D. immitis) and treatment/control of adult roundworm, hookworm, whipworm and tapeworm (Taenia pisiformis, Echinococcus multilocularis, E. granulosus) infections in dogs and puppies 2 lb or greater and 6 weeks of age and older.
Dose regimen
minimum 0.23 mg/pound (0.5 mg/kg) milbemycin oxime and 2.28 mg/pound (5 mg/kg) praziquantel, oral, once a month, for heartworm prevention, begin within 1 month of first seasonal mosquito exposure and continue until at least 6 months after last exposure
INTERCEPTOR SPECTRUM is given orally, once a month, at the minimum dosage of 0.23 mg/pound (0.5 mg/kg) body weight of milbemycin oxime and 2.28 mg/pound (5 mg/kg) of praziquantel.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| auc | 887 ng/mL·h (geometric mean AUC(0-t), praziquantel) INTERCEPTOR SPECTRUM chewable vs 719 ng/mL·h tablet; ratio 123 (CI 116.2-131.3) | Study NAH-10-0015 crossover bioequivalence, 24 female Beagles, fasted, single 57 mg praziquantel chewable vs tablet; columns: INTERCEPTOR SPECTRUM, tablet, ratio, 90% CI, p-value | AUC(0-t) (ng/mL·h)† 887 719 123 116.2-131.3 <0.0001 |
| cmax | 602 ng/mL (geometric mean, praziquantel) INTERCEPTOR SPECTRUM chewable vs 326 ng/mL tablet; ratio 185 (CI 160.1-213.0) | Study NAH-10-0015 crossover, 24 female Beagles, fasted; columns: INTERCEPTOR SPECTRUM, tablet, ratio, 90% CI, p-value | Cmax (ng/mL)† 602 326 185 160.1-213.0 <0.0001 |
| tmax | 1 h (median, praziquantel) for both formulations | Study NAH-10-0015 crossover, 24 female Beagles, fasted | Tmax (h)^ 1 1 NA NA 0.9938 |
| bioavailability | praziquantel in INTERCEPTOR SPECTRUM chewable more bioavailable than in the milbemycin oxime/praziquantel tablet | Study NAH-10-0015, fasted dogs | The results of this study demonstrate that the praziquantel in INTERCEPTOR SPECTRUM is more bioavailable than the praziquantel in the milbemycin oxime and praziquantel tablet formulation. |
Target-animal safety
dose multiples 1X, 3X, 5X; duration dosed every two weeks for four treatments, beginning at 6 weeks of age; animals Sixty-four purpose-bred beagles.
Objective: To evaluate the safety of repeated doses of INTERCEPTOR SPECTRUM when administered to Beagle puppies at six weeks of age at approximately 1, 3, and 5X the maximum label exposure.
| Finding | Quote |
|---|---|
| Decreased activity in 1X group after first and third treatments | In the 1X treatment group decreased activity was reported in five of the 16 animals following the first treatment and six of the 16 animals following the third treatment. |
| Salivation and tremors in 3X and 5X dogs up to six hours post-dose | Salivation and tremors were observed in the 3X and 5X treated dogs beginning immediately after dosing and up to six hours post-dose. |
| Vomiting in 5X group on most treatment days | Vomiting was observed in the 5X treatment group on most, but not all, treatment days. |
| Well tolerated in puppies 6 weeks and older; dose-related avermectin-type signs at multiples of label exposure | INTERCEPTOR SPECTRUM, when dosed at multiples of the maximum label exposure, produced clinical signs consistent with avermectin toxicity (ataxia, decreased activity, salivation, tremors and vomiting) that followed a dose- related pattern in onset, overall incidence, and duration. |
Effectiveness
Pivotal laboratory dose confirmation study NAH-10-0008 (GCP): Beagles inoculated with 50 D. immitis L3 on Day -30, treated on Days 0-150 monthly (6 doses) vs multi-vitamin control (9 per group), necropsy worm counts Day 180; n = Eighteen; primary endpoint: Percent reduction in geometric mean adult heartworm count vs control at necropsy; result: 100% effectiveness (treated GM 0.0 vs control 40.9, p<0.0001)
Study NAH-10-0008 Results Treatment Geometric Mean D. immitis Worm Count (Range) % Effectiveness p-value INTERCEPTOR SPECTRUM 0.0 (NA) 100.0 p<0.0001 Control (6 doses) 40.9 (36-46) NA p<0.0001 NA = not applicable.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Vomiting (field palatability study NAH-02-0054) | On one occasion, one dog vomited immediately after accepting the chewable from the owner's hand. |
