Moxidectin: what the FDA reviewed for dog products
6 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Moxidectin, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs; Dogs 1 year of age and older; Dogs over 6 months of age.
Products
- CORAXIS™ (NADA/ANADA 141-417)
- ProHeart® 12 (NADA/ANADA 141-519)
- ProHeart® 6 (NADA/ANADA 141-189)
- ProHeart™ (NADA/ANADA 141-051)
ProHeart® 12 NADA 141-519, Original approval, July 02, 2019; sponsor Zoetis Inc.; species: Dogs 1 year of age and older; foi_id 7307; FDA PDF
Indication
Prevention of heartworm disease (D. immitis) for 12 months in dogs 12 months of age and older; treatment of existing larval and adult hookworm (A. caninum, U. stenocephala) infections.
Dose regimen
0.05 mL constituted suspension/kg (0.023 mL/lb) = 0.5 mg moxidectin/kg (0.23 mg/lb), subcutaneous injection, once every 12 months, constituted suspension (10 mg/mL) ready 30 minutes after mixing
The recommended subcutaneous dose is 0.05 mL of the constituted suspension/kg body weight (0.023 mL/lb). This amount of suspension will provide 0.5 mg moxidectin/kg body weight (0.23 mg/lb).
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | 8.5 - 15.9 ng/mL (range) | first 1X (0.5 mg/kg) SC dose, 8 Beagles, margin-of-safety study A362N-US-15-524 | Following the first dose, the maximum concentration ("Cmax") ranged from 8.5 - 15.9 ng/mL and the time of Cmax (Tmax) ranged from 10 - 30 days in 8 dogs receiving the therapeutic dose. |
| tmax | 10 - 30 days (range) | first 1X (0.5 mg/kg) SC dose, 8 Beagles | Following the first dose, the maximum concentration ("Cmax") ranged from 8.5 - 15.9 ng/mL and the time of Cmax (Tmax) ranged from 10 - 30 days in 8 dogs receiving the therapeutic dose. |
| other | minimum plasma concentration 6 months after first dose 0.326 ng/mL to 2.26 ng/mL | 8 dogs receiving 1X dose | The minimum drug concentrations measured 6 months after the first dose - which is halfway through the prescribed dosing regimen - ranged from 0.326 ng/mL to 2.26 ng/mL in 8 dogs receiving the 1X dose. |
| auc | AUC0-t and Cmax increased less than dose-proportionally from 1X to 5X | 1X, 3X, 5X SC doses every 6 months | Area under the concentration-time curve to the last measured time point ("AUC0-t") and Cmax increased in a less than dose-proportional manner from 1X to 5X. |
| other | little or no accumulation of Cmax over three administrations 6 months apart | 1X-5X SC doses on Days 1, 183, 365 | The observed Cmax values following the three administrations 6 months apart showed little or no accumulation. |
| other | moxidectin residue at 1X injection site after one year 1.8 to 1506 μg (0.045% to 37.6% of dose) | 1X (0.5 mg/kg) injection sites, one year post-dose | The amount of moxidectin remaining in the microspheres at the injection site one year after administration of the 1X (0.5 mg/kg) dose had relatively large between-subject variability, with amounts ranging from 1.8 to 1506 μg, corresponding to 0.045% to 37.6% of the administered dose. |
Target-animal safety
dose multiples 1X, 3X, 5X; duration three SC doses at 6-month intervals (Days 1, 183, 365); necropsy Day 379; animals Thirty-two (32) purpose-bred Beagle dogs (16 males and 16 females).
The purpose of this study was to demonstrate the margin of safety of ProHeart® 12 administered by subcutaneous injection, once every 6 months, in dogs at 1, 3, and 5 times the label dose of 0.5 mg/kg body weight. Related secondary objectives include characterizing the pharmacokinetics and evaluating residual moxidectin concentration at the 1X dose injection sites after 1 year. Study Animals: Thirty-two (32) purpose-bred Beagle dogs (16 males and 16 females) approximately 6 to 7 months of age at initiation of the study and weighing between 8.5 to 11.2 kg for males and 7.1 to 8.9 kg for females were enrolled.
