Ivermectin: what the FDA reviewed for dog products

Ivomec® .27% Injection Grower And Feeder Pigs Ivomec® 1% Injection Ivomec® 1% Injection for Cattle And Swine Ivomec® Injection for Cattle NADA 128-409, Supplemental approval, April 01, 1999; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Cattle; foi_id 387; FDA PDF

Indication

Supplement extends the persistent activity claim against Dictyocaulus viviparus (lungworm) in cattle from 21 to 28 days after treatment; base indications are treatment and control of gastrointestinal roundworms, lungworms, grubs, sucking lice and mange mites in cattle.

Dose regimen

200 mcg ivermectin/kg body weight (1 mL/110 lb body weight), subcutaneous injection, single treatment, 10 mg ivermectin/mL sterile solution

IVOMEC Injection should be administered by subcutaneous injection. C. Approved Dose: 200 mcg ivermectin/kg body weight (1 mL/110 lb body weight)

Effectiveness

Two dose-confirmation trials (ASR 15065: 30 Holstein calves, 10/group; ASR 15100: 20 Holstein calves, 10/group) with vehicle-injected controls; D. viviparus larvae given daily for 28 days starting the day after a single SC dose of 200 mcg/kg; worm counts at necropsy 49-50 days after treatment.; primary endpoint: Arithmetic mean D. viviparus worm counts at necropsy (percent efficacy vs controls); result: 100% efficacy in both trials (control arithmetic mean counts 20.3 and 14.7 vs 0.0 in IVOMEC-treated calves); persistent efficacy for 28 days established.

Data from the following dose confirmation trials demonstrate that IVOMEC Injection for Cattle given at the recommended dosage controls infection and protects against reinfection with Dictyocaulus viviparus for 28 days after treatment.

Adverse reactions

Extraction notes: Cattle summary filed under a dog-subset application list; species recorded as stated. In the extracted text the registered-trademark glyph after IVOMEC is a private-use character (U+F6DA), which is reproduced verbatim in the dose and effectiveness quotes. Supplemental approval: effectiveness and animal safety of previously approved indications refer to the parent NADA 128-409 FOI summaries (1984, 1997); no target animal safety or PK data in this summary. Also assigns a 10 ppb ivermectin B1a muscle tolerance (human food safety). Efficacy table values (20.3 / 14.7 control means) quoted from flattened Tables 4.1 and 4.2. n_dogs left null because the study animals are calves.

Ivomec® .27% Injection Grower And Feeder Pigs Ivomec® 1% Injection Ivomec® 1% Injection for Cattle And Swine Ivomec® Injection for Cattle NADA 128-409, Supplemental approval, August 16, 2004; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Cattle, Swine, Reindeer, American Bison; foi_id 388; FDA PDF

Indication

Supplement extends the persistent effect periods in cattle for Oesophagostomum radiatum from 14 to 28 days and for Cooperia punctata and Trichostrongylus axei from 14 to 21 days after treatment (plus labeling revisions for environmental information and a veal calf warning).

Dose regimen

200 mcg ivermectin/kg body weight (1 mL per 50 kg / 110 lb), subcutaneous, single treatment, cattle only for this supplement; 10 mg (1%) ivermectin/mL

i. Route of Administration: Subcutaneous j. Species/Class: Cattle, Swine, Reindeer, American Bison. This supplemental approval only affects cattle. k. Recommended Dosage: Cattle: 1 mL for each 50 kg (110 lb) or 200 mcg ivermectin of body weight per kg

Effectiveness

Re-evaluation using geometric means (VICH GL7) of three previously submitted dose-confirmation studies in Holstein calves with induced infections (ASR 15065, 15110, 15111; 30 calves each, 10 per group, untreated negative controls), single SC dose of 200 mcg/kg, necropsy worm counts 49-50 days after treatment.; primary endpoint: Percent efficacy from geometric mean worm counts at the 21-day (C. punctata, T. axei) and 28-day (O. radiatum) persistent-effect periods; result: Average efficacy across three studies at 21 days: T. axei 93%, C. punctata 90%; O. radiatum >90% in both 28-day studies (individual study efficacies 75-99%).

The overall percent efficacies from three studies for Trichostrongylus axei and Cooperia punctata at 21 days are 93% and 90%, respectively. Two studies at 28 days for Oesophagostomum radiatum both demonstrated percent efficacy >90%.

