Ivermectin, Pyrantel Pamoate: what the FDA reviewed for dog products
4 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Ivermectin, Pyrantel Pamoate, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Canine; Dogs.
Products
- Heartgard® Plus (NADA/ANADA 140-971)
- Iverhart™ Plus Flavored Chewables (NADA/ANADA 200-302)
- Tri-Heart Plus Chewable Tablets (NADA/ANADA 200-338)
Tri-Heart Plus Chewable Tablets NADA 200-338, Original approval, August 13, 2003; sponsor Diamond Animal Health, Inc.; species: Canine; foi_id 1083; FDA PDF
Indication
Prevention of canine heartworm (Dirofilaria immitis) disease and treatment and control of adult Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Uncinaria stenocephala and Ancylostoma braziliense (generic of Heartgard Plus, NADA 140-971).
Dose regimen
minimum 6 mcg ivermectin and 5 mg pyrantel (as pamoate salt) per kg of body weight, oral (compressed chewable tablet), monthly, 68 mcg/57 mg, 136 mcg/114 mg and 272 mcg/227 mg tablets by weight class
Recommended Dosage: A minimum of 6 mcg of iverm ectin and 5 mg of pyrantel (as the pamo ate salt)/kg of body weight at monthly intervals.
Effectiveness
Clinical end-point bioequivalence studies vs HEARTGARD Plus: (a) heartworm study in 30 beagles (10 per group: untreated, TRI-HEART Plus, HEARTGARD Plus) artificially infected with D. immitis L3, single treatment 29 days post-infection, necropsy 182-189 days post-infection (a first study was invalidated for inadequate control infections); (b) T. canis study in 30 naturally infected puppies (10 per group), single treatment, necropsy Day 7; (c) two-day crossover palatability study in 50 adult beagles.; primary endpoint: Geometric mean heartworm counts at necropsy (percent efficacy vs untreated controls); T. canis geometric mean worm counts; result: Heartworm: geometric mean 48.2 worms (range 37-60) in controls vs 0 for both products (100%). T. canis: 92.4% (TRI-HEART Plus) vs 97.5% (HEARTGARD Plus), both >90% and significantly lower than controls. Palatability equivalent (45 of 50 dogs ate both).
The generic product and the pioneer product were both 100% effective against developing stages of heartworms in dogs and no further statistical analysis was conducted.
Extraction notes: Generic (ANADA) approval relying on pioneer NADA 140-971; no target animal safety or PK studies (blood-level bioequivalence not feasible for ivermectin and not relevant for poorly absorbed pyrantel). Dose quote contains the extraction artifacts 'iverm ectin' and 'pamo ate'. Result tables were flattened (columns: group, treatment, geometric mean worm count, range, percent efficacy). No adverse reactions are reported. Animal numbers are spelled out ('Thirty'), so n_dogs is null.
Heartgard® Plus NADA 140-971, Original approval, January 15, 1993; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 542; FDA PDF
Indication
For use in dogs: ivermectin to prevent canine heartworm disease by eliminating tissue larval stages of Dirofilaria immitis for a month (30 days) after infection; pyrantel pamoate for the treatment and control of adult Toxocara canis, Toxascaris leonina, Ancylostoma caninum and Uncinaria stenocephala.
Dose regimen
minimum 6 mcg ivermectin/kg (2.72 mcg/lb) and 5 mg pyrantel/kg (2.27 mg/lb), oral (meat-based chewable tablet), once monthly, during the mosquito season; 68 mcg/57 mg, 136 mcg/114 mg and 272 mcg/227 mg chewables by weight class
HEARTGARD-30® Plus chewable tablets are administered once monthly and provide a minimum of 6 mcg ivermectin per kg of body weight (2.72 mcg/lb) and a minimum of 5 mg pyrantel per kg of body weight (2.27 mg/lb) when given as follows:
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| auc | not statistically different from HEARTGARD-30 Chewables (p>.20) | tritiated ivermectin 6 mcg/kg (+ pyrantel 5 mg/kg) oral, two-period crossover, 18 non-pregnant female dogs, Trial 12664 | HEARTGARD-30® Plus was equivalent to the HEARTGARD-30® Chewable formulation with respect to the bioavailability of ivermectin. The AUC and Cmax were not statistically significantly different for the two formulations (p>.20). |
| auc | within 10% of the HEARTGARD-30 Chewable formulation (confidence intervals) | tritiated ivermectin 6 mcg/kg oral, crossover, 18 female dogs, Trial 12664 | Confidence intervals confirmed that the AUC and Cmax for HEARTGARD-30® Plus fell within 10% and 15%, respectively, of the HEARTGARD-30® Chewable formulation. |
| cmax | within 15% of the HEARTGARD-30 Chewable formulation (confidence intervals) | tritiated ivermectin 6 mcg/kg oral, crossover, 18 female dogs, Trial 12664 | Confidence intervals confirmed that the AUC and Cmax for HEARTGARD-30® Plus fell within 10% and 15%, respectively, of the HEARTGARD-30® Chewable formulation. |
| tmax | about 2.5 hours longer for HEARTGARD-30 Plus than for the Chewables | tritiated ivermectin 6 mcg/kg oral, crossover, 18 female dogs, Trial 12664 | The Tmax was longer by about 2.5 hours for HEARTGARD-30® Plus, but since the formulation is intended for monthly use, this difference is of no clinical significance. |
Target-animal safety
dose multiples 1X, 3X, 5X; duration 3 successive days, repeated 3 times within a 30-day period (Days 0-2, 14-16, 28-30); necropsy Day 35-36; animals Thirty-two pups (4 pups from each of 8 litters).