| Finding | Quote |
|---|---|
| Only treatment-related clinical finding: edema and skin thickening at injection sites | The only ProHeart® 12-related clinical finding was edema and thickening of skin at injection sites. |
| Granulomatous inflammation at injection sites (microsphere response) | Microscopically, there was granulomatous inflammation noted at the injection site of treated dogs consistent with a gradually resolving, steady state tissue response to the presence of microspheres. |
| Well tolerated, no systemic adverse effects | Subcutaneous administration of ProHeart® 12 to male and female Beagle dogs at 0.5, 1.5, or 2.5 mg/kg on Days 1, 183, and 365 was well tolerated and did not result in any systemic adverse effects. |
Effectiveness
Multi-center (19 practices) GCP clinical field study A161C-US-13-330: ProHeart 12 0.5 mg/kg SC on Days 0 and 365 vs monthly oral ivermectin/pyrantel active control; heartworm antigen/microfilariae testing at Days 365, 480, 605; approximately 605 days; n = 593 (297 ProHeart 12, 296 active control); primary endpoint: Heartworm testing (adult antigen and microfilariae) at Days 365 and 605; result: No ProHeart 12-treated dog tested positive at any test day (235, 226 and 222 dogs completed testing at Days 365, 480, 605); 100% effective
Study Animals: A total of 593 client-owned dogs (297 in the ProHeart® 12 group, 296 in the active control group) of various breeds from 1 year to 14 years of age.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Vomiting | 75 (25.3%) | 78 (26.4%) | Vomiting 75 (25.3) 78 (26.4) |
| Lethargy | 46 (15.5%) | 34 (11.5%) | Lethargy 46 (15.5) 34 (11.5) |
| Diarrhea (with and without blood) | 43 (14.5%) | 46 (15.5%) | 43 (14.5) 46 (15.5) |
| Anorexia | 41 (13.8%) | 31 (10.5%) | Anorexia 41 (13.8) 31 (10.5) |
| Seizures | 10 (3.4%) | 7 (2.4%) | Seizures 10 (3.4) 7 (2.4) |
| Hepatopathy | 8 (2.7%) | 3 (1.0%) | Hepatopathy 8 (2.7) 3 (1.0) |
Extraction notes: Adverse reactions from Table II.4 of the field study: number of dogs (%) with ProHeart 12 n=297 vs ivermectin/pyrantel pamoate n=296; also hypersalivation 7 (2.4) vs 3 (1.0) and hypersensitivity reactions 6 (2.0) vs 4 (1.4); two ProHeart 12 dogs had anaphylactoid/hypersensitivity reactions within 24 h of first dose. Field-study result quote: 'A total of 235, 226, and 222 ProHeart® 12-treated dogs completed the heartworm testing on Days 365, 480, and 605, respectively. None of these animals tested positive for heartworm on any of the test days.' Two laboratory dose-confirmation studies (20 Beagles each) showed 100% effectiveness against induced D. immitis 12 months after a single injection. Hookworm effectiveness is by reference to ProHeart 6 (NADA 141-189). Note the TAS conclusion states doses of 0.5, 1.5 or 2.5 mg/kg while the treatment-group table lists the 5X dose as 3.5 mg/kg (source inconsistency). Other safety studies: heartworm-positive dogs (16, 3X), ivermectin-sensitive Collies (15, 1X/3X/5X, no adverse reactions), female (40) and male (16) reproductive safety at 3X.
ProHeart® 6 NADA 141-189, Original approval, June 06, 2001; sponsor Zoetis Inc.; species: Dogs; foi_id 700; FDA PDF
Indication
Prevention of heartworm disease (D. immitis) in dogs six months of age and older; treatment of existing larval and adult hookworm (A. caninum) infections.
Dose regimen
0.05 mL constituted suspension/kg (0.0227 mL/lb) = 0.17 mg moxidectin/kg (0.0773 mg/lb), subcutaneous injection (dorsum of neck cranial to scapula), single injection every 6 months, constituted suspension ready 30 minutes after mixing; no more than 3.0 mL per site
The constituted product is administer ed at the dose of 0.05 mL/kg body weight (0.0227 mL/lb) which provides 0.17 mg moxidectin/kg body weight (0.0773 mg/lb).
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| tmax | approximately 7 - 14 days | single 1X (0.17 mg/kg) SC injection, male beagles, repeated-treatment study 0899-C-US-9-98 (12 treated dogs) | Following injection with the 1X dose of ProHeart 6, peak moxidectin blood levels were observed approximately 7 - 14 days after treatment. |
| cmax | 5.12 ppb mean serum moxidectin at Day 7 (Day -1 <0.5, Day 1 1.30, Day 3 3.34, Day 5 4.76, Day 7 5.12, Day 10 5.06, Day 14 4.52, Day 21 3.56, Day 28 3.11) | mean serum levels after first 1X SC injection; table row order is days -1, 1, 3, 5, 7, 10, 14, 21, 28 | Mean Moxidectin Serum Levels (ppb) from Day -1 to Day 28 -1 1 3 5 7 10 14 21 28 <0.5 1.30 3.34 4.76 5.12 5.06 4.52 3.56 3.11 |
| other | serum moxidectin below LOQ (0.5 ppb) by Day 112 in 10 of 12 treated dogs | after first 1X SC injection; little or no accumulation with repeated 6-monthly dosing | By Day 112 after the first treatment, moxidectin serum levels were below the limit of quantification (0.5 ppb) in 10 of the 12 treated dogs. |
Target-animal safety
dose multiples 1X, 3X, 5X; duration single SC injection, observed three months; animals Thirty-two purpose-bred beagles (16 males and 16 females).
