Ivermectin, Praziquantel, Pyrantel Pamoate: what the FDA reviewed for dog products
3 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Ivermectin, Praziquantel, 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
- IVERHART MAX® (NADA/ANADA 141-257)
- IVERHART MAX® Chew (NADA/ANADA 141-441)
IVERHART MAX® Chew NADA 141-441, Original approval, December 11, 2017; sponsor Virbac AH, Inc.; species: Dogs; foi_id 2901; FDA PDF
Indication
Prevention of canine heartworm disease (eliminates D. immitis tissue larvae for 30 days after infection) and treatment and control of roundworms (T. canis, T. leonina), hookworms (A. caninum, U. stenocephala, A. braziliense) and tapeworms (D. caninum, T. pisiformis).
Dose regimen
minimum 6 mcg ivermectin/kg (2.72 mcg/lb), 5 mg pyrantel (as pamoate)/kg (2.27 mg/lb) and 5 mg praziquantel/kg (2.27 mg/lb), oral (soft chew), monthly, dogs 8 weeks of age or older; Toy/Small/Medium/Large chews for 6-12, 12.1-25, 25.1-50 and 50.1-100 lb
IVERHART MAX® Soft Chew should be administered orally at monthly intervals at the recommended minimum dose level of 6 mcg of ivermectin per kilogram (2.72 mcg/lb), 5 mg of pyrantel (as pamoate salt) per kg (2.27 mg/lb) and 5 mg of praziquantel per kg (2.27 mg/lb) of body weight, as follows:
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| auc | 7.2 ng*hour/mL (SD 2.1; range 1.1-12.8), ivermectin, Chewable Tablet medium (reference) | bioequivalence Study 963-008: 60 healthy male Beagles (8.4-10.9 kg), three-period crossover, single oral dose, dose- and body-weight-corrected arithmetic mean; table columns: parameter, treatment, N, mean, SD, min, max | AUC0-Last, ng*hour/mL Chewable tablet, medium 60 7.2 2.1 1.1 12.8 |
| auc | 9.5 ng*hour/mL (SD 2.1; range 2.2-13.8), ivermectin, Soft Chew medium | bioequivalence Study 963-008: 60 healthy male Beagles (8.4-10.9 kg), three-period crossover, single oral dose, dose- and body-weight-corrected arithmetic mean; table columns: parameter, treatment, N, mean, SD, min, max | AUC0-Last, ng*hour/mL Soft chew, medium 60 9.5 2.1 2.2 13.8 |
| cmax | 0.5 ng/mL (SD 0.2; range 0.1-1.1), ivermectin, Chewable Tablet medium (reference) | bioequivalence Study 963-008: 60 healthy male Beagles (8.4-10.9 kg), three-period crossover, single oral dose, dose- and body-weight-corrected arithmetic mean; table columns: parameter, treatment, N, mean, SD, min, max | Cmax, ng/mL Chewable tablet, medium 60 0.5 0.2 0.1 1.1 |
| cmax | 0.7 ng/mL (SD 0.2; range 0.1-1.1), ivermectin, Soft Chew medium | bioequivalence Study 963-008: 60 healthy male Beagles (8.4-10.9 kg), three-period crossover, single oral dose, dose- and body-weight-corrected arithmetic mean; table columns: parameter, treatment, N, mean, SD, min, max | Cmax, ng/mL Soft chew, medium 60 0.7 0.2 0.1 1.1 |
| tmax | 2.7 hours (SD 0.7; range 1.5-4.0), ivermectin, Chewable Tablet medium (reference) | bioequivalence Study 963-008: 60 healthy male Beagles (8.4-10.9 kg), three-period crossover, single oral dose, dose- and body-weight-corrected arithmetic mean; table columns: parameter, treatment, N, mean, SD, min, max | Tmax, hours Chewable tablet, medium 60 2.7 0.7 1.5 4.0 |
| tmax | 3.4 hours (SD 1.0; range 1.5-6.0), ivermectin, Soft Chew medium | bioequivalence Study 963-008: 60 healthy male Beagles (8.4-10.9 kg), three-period crossover, single oral dose, dose- and body-weight-corrected arithmetic mean; table columns: parameter, treatment, N, mean, SD, min, max | Tmax, hours Soft chew, medium 60 3.4 1.0 1.5 6.0 |
| bioavailability | ivermectin test/reference ratios AUC0-Last 1.35 and Cmax 1.33 (Soft Chew medium vs Chewable Tablet medium, not bioequivalent; about 35% more bioavailable) | Study 963-008, 60 male Beagles, crossover; 90% CI acceptance range 0.80-1.25 | The IVERHART MAX® Soft Chew, medium size was not bioequivalent to IVERHART MAX® Chewable Tablets, medium size (ratios of test/reference AUC0-Last and Cmax were 1.35 and 1.33, respectively). Based on the AUC0-Last ratio, ivermectin was approximately 35% more bioavailable in the IVERHART MAX® Soft Chew, medium size. |