Adverse reactions

Extraction notes: Species/Class as stated in the summary lists four species, but this supplemental approval only affects cattle and all studies are in calves. No new target animal safety, PK or human safety data (refers to parent NADA 128-409, 1984). Per-study efficacies from flattened Tables 2.1-2.3: ASR 15065 C. punctata 98, T. axei 98; ASR 15110 C. punctata 75, T. axei 81, O. radiatum 91; ASR 15111 C. punctata 99, T. axei 99, O. radiatum 99.

Ivomec® .27% Injection Grower And Feeder Pigs Ivomec® 1% Injection Ivomec® 1% Injection for Cattle And Swine Ivomec® Injection for Cattle NADA 128-409, Supplemental approval, December 19, 1997; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: American bison; foi_id 1627; FDA PDF

Indication

New claim for the treatment and control of grubs (Hypoderma bovis) in American bison (added to existing cattle, swine and reindeer indications).

Dose regimen

200 mcg ivermectin/kg body weight (1 mL/110 lb body weight), subcutaneous injection, single treatment, sterile 1% solution

Dosage Regimen G. 200 g ivermectin/kg body weight (1 mL/110 lb body weight) Route of Administration H. IVOMEC Injection should be administered by subcutaneous injection.

Target-animal safety

dose multiples 5X.

Target animal safety data from PMF 5059, 61 FR 4442, February 6, 1996, demonstrated that based on clinical observation and evaluation of hematology, serum chemistry, and gross pathology, American bison treated with ivermectin at a dosage of 1000 g/kg body weight (5X the optimal dose) were not adversely affected by the elevated level of the drug.

Effectiveness

Effectiveness supported by data in Public Master File 5059 (Michigan State University); no study details given in the summary.; result: Ivermectin injection at 200 mcg/kg SC was efficacious in treating and controlling Hypoderma bovis grubs in American bison.

Effectiveness data from PMF 5059, 61 FR 4442, February 6, 1996, demonstrated that ivermectin injection, when administered subcutaneously at a dose of 200 g/kg body weight, was efficacious in treating and controlling grubs (Hypoderma bovis) in American bison.

Extraction notes: American bison summary (not dogs). The micro sign was lost in PDF extraction: the text reads '200 g ivermectin/kg' and '1000 g/kg' where the label means 200 mcg/kg and 1000 mcg/kg; quotes are verbatim as extracted. No animal numbers, study duration or PK are given; all data come from PMF 5059. A 56-day withdrawal period was assigned for bison.

Ivomec® .27% Injection Grower And Feeder Pigs Ivomec® 1% Injection Ivomec® 1% Injection for Cattle And Swine Ivomec® Injection for Cattle NADA 128-409, Supplemental approval, February 24, 1997; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Cattle; foi_id 3606; FDA PDF

Indication

New persistent-control claims in cattle: control of Dictyocaulus viviparus and Ostertagia ostertagi infections for 21 days after treatment and of Oesophagostomum radiatum, Haemonchus placei, Trichostrongylus axei, Cooperia punctata and Cooperia oncophora for 14 days after treatment.

Dose regimen

200 mcg ivermectin/kg body weight (1 mL/50 kg), subcutaneous injection, once, 10 mg ivermectin per mL injectable solution

f. Route of administration: Subcutaneous injection g. Dose: 1 mL/50 kg body weight (200 mcg ivermectin/kg body weight) once.

Effectiveness

Five dose-confirmation trials in calves with induced infections (ASR 14553: 28 crossbred calves, 7/group; ASR 15065, 15071, 15073: 30 calves each, 10/group; ASR 13980: 35 Holstein calves, 7/group), untreated or vehicle-injected negative controls, single SC dose of 200 mcg/kg, infective larvae given daily after treatment, worm counts at necropsy 42-51 days after treatment.; primary endpoint: Percent reduction in arithmetic mean worm counts vs controls for parasites with at least six adequately infected controls; result: Percent reductions of 93.5-100% across parasites and trials (e.g., ASR 14553: O. ostertagi 100, H. placei 96.0, T. axei 99.7, C. punctata 100, C. oncophora 100, O. radiatum 98.8; ASR 15065: D. viviparus 100, O. ostertagi 93.5), supporting the 21-day and 14-day persistent-control claims.

