Febantel, Praziquantel, Pyrantel Pamoate: what the FDA reviewed for dog products

Drontal™ Plus Drontal™ Plus Taste Tabs™ Quad Dewormer NADA 141-007, Supplemental approval, February 10, 2003; sponsor Elanco US Inc.; species: Canine; foi_id 556; FDA PDF

Indication

Removal of tapeworms (Dipylidium caninum, Taenia pisiformis, Echinococcus granulosus; removal and control of Echinococcus multilocularis), hookworms (Ancylostoma caninum, Uncinaria stenocephala), ascarids (Toxocara canis, Toxascaris leonina) and whipworms (Trichuris vulpis) in dogs

Dose regimen

Large-dog tablet: 1.0 tablet (45-60 lb), 1.5 tablets (61-90 lb), 2.0 tablets (91-120 lb), Oral (directly by mouth or in a small amount of food), Single treatment, Fasting is neither necessary nor recommended before or after treatment

Body Weight (lbs.) Number of Tablets 45-60 1.0 61-90 1.5 91-120 2.0 Tablets may be given directly by mouth or offered in a small amount of food.

Extraction notes: Supplemental NADA (February 10, 2003; Category II) adding a large-dog tablet (136.0 mg praziquantel, 136.0 mg pyrantel base as pyrantel pamoate, 680.4 mg febantel). No new effectiveness or target animal safety data were required (minimum and maximum doses unchanged); approval based on manufacturing, labeling, dissolution and stability. Dose is given only as tablets per body-weight band for the new tablet; the mg/kg label dose is not stated in this summary. The product name in the text carries an unprintable character after 'Drontal', so the indication quote starts at 'Plus Tablets'. Validator warning expected.

Drontal™ Plus Drontal™ Plus Taste Tabs™ Quad Dewormer NADA 141-007, Supplemental approval, January 12, 2006; sponsor Elanco US Inc.; species: Canine; foi_id 557; FDA PDF

Indication

Removal of tapeworms (Dipylidium caninum, Taenia pisiformis, Echinococcus granulosus; removal and control of Echinococcus multilocularis), hookworms (Ancylostoma caninum, Uncinaria stenocephala), ascarids (Toxocara canis, Toxascaris leonina) and whipworms (Trichuris vulpis) in dogs

Dose regimen

Minimum 5.0 mg/kg each of praziquantel and pyrantel base and at least 25 mg/kg febantel (tablet chart by body weight), Oral (offered by hand, given directly by mouth, or in a small amount of food), Single treatment, Confirm parasites by fecal examination and weigh before treatment; fasting neither necessary nor recommended; not for puppies under 3 weeks of age or dogs under 2 lbs

The tablet sizes and dosage table are designed to provide a minimum of 5.0 mg/kg (2.27 mg/lb) each of praziquantel and pyrantel base, and at least 25 mg /kg (11.35 mg/lb) febantel.

Effectiveness

Well-controlled laboratory anthelmintic study (Study No. 151.657) in 20 purpose-bred beagle puppies (2-2.5 months) experimentally infected with Ancylostoma caninum and Uncinaria stenocephala, randomized by sex and body weight to a single labeled oral dose of Drontal Plus Taste Tabs (10 dogs) or untreated control (10 dogs); necropsy worm recovery on day 7; n = 10 treated, 10 untreated control; primary endpoint: Percent effectiveness = reduction in geometric mean hookworm count per dog at necropsy vs untreated controls; result: 100% effectiveness against A. caninum and 99.4% against U. stenocephala (upper intestinal tract). Three pooled natural Trichuris vulpis studies (60 dogs, 30 treated/30 untreated): 90% effectiveness (85.74%, 91.57%, 91.50% by study). Palatability field study: 133 of 149 client-owned dogs accepted the tablets (89.3%)

At necropsy adult A. caninum and U. stenocephala were recovered from all 10 control dogs. (A. caninum = 8 - 24 worms/dog, geometric mean = 16.60 worms/dog; U. stenocephala = 8 -16 worms/dog, geometric mean = 13.02 worms/dog). By contrast no A. caninum and only one U. stenocephala were recovered at necropsy from the 10 dogs treated with DRONTAL Plus TASTE TABS (geometric mean A. caninum and U. stenocephala counts of 0.0 and 0.07 worms/dog, respectively). Anthelmintic effectiveness of DRONTAL Plus TASTE TABS against A. caninum and U. stenocephala was 100 and 99.4%, respectively.

Adverse reactions

Extraction notes: Supplemental NADA (January 12, 2006) adding a flavored chewable formulation with the same actives and indications; qualified for 3 years of exclusivity on four laboratory studies. No new target animal safety data were required (same amounts of active ingredients as the approved unflavored tablets), so target_animal_safety is null. Effectiveness entry is the hookworm confirmation study; the pooled whipworm studies and palatability field study are summarized in the result text. Adverse reaction counts are given in words ('One dog'), so treated/control are left null.

Drontal™ Plus Drontal™ Plus Taste Tabs™ Quad Dewormer NADA 141-007, Supplemental approval, March 28, 1996; sponsor Elanco US Inc.; species: Dogs; foi_id 2505; FDA PDF

Indication

Removal of tapeworms (Dipylidium caninum, Taenia pisiformis, Echinococcus granulosus, Echinococcus multilocularis), hookworms, ascarids and whipworms in dogs; this supplement adds the E. multilocularis claim.