The objective of this study was to evaluate the clinical and pathological effects when the final ProHeart 6 formulation was administered to healthy dogs at either 1X, 3X or 5X the recommended dose rate of 0.17 mg moxidectin/kg body weight. Animals: Thirty-two purpose-bred beagles (16 males and 16 females) approximately 7 to 8 months of age at the time of treatment were used in this study.
| Finding | Quote |
|---|---|
| Injection-site swelling/slight edema in treated groups within 8 hours, lasting up to 3 weeks | A single subcutaneous injection of the final ProHeart 6 formulation equivalent to either 1X, 3X or 5X the recommended dose level caused swelling/slight edema at the site of injection starting within 8 hours of injection and lasting for up to 3 weeks. |
| Gross lesion: 2.0 cm red foci at injection site in one 5X male; no histopathologic toxicity | The only gross lesion associated with the test article was a 2.0 cm red foci at the injection site in one 5X male. |
| Excessive salivation in one 5X dog at Day 78 | One dog at the 5X dose displayed excessive salivation at Day 78 post treatment. |
Effectiveness
Multi-site clinical field study: client-owned heartworm-negative dogs given ProHeart 6 SC at Month 0 and Month 6 (0.17 mg/kg) vs monthly oral ProHeart tablets (3 mcg/kg) control; antigen and microfilaria tests at 3, 6 and 12 months; approximately 365 days; n = 374 completed (280 treated, 94 control); primary endpoint: Heartworm antigen/microfilaria test status at 3, 6 and 12 months; result: No dog tested positive for heartworms; safe and effective for six-month protection
Animals: A total of 374 client-owned dogs (280 treated, 94 control) of various breeds from six months to 15 years of age completed this study.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Vomiting | 3 | vomiting (3), diarrhea (2), weight loss (2), listlessness (1), seizures (1), injection site pruritus (3), elevated body temperature (1) | |
| Diarrhea | 2 | vomiting (3), diarrhea (2), weight loss (2), listlessness (1), seizures (1), injection site pruritus (3), elevated body temperature (1) | |
| Weight loss | 2 | vomiting (3), diarrhea (2), weight loss (2), listlessness (1), seizures (1), injection site pruritus (3), elevated body temperature (1) | |
| Injection site pruritus | 3 | vomiting (3), diarrhea (2), weight loss (2), listlessness (1), seizures (1), injection site pruritus (3), elevated body temperature (1) | |
| Seizures | 1 | vomiting (3), diarrhea (2), weight loss (2), listlessness (1), seizures (1), injection site pruritus (3), elevated body temperature (1) | |
| Listlessness | 1 | vomiting (3), diarrhea (2), weight loss (2), listlessness (1), seizures (1), injection site pruritus (3), elevated body temperature (1) |
Extraction notes: Sections were not parsed for this summary; quotes taken from raw text. Adverse reactions are case counts in the ProHeart 6 field-study group (280 dogs); control counts not reported. Also in field study: 'Two geriatric dogs with a history of weight loss after the initial ProHeart 6 injection died within a month of the second 6-month injection.' and a third underweight dog with congenital problems died 3 months after lethargy following injection; treatment could not be ruled out. Field-study result quote: 'None of the 374 dogs that completed this study tested positive for heartworms at either the 3-, 6- or 12-month checks.' TAS injection-site incidence table (Table 6: control 0/8, 1X 3/8, 3X 5/8, 5X 3/8) could not be retrieved as a greppable sentence; one 5X female had excessive salivation on Day 78. PK values are from the repeated-treatment study (16 male beagles, 4 per group; serum table columns are study days). Other safety studies: heartworm-positive dogs (20, 3X), ivermectin-sensitive collies (15, up to 3X, no adverse reactions), female (40) and male (16) reproductive safety, repeated treatment up to six injections at six-month intervals (mild granulomatous panniculitis at injection sites). Dose-determination studies: two 32-dog studies established 0.17 mg/kg as protective for six months (100% effectiveness); hookworm studies showed >= 90% effectiveness against A. caninum.