Extraction notes: Summary uses the name INTERCEPTOR SPECTRUM (marketed as INTERCEPTOR PLUS). n_dogs is spelled 'Eighteen' in the source ('Study Animals: Eighteen purpose-bred Beagles from 20 to 23 weeks of age'); digits 18 do not appear, so the effectiveness quote is the results table instead. PK values are from a praziquantel bioequivalence/bioavailability comparison of the chewable vs a tablet formulation (Table 8); columns are chewable, tablet, ratio (%), 90% CI, p-value. TAS: a second margin-of-safety study NAH-03-0004 (40 Beagles, 10 weeks old, 1X/3X/5X every two weeks for seven treatments) showed ataxia, decreased activity, salivation and vomiting in 3X/5X. Field study NAH-02-0054 was a palatability/acceptability study (120 enrolled, 115 evaluated; 108 accepted from hand, 4 refused) with a single vomiting event; no field effectiveness study. TAS study NAH-04-0001 used 64 beagles (32 males and 32 females; 16 per group). PK CI values are 90% confidence intervals.
INTERCEPTOR™ PLUS NADA 141-338, Supplemental approval, June 21, 2017; sponsor Elanco US Inc.; species: Dogs; foi_id 1504; FDA PDF
Indication
Supplement adds treatment and control of adult tapeworm (Dipylidium caninum) infections in dogs and puppies 2 lb or greater and 6 weeks of age and older (to existing heartworm prevention and roundworm/hookworm/whipworm/tapeworm indications).
Dose regimen
minimum 0.23 mg/lb (0.5 mg/kg) milbemycin oxime and 2.28 mg/lb (5 mg/kg) praziquantel, oral, once every month, for heartworm prevention, give once monthly for at least 6 months after exposure to mosquitoes; dosage unchanged by this supplement
INTERCEPTORTM PLUS should be administered orally, once every month, at the minimum dosage of 0.23 mg/lb (0.5 mg/kg) milbemycin oxime, and 2.28 mg/lb (5 mg/kg) praziquantel.
Effectiveness
Laboratory dose confirmation study NAH-14-093 (GLP): dogs experimentally infected with US-derived D. caninum via infected fleas, single oral dose on Day 82 of INTERCEPTOR PLUS (0.5 mg/kg milbemycin oxime / 5 mg/kg praziquantel) vs untreated control, 8 per group, necropsy tapeworm counts on Day 92; n = 8 per group (Sixteen dogs total); primary endpoint: Percent reduction in geometric mean D. caninum count vs control at necropsy; result: 100% effectiveness (treated GM 0.0 vs control 30.7, p < 0.0001); no test article-related adverse reactions
Table 4: Study NAH-14-093 Results Treatment Group Number of Dogs Geometric mean of D. caninum Recovered (range) Percent Effectiveness INTERCEPTORTM PLUS 8 0.0 (NA) 100% Control (untreated) 8 30.7 (8-124) NA NA=Not applicable Adverse Reactions: No test article-related adverse reactions were observed.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Diarrhea (study NAH-02-0032, non-final tablet formulation) | Diarrhea was observed in two dogs in the control group and five dogs in the milbemycin oxime/praziquantel tablet group. |
Extraction notes: Supplemental approval adding Dipylidium caninum; no PK or new target animal safety studies ('CVM did not require target animal safety studies for this supplemental approval.'). Two effectiveness studies: NAH-02-0032 (29 naturally infected dogs, non-final milbemycin oxime/praziquantel tablet, 100% effective, GM 0.0 vs control 13.6, p = 0.0022; bridged to the chewable via PK study NAH-10-0015 from the original approval) and the pivotal NAH-14-093 recorded here. Adverse-reaction row counts are given in words in the source (two control, five treated of 9 and 10 dogs respectively) so treated/control are left null. The trademark symbol renders as 'TM' in the extracted text (INTERCEPTORTM PLUS).
Reproduce: foi_structured_search(query="Milbemycin oxime/praziquantel") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).