| cmax | praziquantel test/reference Cmax ratio 2.30 with mean Tmax 1.1 hours (Soft Chew toy) vs 1.7 hours (Chewable Tablet medium); AUC0-Last ratio 1.04 (bioequivalent in extent) | Study 963-008, 60 male Beagles, crossover, dose-corrected praziquantel | The IVERHART MAX® Soft Chew, toy size was bioequivalent to the IVERHART MAX® Chewable Tablets, medium size in extent of absorption (ratio of test/reference AUC0-Last 1.04), but had a faster rate of absorption (ratio of test/reference Cmax 2.30, mean Tmax 1.1 hours for IVERHART MAX® Soft Chew, toy size versus 1.7 hours for IVERHART MAX® Chewable Tablets, medium size). |
Target-animal safety
dose multiples 1X (label dose, field study); duration three monthly doses; animals 132 client-owned dogs.
Three doses, one month apart, were administered orally to 132 client-owned dogs in an open-label, field study conducted at five veterinary clinics. The study did not include a control group.
| Finding | Quote |
|---|---|
| Self-limiting adverse reactions: vomiting, diarrhea, lethargy, difficulty swallowing, excessive salivation, increased water consumption, coughing. | Self-limiting adverse reactions included vomiting, diarrhea, lethargy, difficulty swallowing, excessive salivation, increased water consumption, and coughing. |
| Conclusion: well accepted and safe; supports safety of the higher ivermectin and praziquantel bioavailability of the soft chew at the label dose. | In this field study, IVERHART MAX® Soft Chew was shown to be a well-accepted and a safe oral dosage form for dogs. This study supports the safety of the increased bioavailability of ivermectin and praziquantel in the IVERHART MAX® Soft Chew when administered at the labeled dose. |
Effectiveness
Laboratory dose-confirmation study with experimental T. canis infection (300 embryonated eggs Day -49) in 16 mixed-breed dogs: IVERHART MAX Soft Chew once on Day 0 (n=8) vs untreated control (n=8), necropsy worm counts Day 7; a second study with natural T. canis infection (20 dogs, 10/10) gave 94.6%. Heartworm and tapeworm claims bridged to NADA 141-257 by the bioequivalence study.; primary endpoint: Post-treatment adult T. canis worm count reduction (geometric means) vs control; result: 98.4% effectiveness against experimental T. canis (control GM 11.8 vs 0.2 treated; p<0.0001); 94.6% against natural infection (GM 6.9 vs 0.37).
The IVERHART MAX® Soft Chew treated groups demonstrated a significant reduction (p < 0.0001) in the number of T. canis adults when compared to the control group. Dogs in the control group had a geometric mean adult worm count of 11.8 compared to 0.2 in the IVERHART MAX® Soft Chew treatment group. The combination product demonstrated 98.4% post-treatment effectiveness against T. canis.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| vomiting, diarrhea, lethargy, difficulty swallowing, excessive salivation, increased water consumption, coughing (field study; self-limiting; no counts given) | Self-limiting adverse reactions included vomiting, diarrhea, lethargy, difficulty swallowing, excessive salivation, increased water consumption, and coughing. |
Extraction notes: Margin-of-safety studies are referenced to NADA 141-257 (IVERHART MAX Chewable Tablets); this summary's target_animal_safety block is the uncontrolled label-dose field safety/palatability study (389 dosing attempts: 336 voluntarily accepted (86.3%), 50 with enticement or pilled (13.0%), 3 not accepted). PK table rows (Tables 3-4) were flattened; quotes are the extracted rows and column order is given in 'conditions'. Praziquantel absolute values (e.g. AUC 424.5 vs 531.6 ng*hour/mL, Cmax 104.1 vs 177.0 ng/mL for tablet vs soft chew medium) are in Table 4 but not itemized here. The T. canis study n (sixteen) is spelled out, so n_dogs is null.