CORAXIS™ NADA 141-417, Original approval, June 06, 2015; sponsor Elanco US Inc.; species: Dogs; foi_id 915; FDA PDF
Indication
Prevention of heartworm disease (D. immitis) and treatment/control of A. caninum and U. stenocephala (adults, immature adults, L4), T. canis (adults, L4), T. leonina (adults) and T. vulpis (adults) in dogs and puppies at least 7 weeks of age and at least 3 pounds.
Dose regimen
minimum 1.1 mg/lb (2.5 mg/kg) moxidectin, topical, once a month, 2.5% solution; tube size by body weight (0.4 to 5.0 mL)
The recommended minimum dose is 1.1 mg/lb (2.5 mg/kg) moxidectin, once-a- month, by topical administration.
Extraction notes: Original NADA but contains no new studies: effectiveness and target animal safety are established by reference to ADVANTAGE MULTI for Dogs (NADA 141-251; 10% imidacloprid + 2.5% moxidectin) because the moxidectin concentration is identical ('the substantial evidence for CORAXIS is established based on the effectiveness studies conducted for the approval of ADVANTAGE MULTI for Dogs'; 'the target animal safety for CORAXIS is established based on the target animal safety studies conducted for the approval of ADVANTAGE MULTI for Dogs'). Three non-interference studies (Reports #75490, #75312, #75326) showed equivalent effectiveness of 2.5% moxidectin alone vs with imidacloprid. No PK or adverse-reaction data in this summary. Dose quote contains the extraction artifact 'once-a- month'.
ProHeart® 6 NADA 141-189, Supplemental approval, June 13, 2002; sponsor Zoetis Inc.; species: Dogs; foi_id 701; FDA PDF
Indication
Supplement adds treatment of existing larval and adult hookworm (Uncinaria stenocephala) infections to the heartworm prevention and A. caninum indications in dogs six months of age and older.
Dose regimen
0.05 mL constituted suspension/kg (0.0227 mL/lb) = 0.17 mg moxidectin/kg (0.0773 mg/lb), subcutaneous injection, single injection (every 6 months), dose level, frequency and route unchanged by this supplement
The constituted product is administer ed at the dose of 0.05 mL/kg body weight (0.0227 mL/lb) which provides 0.17 mg moxidectin/kg body weight (0.0773 mg/lb).
Effectiveness
Laboratory study 0899-C-US-19-99 with induced U. stenocephala infection (400 L3 on Day 0): saline control vs single 0.17 mg/kg SC ProHeart 6 on Day 6 (larval stages) or Day 28 (adults), 10 dogs per group, necropsy worm counts Day 42; n = 30; primary endpoint: Percent reduction in geometric mean U. stenocephala count vs control at necropsy; result: 99.6% effective against larvae (Day 6 treatment) and 99.5% against adults (Day 28 treatment); control GM 225.4
Animals: A total of 30 purpose-bred beagle dogs (6 males and 24 females) weighing between 7.15 to 13.30 kg were used in this study.
Extraction notes: Supplemental approval (2002) for the U. stenocephala indication; sections unparsed, quotes from raw text. Four laboratory effectiveness studies (0899-C-US-16-99, -17-99, -18-99, -19-99; 30-40 beagles each) all showed >= 90% effectiveness; the pivotal larval/adult study -19-99 is recorded. Results table quote: 'U. stenocephala Control 225.4 Moxidectin - Day 6 0.93 99.6% (larvae) Moxidectin - Day 28 1.24 99.5% (adults)'. No adverse reactions or injection-site abnormalities were reported in any study. Animal safety: 'Consequently, no additional animal safety data were required for approval of this new indication.' No PK data.
ProHeart® 6 NADA 141-189, Supplemental approval, May 23, 2008; sponsor Zoetis Inc.; species: Dogs over 6 months of age; foi_id 702; FDA PDF
Indication
Prevention of heartworm disease (D. immitis) in dogs six months of age and older; treatment of existing larval and adult hookworm (A. caninum, U. stenocephala) infections. Supplement revises animal safety labeling only.
Dose regimen
0.05 mL constituted suspension/kg (0.227 mL/lb) = 0.17 mg moxidectin/kg (0.0773 mg/lb), subcutaneous injection, single injection (sustained release, 6 months), dosage unchanged by this supplement
The recommended subcutaneous dose is 0.05 mL of the constituted suspension/kg body weight (0.227 mL/lb). This amount of suspension will provide 0.17 mg moxidectin/kg body weight (0.0773 mg/lb).
