Levothyroxine sodium: what the FDA reviewed for dog products
2 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Levothyroxine sodium, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- Thyro-Tabs® Canine (NADA/ANADA 141-448)
- ThyroKare™ (NADA/ANADA 141-539)
ThyroKare™ NADA 141-539, Original approval, January 15, 2021; sponsor Neogen Corp.; species: Dogs; foi_id 10310; FDA PDF
Indication
Replacement therapy for diminished thyroid function in dogs
Dose regimen
0.1 mg/10 lb (0.01 mg/lb, 0.022 mg/kg) initial dose, oral (tablet), twice daily, Administer consistently with or without food; therapeutic monitoring every 4 weeks until maintenance dose established, then as needed
The initial dose is 0.1 mg/10 lb (0.01 mg/lb, 0.022 mg/kg) body weight twice daily.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| bioavailability | 19% (absolute) | Single oral dose 0.1 mg/10 lb (0.022 mg/kg), 7 thyroidectomized fasted Beagles | When ThyroKare™ was administered as a single oral dose of 0.1 mg/10 lb body weight (0.01 mg/lb, 0.022 mg/kg) to 7 thyroidectomized, fasted Beagles, the absolute bioavailability of levothyroxine sodium was low (19%). |
| other | Css 3.0 (± 1.0) µg/dL; Cmin 2.2 µg/dL (steady state) | 0.022 mg/kg twice daily for 7 days, thyroidectomized Beagles | After 7 days of twice daily dosing of 0.1 mg/10 lb (0.01 mg/lb, 0.022 mg/kg), the mean (± standard deviation) concentration at steady state (Css) and minimum concentration at steady state (Cmin) were 3.0 (± 1.0) µg/dL and 2.2 µg/dL, respectively. |
| tmax | 1.3 to 4 hours (peak serum tT4) | 0.022 mg/kg twice daily, thyroidectomized Beagles | The peak serum total thyroxine (tT4) concentrations were reached within 1.3 to 4 hours. |
| half-life | 9.6 (± 3.4) hours (terminal phase) | 0.022 mg/kg twice daily, thyroidectomized Beagles | The mean (± standard deviation) terminal phase half-life was 9.6 (± 3.4) hours. |
| other | food reduced bioavailability by approximately 55% (oral solution, literature) | Literature (oral solution), fed vs fasted | Compared to the fasted state, food reduced the bioavailability of levothyroxine sodium in an oral solution by approximately 55%. |
Target-animal safety
dose multiples 0.5X to 250X (oral exposures in reviewed literature), 1X to 5X (26-week study, literature ref. 11); duration Single dose to longer than one year (literature); no product-specific margin-of-safety study.
The safety of ThyroKare™ in dogs was evaluated by critically reviewing publicly available literature regarding the use of levothyroxine in dogs and analyzing pharmacovigilance data for ThyroKare™ reported to Neogen Corp.
| Finding | Quote |
|---|---|
| Oral levothyroxine, even at high doses, well tolerated in reviewed studies | Reported oral exposure to levothyroxine sodium, even at high-doses, was well tolerated in the dogs included in the studies. |
| 1X-5X for 26 weeks in euthyroid dogs: excitation, tachycardia, tachypnea, vomiting, diarrhea; mild decreases in albumin/globulin/total protein and increases in ALT, hemoglobin, hematocrit, RBC | Daily exposure of euthyroid dogs to levothyroxine sodium equivalent to 1X to 5X the initial ThyroKare™ daily dose during a 26-week study resulted in instances of excitation, tachycardia, tachypnea, vomiting, and diarrhea. |
| Parenteral levothyroxine (2.5X-25X) produced more severe reactions including deaths in experimental studies | Adverse reactions reported in experimental studies that evaluated parenteral exposures to levothyroxine were more severe. |
| Pharmacovigilance: 22 case reports / 42 adverse reactions as of 2020 | As of 2020, 22 individual case reports describing 42 adverse reactions related to the clinical use of ThyroKare™ tablets in dogs were reported voluntarily to Neogen Corp. |