Data from the following dose confirmation trials demonstrate that IVOMEC Injection for Cattle given at the recommended dosage controls infections of Dictyocaulus viviparus and Ostertagia ostertagi for 21 days after treatment, and Oesophagostomum radiatum, Haemonchus placei, Trichostrongylus axei, Cooperia punctata, and Cooperia oncophora for 14 days after treatment.

Adverse reactions

Extraction notes: Cattle summary. No target animal safety, PK or human food safety data in this supplement (refers to parent NADA 128-409, 1984, and the 1994 supplement). Result tables were flattened by PDF extraction (columns: parasite, control arithmetic mean, IVOMEC arithmetic mean, percent reduction); values in 'result' were read from those rows. The dose quote is taken from trial ASR 14553 (identical dosing in all five trials).

Heartgard® Chewables For Dogs NADA 140-886, Original approval, July 03, 1989; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 3669; FDA PDF

Indication

Prevention of canine heartworm disease by eliminating the tissue stage of Dirofilaria immitis larvae up to a month after infection.

Dose regimen

6.0 mcg ivermectin/kg (2.72 mcg/lb) minimum, oral (meat-based chewable), monthly, during the mosquito season; 68/136/272 mcg chewables for dogs up to 25 lb, 26-50 lb and 51-100 lb

HEARTGARD-30 Chewables supply a minimum of 6.0 mcg ivermectin per kg (2.72 mcg/lb) of body weight when given at the following recommended dose levels: Dog Weight Chewables Per Month Ivermectin Content Up to 25 lb 1 68 mcg 26 to 50 lb 1 136 mcg 51 to 100 lb 1 272 mcg Give dogs heavier than 100 lb the appropriate combination of these sizes. Route of Administration G. HEARTGARD-30 Chewables are orally administered at monthly intervals during the period of the year when mosquitoes (vectors), potentially carrying heartworm larvae, are active.

Pharmacokinetics

Target-animal safety

dose multiples 1X (label dose, field trials); duration monthly; most dogs received 3 to 6 doses; animals 384 client-owned dogs (255 on ivermectin chewables).

Of the 384 dogs, 255 received monthly treatment with ivermectin chewables according to the recommended dosage schedule. Control dogs received monthly treatment with HEARTGARD-30 tablets, or daily treatment with Filaribits® and monthly placebo (ALPO Beef Bites(TM)). Most of the dogs received 3 to 6 doses of monthly trial medication.

Effectiveness

No new efficacy trials: effectiveness bridged from HEARTGARD-30 tablets (NADA 138-412) by a radiolabeled bioavailability crossover study in 16 Beagles at 6 mcg/kg, plus four controlled field trials (384 client-owned dogs) in which all re-examined dogs remained heartworm negative.; primary endpoint: Plasma ivermectin AUC and Cmax equivalence to the tablet; result: Chewable and tablet were pharmacokinetically similar (AUC 22% greater for the chewable, comparable Cmax); chewables judged effective at a minimum monthly dose of 6 mcg/kg.

chewable dosage forms have been shown to be pharmacokinetically similar and the chewables are as bioavailable to dogs as the tablets, HEARTGARD-30 Chewables are effective in preventing canine heartworm disease with a minimum monthly dose of 6 mcg ivermectin/kg body weight.

Adverse reactions

Extraction notes: The 'target_animal_safety' block records the four controlled field safety trials (label dose only); margin-of-safety and reproductive studies are referenced to NADA 138-412 and are not in this summary. PK values are total tritium radioactivity, reported only as relative comparisons (no absolute concentrations); the p-value symbols are garbled in extraction ('pÐ0.03', 'p ð.05') and quoted as-is. Palatability trial: more than 93% of 91 dogs consumed the chewable when offered free choice.

Ivomec® .27% Injection Grower And Feeder Pigs Ivomec® 1% Injection Ivomec® 1% Injection for Cattle And Swine Ivomec® Injection for Cattle NADA 128-409, Supplemental approval, July 13, 1995; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Grower and Feeder Pigs and Ranch-Raised Foxes; foi_id 386; FDA PDF

Indication

Ranch-raised foxes: treatment and control of ear mites (Otodectes cynotis) (this supplement adds the fox indication).