IVERHART MAX® NADA 141-257, Supplemental approval, February 15, 2007; sponsor Virbac AH, Inc.; species: Dogs; foi_id 810; FDA PDF
Indication
Supplement removes the label precaution that tapeworm effectiveness had not been evaluated in dogs under 15 pounds; indications unchanged (heartworm prevention; roundworms, hookworms, tapeworms).
Dose regimen
5 mg/kg praziquantel minimum, oral (chewable tablet), once monthly, given with 6 mcg/kg ivermectin and 5 mg/kg pyrantel pamoate (unchanged); dogs weighing less than 15 pounds now covered for tapeworms
The minimum dose of 5 mg/kg praziquantel for dogs weighing 25 pounds or greater is supported by published literature1,2. The minimum dose of 5 mg/kg praziquantel for smaller dogs is supported by the laboratory effectiveness and dose confirmation study listed under Substantial Evidence.
Effectiveness
Laboratory dose-confirmation study (ClinVet, South Africa) in 16 naturally D. caninum-infected dogs of various breeds weighing 5.61-11.77 lb: placebo (n=8) vs ivermectin 6 mcg/kg + pyrantel pamoate 5 mg/kg + praziquantel 5 mg/kg (n=8), single oral dose Day 0, necropsy worm counts Day 14.; n = 8 per group; primary endpoint: D. caninum worm counts at necropsy (geometric means); result: 100% effectiveness (control GM 10.27; 0 tapeworms in all treated dogs; statistically significant).
Study results: Group 1: 8 dogs with D. caninum GM = 10.27 (range: 1- 164) Group 2: 0 dogs with tapeworms GM = 0 Group 2 Vs. Group 1* - Effectiveness: 100%
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| isolated diarrhea episodes up to 7 days after treatment (7 dogs; four in the treated group; diarrhea also present pre-treatment) | four (treated group) | and 7 dogs (four from the treated group) had isolated episodes of diarrhea up to 7 days after treatment. | |
| death (canine distemper, not treatment related) | Following a post- mortem examination on Day 10, a diagnosis of canine distemper virus infection was made. |
Extraction notes: Supplemental approval; CVM did not require target animal safety studies (refers to the October 13, 2006 original FOI summary). The product name appears as 'IVERHEART MAX' throughout this summary. Extraction broke several words (e.g. 'iverme ctin', 'treatm ent'), so quotes avoid those spans.
IVERHART MAX® NADA 141-257, Original approval, October 13, 2006; sponsor Virbac AH, Inc.; species: Canine; foi_id 809; FDA PDF
Indication
Prevention of canine heartworm disease (eliminates D. immitis tissue larvae for 30 days after infection) and treatment and control of roundworms (T. canis, T. leonina), hookworms (A. caninum, U. stenocephala, A. braziliense) and tapeworms (D. caninum, T. pisiformis).
Dose regimen
minimum 6 mcg/kg ivermectin, 5 mg/kg pyrantel (as pamoate) and 5 mg/kg praziquantel, oral (chewable tablet), once monthly, Toy/Small/Medium/Large tablets (34/68/136/272 mcg ivermectin) for dogs 6-12, 12.1-25, 25.1-50 and 50.1-100 lb
The minimum dosage of 6 mcg/kg ivermectin and 5 mg/kg pyrantel (as pamoate) in dogs weighing 6 lbs or greater is supported by data contained in Virbac’s ANADA 200-302 for IVERHART PLUS (ivermectin/pyrantel pamoate) Flavored Tablets. The dosage of 5 mg/kg praziquantel for dogs 15 pounds or greater is supported by
Target-animal safety
dose multiples 0X, 1X, 3X, 5X; duration every 30 days for 6 consecutive treatments (Days 1, 31, 61, 91, 121, 151); necropsy Days 182-183; animals Thirty-two Beagles (4 dogs per sex per treatment).
Test Animals: Thirty-two (4 dogs per sex per treatment) healthy Beagle dogs (8 weeks of age at the first treatment and weighing 1.48 to 2.46 kg at randomization).