| Poison control: no deaths in 98 symptomatic dogs despite exposures up to 8.6 mg/kg | There were no deaths despite exposures as high as 8.6 mg/kg. |
Effectiveness
Prospective, uncontrolled (no concurrent control group), multi-site (22 US sites) GCP field study (Study 153-130-HPO): 120 hypothyroid, levothyroxine-naive client-owned dogs, 0.1 mg/10 lb twice daily for 168±5 days with dose adjustments permitted; n = 107; primary endpoint: Treatment success at Day 84±5: serum tT4 within therapeutic reference range 1.0-5.4 µg/dL; effective if lower one-sided 95% CI >=70%; result: 87/107 (81.3%) treatment successes at Day 84 (lower 95% CI 74.3%); 81.3% (87/107) also at Day 168 (lower bound 73.6%); clinical signs improved
Of the 107 dogs in the effectiveness population, 87 dogs (81.3%) were considered a treatment success. The lower bound of the one-sided 95% confidence interval (CI) was estimated as 74.3%.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Polydipsia | 30.8% | Polydipsia 30.8 | |
| Polyuria | 20.0% | Polyuria 20.0 | |
| Tachypnea | 16.7% | Tachypnea 16.7 | |
| Lethargy | 11.7% | Lethargy 11.7 | |
| Anorexia | 10.0% | Anorexia 10.0 | |
| Emesis | 10.0% | Emesis 10.0 Muscle tremor/shaking 10.0 |
Extraction notes: No product-specific margin-of-safety study: the target animal safety section is a literature review (34 publications), pharmacovigilance (22 reports) and poison-control database analysis, captured as such with dose multiples expressed relative to the initial ThyroKare dose. Field study was uncontrolled; 120 enrolled, 107 evaluable at Day 84. Adverse reaction percentages (Table II.1) are of the 120 treated dogs; table preserved as 'term percent' rows. Trademark symbol normalizes to 'TM' in the extracted text.
Thyro-Tabs® Canine NADA 141-448, Original approval, January 25, 2016; sponsor Lloyd, Inc.; species: Dogs; foi_id 937; FDA PDF
Indication
Replacement therapy for diminished thyroid function in dogs
Dose regimen
0.1 mg/10 pounds (0.01 mg/lb; 0.022 mg/kg) initial daily dose, oral (tablet), single dose every 24 hours or divided dose every 12 hours, Adjust dose by monitoring serum TT4 4-6 hours post-dose and clinical response every 4-8 weeks until maintenance dose established
The initial daily dose is 0.1 mg/10 pounds (0.01 mg/lb; 0.022 mg/kg) body weight as a single dose every 24 hours or as a divided dose every 12 hours.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| bioavailability | 10%-20% (oral tablet formulations) | Literature-derived (dosage characterization); further decreased with food | Bioavailability of oral tablet formulations range from 10%- 20%, and is further decreased when taken with food. |
| tmax | 4-6 hours (peak serum total thyroxine) | Literature-derived | Peak serum total thyroxine (TT4) concentrations are expected 4-6 hours after dosing. |
| protein binding | > 99% (< 1% free thyroxine) | Literature-derived | Levothyroxine sodium is highly (> 99%) protein bound, with < 1% available as free thyroxine (fT4). |
| half-life | approximately 10-14 hours | Literature-derived, most dogs | In most dogs, the estimated half-life is approximately 10-14 hours. |
Target-animal safety
dose multiples 2X (0.044 mg/kg once daily), 6X (0.132 mg/kg once daily), 10X (0.220 mg/kg once daily); duration 26 weeks, once daily oral, GLP; animals 32.
To evaluate the tolerance of repeated oral administration of levothyroxine sodium tablets to dogs treated for 26 weeks. This study was conducted in accordance with the Good Laboratory Practice Regulations (GLPs; 21 CFR 58). (2) Study Animals: 32 Beagle dogs (16 intact males and 16 intact females) aged 7 to 10 months, and weighing 5.2 to 11.0 kg.