Dose regimen

200 µg/kg body weight (.25 mL/6.5 lb), Subcutaneous, two treatments, repeated in three weeks, foxes; 2.7 mg/mL (0.27%) injectable

Foxes: 200 µg/kg body weight (.25 mL/6.5 lb), repeat in three weeks.

Target-animal safety

dose multiples 5X (1000 µg/kg).

Target animal safety data from the FOI summary for PMF 5307, 56 FR 61021, November 29, 1991, demonstrated that based on clinical observation, foxes treated with ivermectin at a dosage of 1000 µg/kg body weight (5X the optimal dose) were not adversely affected by the elevated level of the drug.

Effectiveness

Efficacy data referenced from Public Master File 5307 (56 FR 61021; data generated by W. J. Foreyt, Washington State University); no study design, animal numbers or results detailed in this summary; primary endpoint: control of ear mites (Otodectes cynotis) in ranch-raised foxes; result: 200 µg/kg SC twice at a 3-week interval was efficacious in controlling ear mites

Efficacy data from the FOI summary for PMF 5307, 56 FR 61021, November 29, 1991, demonstrated that ivermectin injection, when administered subcutaneously at a dose of 200 µg/kg body weight, twice at a 3 week interval, was efficacious in controlling ear mites (O. cynotis).

Extraction notes: Supplemental approval (1995, Category II) for RANCH-RAISED FOXES, not dogs; the label species field reads 'Grower and Feeder Pigs and Ranch-Raised Foxes' and pig indications/dose (300 µg/kg) are not captured. All safety and efficacy data are cited from PMF 5307 with no animal numbers, study duration or results beyond the conclusions quoted; no PK or adverse reaction data. OTC marketing status. Summary lacks a General Information parse (fields taken from raw text).

Heartgard 30® Heartgard® Tablets NADA 138-412, Original approval, March 02, 1987; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 420; FDA PDF

Indication

Prevention of canine heartworm disease by eliminating the tissue stage of Dirofilaria immitis larvae.

Dose regimen

6.0 mcg ivermectin/kg (2.72 mcg/lb) minimum, oral (swallow tablet), monthly, tablets of 68, 136 and 272 mcg for dogs up to 25 lb, 26-50 lb and 51-100 lb

The ingredients in HEARTGARD30 are formulated into various sized tablets to be administered orally (swallow) as appropriate for the weight of the dogs (see below) at monthly dosing intervals. The tablets supply the recommended minimum dose level of 6.0 mcg ivermectin per kilogram (2.72 mcg/lb) of body weight.

Target-animal safety

dose multiples 500 mcg/kg/day, 1,000 mcg/kg/day, 2,000 mcg/kg/day; duration daily for 94 to 95 consecutive days (14 weeks); animals 20 male and 20 female beagles (five groups of eight).

Twenty male and 20 female beagles from 39 to 43 weeks of age were divided into five treatment groups of eight dogs each, four of each sex, and were allocated to treatment. Treatments were administered daily for 94 to 95 consecutive days by intubation. Three groups received ivermectin at 500, 1,000 or 2,000 mcg/kg/day

Effectiveness

Eleven controlled necropsy dose titration/confirmation trials (370 ivermectin-treated and 83 unmedicated control dogs; natural or induced D. immitis infection, doses 0.33-33 mcg/kg, some with 45- or 60-day dosing intervals) plus seven controlled clinical field trials (701 dogs on monthly ivermectin tablets vs 194 controls on daily diethylcarbamazine, 7-16 months).; n = 83 dogs (monthly or 30-day post-infection, ivermectin >=3.0 mcg/kg) and 88 dogs (45- or 60-day interval, >=6.0 mcg/kg); primary endpoint: Adult D. immitis counts at necropsy (percent efficacy from geometric means); microfilariae tests in field trials; result: Only 2 of 83 dogs at >=3.0 mcg/kg and 2 of 88 dogs at >=6.0 mcg/kg with extended intervals developed infections; 6.0 mcg/kg monthly is effective. In field trials only one ivermectin-treated dog (owner-admitted missed doses) and one DEC control became microfilaria-positive.