| Finding | Quote |
|---|---|
| Dose-dependent vomiting after dosing; 49 episodes in the 5X group. | Vomiting was observed in dogs after treatment. Animals at 5X had the highest incidence of vomiting with 49 separate occurrences in both sexes during the course of the study. There was a dose dependent increase in vomiting episodes. |
| Dose-related increase in soft or watery feces (37, 48, 69 and 90 observations in control, 1X, 3X and 5X). | The occurrence of soft feces suggests a dose-related effect (37 observations in the control group, 48 observations in the 1X group, 69 observations in the 3X group and 90 observations in the 5X group). |
| No test-article effects on hematology, clinical chemistry or urinalysis at any dose. | There were no test article-related adverse effects apparent on hematology, chemistry or urinary parameters at any dose level. |
| Testicular hypoplasia in one 3X dog (bilateral, moderate) and one 5X dog (unilateral, minimal). | Testicular hypoplasia was seen in two dogs, one each in the 3X and 5X group. |
| 90-day weekly study (#813-002) in 12-week-old puppies: lower testicular weights at 3X and 5X, delayed testicular maturation and higher cholesterol at all doses. | Lower testicular weights compared to controls were seen at 3X and 5X. There is a test article-related effect in the rate and/or degree of maturation of the testes. Hypercholesterolemia was significantly higher for all dose groups compared to control at 2 and 3 months. |
| Adult male reproductive study at 3X every 14 days for 119 days: no clinically significant differences in semen parameters. | No clinically significant differences were shown between groups for the following variables: total sperm count, percent normal motility, percent progressive motility, spermatozoa progression (speed), percent normal sperm, sperm morphology, semen volume, semen cytology, and pH. |
| Other transient signs: anogenital swelling, lethargy, tremors (one 5X dog), head movements, shallow breathing, salivation. | The incidence rate is low in dogs receiving the 1X dose and increases with dosage. Testicular hypoplasia was seen in the 3X and 5X groups. |
Effectiveness
Laboratory non-interference/dose-confirmation study for heartworm prevention: 12 male and 12 female parasite-naive Beagles (4-7 months) inoculated with D. immitis larvae, treated orally 30 days later (Day 0) with placebo, praziquantel 5 mg/kg, or ivermectin 6 mcg/kg + pyrantel 5 mg/kg + praziquantel 5 mg/kg (8 per group), necropsy Day 119; supported by two T. canis studies (83.5% and 95.8%), two D. caninum studies (100%) and two T. pisiformis studies (100%).; n = 8 per group (Groups 1-3); primary endpoint: Adult heartworm counts at necropsy (geometric means, Wilcoxon rank sum test); result: 100% effectiveness of the three-way combination vs both placebo and praziquantel-alone groups (all 8 dogs in each control group infected, GM 37.60 and 37.70; 0 in treated).
Study results: Group 1: 8 dogs with heartworms GM=37.60 (range: 32-42) Group 2: 8 dogs with heartworms GM=37.70 (range: 28-45) Group 3: 0 dogs with heartworms GM=0.00 Group 3 vs. Group 1: 100% effectiveness Group 3 vs. Group 2: 100% effectiveness
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| vomiting episodes, 6-month TAS study (row order: group, total vomiting episodes, total soft-feces episodes) | 49 episodes (5X); 3 (1X); 21 (3X) | 2 episodes | Control 2 37 1X 3 48 3X 21 69 5X 49 90 |
| soft feces episodes, 6-month TAS study (same table row order) | 90 episodes (5X); 48 (1X); 69 (3X) | 37 episodes | Control 2 37 1X 3 48 3X 21 69 5X 49 90 |
| adverse drug reactions in field palatability study (decreased appetite, diarrhea, lethargy, licking lips/belching, salivation/limpness), 20 min to 72 h post dose | five dogs (of 44 enrolled) | Safety: Forty-two of the 44 cases were interpretable for complete safety assessments. Adverse drug reactions occurred in five dogs during the study between 20 minutes and 72 hours post treatment. | |
| death from dehydration/diarrhea in a heavily parasitized puppy (T. canis Study 2, treated group) | Adverse reactions: One dog died (group 2) on Day 6 because of dehydration associated with diarrhea. |
Extraction notes: No PK data in this summary. Margin-of-safety multiples are of the maximum label dose (12.5 mcg/kg ivermectin, 10.47 mg/kg pyrantel pamoate, 10.47 mg/kg praziquantel). The TAS design quote animal count is spelled out ('Thirty-two'); the numeric grounding is '4 dogs per sex per treatment'. The seventh TAS finding's quote is the study conclusion sentence; the list of other transient signs is in the text but split across broken lines. Table 3.3 rows were flattened by extraction and are quoted as extracted (column order given in 'term'). Field palatability was 70% (66/95 trials, 32 evaluable dogs); the most significant reactions occurred in the three smallest dogs (<10 lb).
Reproduce: foi_structured_search(query="Ivermectin, Praziquantel, Pyrantel Pamoate") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).