| Finding | Quote |
|---|---|
| Vomiting, diarrhea, excitation, rapid respiration and bloody feces more frequent in treated groups | Vomiting, diarrhea, excitation, rapid respiration, and feces with blood were observed in all treatment groups, but were seen with greater frequency in dogs in the groups administered levothyroxine sodium tablets. |
| Tachycardia more frequent in treated groups | Tachycardia was observed in all treatment groups, but was seen with greater frequency in dogs in the groups administered levothyroxine sodium tablets. |
| Dose-dependent increases in hemoglobin, hematocrit and RBC count | Dogs administered levothyroxine sodium tablets had dose-dependent increases in hemoglobin, hematocrit, and red blood cell counts compared to control dogs. |
| Dose-dependent ALT increase within normal range; lower albumin, calcium, cholesterol, globulin, total protein within normal ranges | Dogs administered levothyroxine sodium tablets had dose-dependent increases in ALT compared to control dogs, but remained within the normal laboratory range. |
| TSH suppressed and dose-dependent fT4/TT4 increase | The mean TSH values in the 2X, 6X, and 10X groups were lower than the untreated control group (approaching or close to the lower limit of quantitation for the assay). |
| No treatment-related gross or histopathologic lesions; dose-dependent decrease in pituitary and thyroid/parathyroid weights | There were no treatment-related gross or histopathologic lesions observed in any treatment group. |
Effectiveness
Multi-site field study without an untreated control group (Study V29B): newly diagnosed hypothyroid client-owned dogs randomized to 0.1 mg/10 lb every 24 h (Group 1) or 0.05 mg/10 lb every 12 h (Group 2), 182±5 days, dose adjustable; owners/investigators unmasked, laboratory masked; n = 78 evaluable (of 92 enrolled); primary endpoint: Treatment success at Visit 6 (Day 182): TT4 15-93.8 nmol/L AND fT4 8-36.4 pmol/L AND TSH <=37 mU/L; effective if lower one-sided 95% CI >=66%; result: 59/78 (75.6%) treatment successes; lower one-sided 95% CI 66.3%; no difference between q24h (26/39, 66.7%) and q12h (33/39, 84.6%) groups (P=0.1121); clinical signs generally improved
Of the 92 dogs enrolled, 78 were included in the effectiveness evaluation. Fourteen dogs were excluded: 11 because of protocol non-compliance and 3 due to serious illness not related to the test article. (1) Primary outcome measures for the determination of effectiveness Of the 78 evaluable cases, 59 dogs (75.6%) were considered treatment successes. The lower bound of the one-sided 95% confidence interval (CI) was estimated as 66.3%.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| anorexia | 17% | The most commonly reported adverse reactions, by percentage of dogs experiencing the reaction included: anorexia (17%), dermatitis (15%), vomiting (15%), otitis externa (14%), lethargy (14%), polydipsia (13%), diarrhea (11%), leukocytosis (9%), pruritus (8%), tachypnea (8%), polyuria (5%), hyperactivity (4%), and seborrhea (1%). | |
| dermatitis | 15% | The most commonly reported adverse reactions, by percentage of dogs experiencing the reaction included: anorexia (17%), dermatitis (15%), vomiting (15%), otitis externa (14%), lethargy (14%), polydipsia (13%), diarrhea (11%), leukocytosis (9%), pruritus (8%), tachypnea (8%), polyuria (5%), hyperactivity (4%), and seborrhea (1%). | |
| vomiting | 15% | The most commonly reported adverse reactions, by percentage of dogs experiencing the reaction included: anorexia (17%), dermatitis (15%), vomiting (15%), otitis externa (14%), lethargy (14%), polydipsia (13%), diarrhea (11%), leukocytosis (9%), pruritus (8%), tachypnea (8%), polyuria (5%), hyperactivity (4%), and seborrhea (1%). | |
| otitis externa | 14% | The most commonly reported adverse reactions, by percentage of dogs experiencing the reaction included: anorexia (17%), dermatitis (15%), vomiting (15%), otitis externa (14%), lethargy (14%), polydipsia (13%), diarrhea (11%), leukocytosis (9%), pruritus (8%), tachypnea (8%), polyuria (5%), hyperactivity (4%), and seborrhea (1%). | |
| lethargy | 14% | The most commonly reported adverse reactions, by percentage of dogs experiencing the reaction included: anorexia (17%), dermatitis (15%), vomiting (15%), otitis externa (14%), lethargy (14%), polydipsia (13%), diarrhea (11%), leukocytosis (9%), pruritus (8%), tachypnea (8%), polyuria (5%), hyperactivity (4%), and seborrhea (1%). | |
| polydipsia | 13% | The most commonly reported adverse reactions, by percentage of dogs experiencing the reaction included: anorexia (17%), dermatitis (15%), vomiting (15%), otitis externa (14%), lethargy (14%), polydipsia (13%), diarrhea (11%), leukocytosis (9%), pruritus (8%), tachypnea (8%), polyuria (5%), hyperactivity (4%), and seborrhea (1%). |
Extraction notes: PK values are literature-derived (dosage characterization section), not product-specific studies. Field study had no untreated control; adverse reaction percentages are of the 92 treated dogs (no control column).
Reproduce: foi_structured_search(query="Levothyroxine sodium") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).