Of the 83 dogs treated at monthly intervals in natural infection trials, or treated 30 days after induced infection, with doses of ivermectin at 3.0 mcg/kg or greater, only 2 dogs developed infections. Even when the treatment interval was extended to 45 or 60 days following infection, only 2 of 88 dogs given ivermectin at 6.0 mcg/kg or more developed infections. Therefore, HEARTGARD30® with a monthly dose of 6.0 mcg/kg is effective in preventing canine heartworm disease.

Adverse reactions

Extraction notes: Original approval, 1987 format: General Information fields E-G are template placeholders ('X mg/ml, g/lb, etc.'). No PK data. Margin-of-safety study (TT#78-038-0) used ivermectin solutions by intubation, not the market tablet; the summary never states dose multiples, so dose_multiples lists the daily dose levels (about 83X, 167X and 333X of 6 mcg/kg by arithmetic, not stated in the summary). Field-trial incidence numbers are not tabulated, so adverse_reactions rows carry no counts; the 701/194 field-trial totals are spelled out ('seven hundred one') in the text and therefore kept out of n_dogs.

Iverhart™ Tablets NADA 200-270, Original approval, November 30, 2001; sponsor Virbac AH, Inc.; species: Canine; foi_id 1026; FDA PDF

Indication

Prevention of canine heartworm (Dirofilaria immitis) disease (generic of Heartgard Tablets, NADA 138-412).

Dose regimen

6 mcg/kg of body weight, oral, monthly (every thirty days in the bioequivalence study), 68 mcg tablet up to 25 lb, 136 mcg 26-50 lb, 272 mcg 51-100 lb

Route of Administration: Oral Species: Canine Labeled Dosage: 6 mcg/kg of body weight

Effectiveness

Clinical end-point bioequivalence study (TRS Labs, Dr. McCall): 36 beagles (18 male, 18 female; 4.7-7.1 months) inoculated SC with 50 D. immitis L3, 30 days later treated every 30 days for four treatments with Iverhart (Group 1) or Heartgard (Group 2) at a minimum 6 mcg/kg, or untreated (Group 3), 12 per group, masked; necropsy 149 days post-inoculation.; primary endpoint: Adult D. immitis counts at necropsy (percent efficacy vs untreated controls); result: Worm counts 0 in both Iverhart and Heartgard groups vs mean 30.9 (range 22-43) in controls: 100% efficacy, products considered equivalent.

Results and Conclusions: The worm counts for both treated groups (Iverhart and Heartgard) were 0 and the mean worm count for the negative control group was 30.9, with all control animals having heartworm infections (range 22 to 43 worms). Thus, the generic product and the pioneer product were considered equivalent with efficacies of 100% for the prevention of heartworm disease, and no additional analysis was needed.

Extraction notes: Generic (ANADA) approval: safety and effectiveness rely on the pioneer NADA 138-412; the only study is the clinical end-point bioequivalence trial recorded under 'effectiveness'. Blood-level bioequivalence was not required because ivermectin plasma levels at the label dose are too low to measure. No adverse reactions are reported. Group size (Thirty-six; 6 males and 6 females per group) is spelled out, so n_dogs is null.

Ivomec® .27% Injection Grower And Feeder Pigs Ivomec® 1% Injection Ivomec® 1% Injection for Cattle And Swine Ivomec® Injection for Cattle NADA 128-409, Supplemental approval, September 13, 1995; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Cattle; foi_id 1693; FDA PDF

Indication

Treatment and control of gastrointestinal roundworms, lungworms, grubs, lice and mange mites of cattle; this supplement only establishes a new tolerance (100 ppb ivermectin B1a in cattle liver) and revised safe concentrations.

Extraction notes: Cattle summary. Supplemental approval limited to human food safety: no dose regimen is stated anywhere in the summary (only 'the recommended use level'), and effectiveness and target animal safety refer to the parent NADA 128-409 FOI summary (February 13, 1984), so dose_regimen, PK, TAS and effectiveness are intentionally null. Content: human clinical safety data (onchocerciasis trials, accidental overdoses), new ADI 1 ug/kg/day from the 90-day dog NOEL of 0.5 mg/kg/day with a 500-fold safety factor, liver tolerance changed from 15 to 100 ppb, injection-site safe concentration 3 ppm, and residue depletion study ASR 13527 supporting a 35-day withdrawal.