Thirty-two pups were treated at 1, 3 or 5X the target dose of HEARTGARD- 30® Plus given on 3 successive days and repeated 3 times within a 30-day period. Replicates of 4 pups from each of 8 litters were formed.
| Finding | Quote |
|---|---|
| No treatment-related effects on physical examination; dehydration and random vomiting occurred in all groups including controls. | Initial and terminal physical examinations did not reveal any treatment related effects. Some dehydration was observed in animals of all groups and was considered to be related to weaning and adapting to solid feed and individual housing. Random vomiting was reported in all groups and was usually of one day duration. |
| Statistical changes in several clinical pathology parameters, none considered biologically or clinically significant. | Clinical pathology results indicated changes in the treated animals in the following parameters: calcium, creatinine, MCHC, phosphorus and WBC. There were also treatment effects seen in eosinophils, platelets, prothrombin time, albumin, BUN, protein, potassium and phosphorus. None of these differences were considered to be biologically or clinically significant. |
| No treatment-related gross or microscopic lesions at necropsy. | On necropsy there were no treatment related lesions. |
| Reproductive safety (Trial 12666): 3X dose through a reproductive cycle had no effect on semen parameters; litter size and pup abnormality rates not different from vehicle. | HEARTGARD-30® Plus, given orally at 3X the target dose through one reproductive cycle, was found to have no effect on semen evaluations in terms of total sperm count, speed of progression, motility or pH. |
| Corroborative 5-day repeated treatment study: ivermectin with up to 2X pyrantel caused no drug-related signs or lesions. | Ivermectin alone or in the presence of up to 2 times the target dose of pyrantel did not cause any drug-related adverse physical or clinical signs in this study. |
| Conclusion: wide margin of safety including 6-week-old pups and breeding animals. | HEARTGARD-30® Plus has a wide margin of safety when administered repeatedly at elevated doses to dogs including 6-week-old pups and breeding studs and bitches. |
Effectiveness
Eight controlled clinical field trials (8 investigators, 6 locations) in client-owned dogs, 3:1 allocation of HEARTGARD-30 Plus vs positive control (HEARTGARD-30 tablets plus pyrantel pamoate), monthly dosing for 5-7 months; supported by pivotal dose-confirmation studies (100% against 30-day D. immitis larvae in two 32-dog studies; pyrantel 5 mg/kg 88-100% against intestinal nematodes).; n = 323 treated, 107 control (280 female, 150 male); primary endpoint: Fecal examinations for hookworm and ascarid eggs and heartworm microfilariae tests during 5-7 months of monthly treatment; result: No hookworm eggs in 94.7% and no ascarid eggs in 99.0% of dogs; completely effective in preventing D. immitis development; overall acceptability 97%.
In all, 323 animals were treated with HEARTGARD-30® Plus, and 107 were included in the control group. The trials included 280 female and 150 male dogs aged 6 months to 14 years and weighing from 1.6 to 68 kg. These animals represented 122 breeds, varieties or types, including Collies or Collie crosses. Although approximately 85-90% of the dogs in the field trials received all scheduled monthly doses, fifty-five dogs did not complete the trials because of lack of owner compliance (#30), death/illness due to unrelated causes (#14), or loss of dog or contact with owner (#11). HEARTGARD-30® Plus was shown to be effective for the treatment and control of hookworms and ascarids under field use conditions. No hookworm eggs were detected in 94.7% of dogs and no ascarid eggs were detected in 99.0% of dogs. HEARTGARD-30® Plus also was shown to be completely effective in preventing the development of D. immitis .
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| vomiting and diarrhea (field trials, both treatment groups) | 1.1% of administered doses | The incidence of vomiting and diarrhea, the most commonly observed clinical conditions, was low (1.1% of administered doses). |
Extraction notes: The General Information indication sentence is split by a page header in the extracted text, so the indication quote is taken from the effectiveness conclusions instead. Pup-safety animal count is spelled out ('Thirty-two'); the numeric part of n_animals (4 pups x 8 litters) is grounded in the design quote. Ivermectin bioequivalence values are reported only as relative statements (no absolute AUC/Cmax numbers). Reproductive-safety breeding indices (conception 8/12 vehicle vs 11/12 treated; weaning 91.1% vs 84.2%) and pup deaths are in the text but not tabulated here.