Dose regimen

Small dogs (2-25 lbs.): 0.5 to 2.5 tablets by body weight chart; separate chart for medium and large dogs, Oral (tablets given directly by mouth or offered in a small amount of food), Single treatment per dosage chart, Small-dog tablet contains 22.7 mg praziquantel, 22.7 mg pyrantel base and 113.4 mg febantel (medium/large tablet 68.0/68.0/340.2 mg); not for use in dogs weighing less than 2 lbs or puppies less than 3 weeks of age; fasting neither necessary nor recommended

Table 1. Drontal(TM) Plus Tablets for Small Dogs*(2-25 lbs.) Body Wt. (lbs.) Number of Tablets 2 - 4 0.5 5 - 7 1.0 8 - 12 1.5 13 - 18 2.0 19 - 25 2.5

Effectiveness

No new studies; the E. multilocularis claim is extrapolated from laboratory data in the Droncit (praziquantel) FOI Summary (NADA 111-798) plus the absence of interference from pyrantel/febantel shown in the original Drontal Plus approval; result: Droncit reported 100% efficacious against E. granulosus and E. multilocularis; praziquantel in Drontal Plus concluded to be as efficacious as Droncit against E. multilocularis

The laboratory data described in the FOI Summary of NADA 111-798 indicate that Droncit (praziquantel) Tablets [NADA 111-798, 58 FR 42852-3, Aug. 12, 1993] is 100% efficacious against both E. granulosus and E. multilocularis.

Extraction notes: Supplemental approval (1996) adding Echinococcus multilocularis to the label. Contains no new animal studies: effectiveness is argued by cross-reference to NADA 111-798 (Droncit), and target animal safety and human safety are cross-referenced to the original 1994 Drontal Plus FOI Summary (foi_id 3619). Dose is expressed only as body-weight tablet charts (Table 1 small dogs quoted; Table 2 medium/large dogs 26-120 lbs, 1.0-4.0 tablets, not quoted). No PK or adverse-reaction data in this summary.

Drontal™ Plus Drontal™ Plus Taste Tabs™ Quad Dewormer NADA 141-007, Original approval, May 19, 1994; sponsor Elanco US Inc.; species: Dogs; foi_id 3619; FDA PDF

Indication

Removal of tapeworms (Dipylidium caninum, Taenia pisiformis, Echinococcus granulosus), hookworms (Ancylostoma caninum, Uncinaria stenocephala), ascarids (Toxocara canis, Toxascaris leonina) and whipworms (Trichuris vulpis) in dogs.

Dose regimen

5 mg/kg (2.27 mg/lb) each of praziquantel and pyrantel base + 25 mg/kg (11.35 mg/lb) febantel, Oral (directly by mouth or offered in the food), Single dosage, Two tablet sizes dosed by body-weight chart; not for use in dogs weighing less than 2 lbs or puppies less than 3 weeks of age

Drontal Plus Tablets: 5 mg/kg (2.27 mg/lb) of praziquantel and pyrantel base + 25 mg/kg (11.35 mg/lb) febantel (The formulation to be marketed)

Target-animal safety

dose multiples 1X, 3X, 5X; duration 3 consecutive days (3 times the labeled single-dose duration); animals 14.

M. Kohlenberg also conducted a general safety study in 14 dogs using the 68.0/68.0/340.2 mg tablet. Two of the dogs, Group 1, were nontreated controls. Groups II, III and IV (4 animals/group) received 1, 3 and 5 times the recommend use rate, respectively, for 3 consecutive days (3 times the duration of treatment).

Effectiveness

Pivotal clinical trial at five U.S. veterinary clinics in naturally infected dogs (each animal its own control; tapeworm clearance checked on Days 5-7 and nematode egg count reduction at 7-10 days), supported by four blinded, placebo-controlled laboratory necropsy studies in 176 dogs (Studies 1-4); n = 103; primary endpoint: Post-treatment percent reduction of mean egg counts and percent of cases cleared to zero (clinical trial); controlled percent efficacy from worm counts at necropsy 7 days after treatment (laboratory studies); result: Clinical trial (Table 7): T. vulpis 94.5% egg reduction (98 infections), T. pisiformis and D. caninum 100%, A. caninum 97.2%, T. canis 89.5%. Laboratory: combined Studies 1 and 4 gave 94.0% T. vulpis removal vs 0% for praziquantel+pyrantel; 99.6-100% A. caninum, 99.8% U. stenocephala, 97.81% T. leonina, 100% T. pisiformis

The investigators treated a total of 103 purebred and mixed-breed dogs (48 males and 55 females) with Drontal Plus Tablets. No side effects following treatment (excellent rating) were reported for any of the 103 cases.

Adverse reactions

Extraction notes: Original approval (1994). Effectiveness rests on four laboratory studies (176 dogs) plus a 103-dog clinical trial; the clinical trial quote is used because it states n. Efficacy tables were flattened by PDF extraction (percentages and dog counts on separate lines), so per-parasite figures are given in the result field rather than quoted. Target animal safety: the margin-of-safety study is the 14-dog General Safety Evaluation (1X/3X/5X for 3 days); a 3-dog 10X single-dose tolerance test and several corroborative praziquantel/pyrantel and puppy tolerance studies are also described. Adverse-reaction counts use treated=null where the figure is not a digit in the quote (e.g. 'any of the 103 cases'). No PK data.