Extraction notes: Labeling-only supplemental approval (2008): 'This supplement provides for the revision of the animal safety information in the warning, precaution, adverse reactions, and post-approval sections of the product labeling.' 'CVM did not require effectiveness studies for this supplemental approval.' and 'CVM did not require target animal safety studies for this supplemental approval.' No studies, PK or adverse-reaction data are presented; the summary refers to the original approval (June 6, 2001) and supplement (June 13, 2002). Frequency ('single injection') is inferred from the product name/sustained-release form, not stated in the dose quote.
ProHeart™ NADA 141-051, Original approval, May 27, 1997; sponsor Zoetis Inc.; species: Dogs; foi_id 3629; FDA PDF
Indication
Once-a-month use in dogs to prevent infection by the canine heartworm, Dirofilaria immitis, and subsequent heartworm disease; recommended for dogs eight weeks of age and older.
Dose regimen
3 mcg moxidectin/kg (1.36 mcg/lb), oral (tablet), once a month, during times when mosquitoes are active; three tablet sizes (30, 68, 136 mcg)
The recommended dose rate of 3 mcg moxidectin/kg (1.36 mcg/lb) body weight is achieved as follows: Weight of Dog Tablets/Month Moxidectin/Tablet Tablet Weight Up to 22 pounds 1 30 mcg 183 mg 23 to 50 pounds 1 68 mcg 412 mg 50 to 100 pounds 1 136 mcg 824 mg
Target-animal safety
dose multiples 10X, 20X, 30X; duration single treatment (0, 30, 60 or 90 mcg/kg), observed 1 month; ivermectin challenge 30 days later; animals Twenty-four collie dogs (6 animals per group).
Animals: Twenty-four collie dogs (eight adult males, eight adult females, and eight collie puppies), 6 animals per group.
| Finding | Quote |
|---|---|
| No toxicity at 10X or 20X in avermectin-sensitive collies | No signs of toxicity were observed in dogs admininstered moxidectin at 10 or 20 times the recommended use level. |
| Mild transient depression, ataxia and salivation in one of six dogs at 30X | One of six dogs receiving the 30X dose of moxidectin showed mild signs of depression and ataxia for approximately six to ten hours, and mild salivation at eight hours following treatment. |
| Signs resolved by 24 hours | These signs disappeared by 24 hours post-treatment. |
| Oral no-effect level about 1120-1150 mcg/kg (chronic dietary study), over 300 times the monthly dose | The oral no- effect-level for moxidectin in dogs was established between 1120 to 1150 mcg/kg, (1.12 to 1.15 mg/kg) an excess of 300 times the recommended monthly dose level. |
Effectiveness
Multi-site clinical field trials (five trials, New Jersey, Illinois, California, Florida; 1990-1991) in heartworm-negative client-owned dogs; moxidectin 3 mcg/kg monthly vs ivermectin 6 mcg/kg positive control (one trial used dogs as their own control); 10 months; heartworm testing (modified Knott's and ELISA) at 4 and 6-10 months; n = 280 moxidectin (236 completing) and 65 ivermectin (57 completing); primary endpoint: Heartworm infection status (modified Knott's test and ELISA) during treatment period; result: No dog developed heartworm infection; 100% efficacy
Total Dogs Starting Trial Program 280 65 Total Dogs Completing Trial Program 236 57
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Lethargy, vomiting, ataxia, anorexia, diarrhea, nervousness, weakness, increased thirst, itching (isolated instances, owner-reported, field trials) | Pet owners noted isolated instances of lethargy, vomiting, ataxia, anorexia, diarrhea, nervousness, weakness, increased thirst, and itching which they associated with treatment. |
Extraction notes: 1997 original approval of the oral ProHeart tablet. No PK data (only a remark that formulations in the chronic study were accepted 'based on bioavailability comparisons with the final market formulation'). Field-trial result quote: 'None of the dogs participating in this study developed heartworm infections during the treatment period.' Laboratory dose determination C-91-1 (40 Beagles, 50 L3, 1.5/3/6 mcg/kg): 'Efficacy of moxidectin was 100% at 1.5, 3 or 6 mcg.' TAS: study C-91-3 (single-dose 10/20/30X in ivermectin-sensitive collies) recorded here; also C-90-12 (27 collies, 0/3/15 mcg/kg = 1X/5X monthly x3, no adverse effects), one-year dietary toxicity (48 Beagles, 0/250/500/1130 mcg/kg/day, no treatment-related effects), male/female reproductive studies, patent heartworm-infected dogs (24) and a 12-day 30 mcg/kg (10X) study in two 8-week-old collie puppies. Note the source spells 'admininstered' and 'no- effect-level' (hyphenation artifacts) in the quoted sentences. Adverse reaction counts are not given numerically.
Reproduce: foi_structured_search(query="Moxidectin") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).