Iverhart™ Plus Flavored Chewables NADA 200-302, Original approval, May 30, 2001; sponsor Virbac AH, Inc.; species: Canine; foi_id 1052; FDA PDF
Indication
Prevention of canine heartworm (Dirofilaria immitis) disease and treatment and control of adult Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Uncinaria stenocephala and Ancylostoma braziliense (generic of Heartgard Plus, NADA 140-971).
Dose regimen
minimum 6 mcg ivermectin and 5 mg pyrantel pamoate per kg of body weight, oral (flavored chewable tablet), monthly, 68 mcg/57 mg, 136 mcg/114 mg and 272 mcg/227 mg tablets by weight class
Labeled Dosage: A minimum of 6 mcg of ivermectin and 5 mg of pyrantel pamoate/kg of body weight at m onthly intervals.
Effectiveness
Clinical end-point bioequivalence studies vs Heartgard Plus: (1) heartworm prevention in 36 beagles (12 per group: Iverhart Plus, Heartgard Plus, untreated) inoculated with 50 D. immitis L3, four monthly treatments starting 30 days later, necropsy 119 days post-inoculation; (2) two T. canis studies in 30 experimentally infected beagle pups each (10 per group), single treatment 49 days post-inoculation, necropsy Day 56; (3) two-day crossover palatability study in 69 client-owned dogs.; primary endpoint: Adult D. immitis counts at necropsy (heartworm study); T. canis worm counts (geometric means); result: Heartworm: 0 worms in both treated groups vs mean 24 in controls (100% efficacy, bioequivalent). T. canis: 93.07% (Iverhart Plus) vs 97.62% (Heartgard Plus) in study one and 97.45% vs 92.34% in study two. Palatability 95.7% vs 100% (no significant difference, p=0.0833).
Results and Conclusions: The worm counts for both treated groups (Iverhart Plus and Heartgard Plus) were 0 and the mean worm count for the negative control group was 24, with all control animals having heartworm infections. Thus, the reference product and the pioneer product were considered bioequivalent with efficacies of 100%, and no statistical analysis was conducted.
Extraction notes: Generic (ANADA) approval relying on pioneer NADA 140-971; no target animal safety or PK studies. Blood-level bioequivalence was not required (ivermectin plasma levels too low; pyrantel poorly absorbed). Dose quote contains the extraction artifact 'm onthly'. No adverse reactions are reported; one Iverhart Plus dog in T. canis study one had 35 worms (possible unobserved vomiting). Animal numbers are spelled out ('Thirty-six'), so n_dogs is null.
Heartgard® Plus NADA 140-971, Supplemental approval, October 03, 1996; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 543; FDA PDF
Indication
Supplement adds treatment and control of adult hookworms Ancylostoma braziliense to the existing heartworm prevention and intestinal nematode indications.
Dose regimen
minimum 6 mcg ivermectin/kg (2.72 mcg/lb) and 5 mg pyrantel/kg (2.27 mg/lb), oral (meat-based chewable tablet), once monthly, during the mosquito season
HEARTGARD™ Plus is admin istered once monthly and provides a minimum of 6 mcg ivermectin per kg of body weight (2.72 mcg/lb) and a minimum of 5 mg pyrantel per kg of body weight (2.27 mg/lb) when given as follows:
Effectiveness
Two dose-confirmation studies with induced A. braziliense infection (ASR 14326: 18 beagles, 9 per group; ASR 14543: 16 beagles, 8 per group), untreated controls, single label dose, necropsy Day 7; supported by five original field trials (20 hookworm-positive dogs) and three supportive field trials (82 positive dogs, average efficacy 92%).; primary endpoint: Adult A. braziliense worm counts at necropsy (geometric means); result: 99.97% efficacy in ASR 14326 (one treated dog had one worm) and 100% in ASR 14543; p<0.001 in both; 100% in the five original field trials.
All nine control dogs had A. braziliense worms (geometric mean = 275.4 worms; range = 104 to 384). One dog treated with HEARTGARD™ Plus had one female A. braziliense. The efficacy of HEARTGARD™ Plus was calculated as 99.97% relative to the control group geometric mean. The difference between treatment groups was highly significant (p<0.001, by a t-test for means with equal variances).
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| vomiting of the chewable (ASR 14543; re-administered, not recurring) | Three dogs vomited the chewable or a portion thereof, and in each case, the chewable that had been vomited was re-administered. | ||
| diarrhea within 24 hours of dosing (supportive field trials) | 15 reported cases | There were 15 reported cases of diarrhea and 8 reported cases of vomiting which occurred within 24 hours of tablet administration. | |
| vomiting within 24 hours of dosing (supportive field trials) | 8 reported cases | There were 15 reported cases of diarrhea and 8 reported cases of vomiting which occurred within 24 hours of tablet administration. |
Extraction notes: Supplemental approval; no new target animal safety data (refers to original NADA 140-971). Dose quote contains the extraction typo 'admin istered'. Study animal numbers are spelled out in the text, so n_dogs is null and counts appear in 'design'. Field-trial denominators for the adverse-reaction counts are not stated.
Reproduce: foi_structured_search(query="Ivermectin, Pyrantel Pamoate") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).