estriol: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing estriol, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dog, ovariohysterectomized females.
Products
- Incurin® (NADA/ANADA 141-325)
Incurin® NADA 141-325, Original approval, July 25, 2011; sponsor Intervet, Inc.; species: Dog, ovariohysterectomized females; foi_id 882; FDA PDF
Indication
Control of estrogen-responsive urinary incontinence in ovariohysterectomized female dogs
Dose regimen
2 mg per dog (2 tablets), not dependent on body weight, Oral, Once per day, Initial dose for a minimum of 14 days; then reduce step-wise (2 mg, 1 mg, 0.5 mg once daily, with at least 7 days between adjustments) to the lowest effective daily dose, which may be given once every two days; never more than 2 mg/day; reassess diagnosis if no response to 2 mg/day
All dogs should receive an initial dose of 2 mg INCURIN Tablets (2 tablets) orally once per day for a minimum of 14 days.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| half-life | 9.1 hr (mean, Day 1) | Table 1 row (columns: Dosing Day, T1/2 lambda z (hr), Tmax (hr), Cmax (pg/mL), Clast at 24 h (pg/mL), AUC 0-24 (hr*pg/mL)); n=6 healthy female Beagles, 2 mg estriol/dog orally once daily for 7 days, 15-30 min before feeding | Mean 1 9.1 0.8 618 44 2075 |
| tmax | 0.8 hr (mean, Day 1) | Table 1 row (columns: Dosing Day, T1/2 lambda z (hr), Tmax (hr), Cmax (pg/mL), Clast at 24 h (pg/mL), AUC 0-24 (hr*pg/mL)); n=6 healthy female Beagles, 2 mg estriol/dog orally once daily for 7 days, 15-30 min before feeding | Mean 1 9.1 0.8 618 44 2075 |
| cmax | 618 pg/mL (mean, Day 1) | Table 1 row (columns: Dosing Day, T1/2 lambda z (hr), Tmax (hr), Cmax (pg/mL), Clast at 24 h (pg/mL), AUC 0-24 (hr*pg/mL)); n=6 healthy female Beagles, 2 mg estriol/dog orally once daily for 7 days, 15-30 min before feeding | Mean 1 9.1 0.8 618 44 2075 |
| auc | 2075 hr*pg/mL (mean, Day 1) | Table 1 row (columns: Dosing Day, T1/2 lambda z (hr), Tmax (hr), Cmax (pg/mL), Clast at 24 h (pg/mL), AUC 0-24 (hr*pg/mL)); n=6 healthy female Beagles, 2 mg estriol/dog orally once daily for 7 days, 15-30 min before feeding | Mean 1 9.1 0.8 618 44 2075 |
| auc | 2865 hr*pg/mL (mean, Day 3) | Table 1 row (columns: Dosing Day, T1/2 lambda z (hr), Tmax (hr), Cmax (pg/mL), Clast at 24 h (pg/mL), AUC 0-24 (hr*pg/mL)); n=6 healthy female Beagles, 2 mg estriol/dog orally once daily for 7 days, 15-30 min before feeding | Mean 3 12.1 0.7 595 55 2865 |
| half-life | 7.8 hr (mean, Day 7) | Table 1 row (columns: Dosing Day, T1/2 lambda z (hr), Tmax (hr), Cmax (pg/mL), Clast at 24 h (pg/mL), AUC 0-24 (hr*pg/mL)); n=6 healthy female Beagles, 2 mg estriol/dog orally once daily for 7 days, 15-30 min before feeding | Mean 7 7.8 0.8 740 36 3639 |
| cmax | 740 pg/mL (mean, Day 7) | Table 1 row (columns: Dosing Day, T1/2 lambda z (hr), Tmax (hr), Cmax (pg/mL), Clast at 24 h (pg/mL), AUC 0-24 (hr*pg/mL)); n=6 healthy female Beagles, 2 mg estriol/dog orally once daily for 7 days, 15-30 min before feeding | Mean 7 7.8 0.8 740 36 3639 |
| auc | 3639 hr*pg/mL (mean, Day 7) | Table 1 row (columns: Dosing Day, T1/2 lambda z (hr), Tmax (hr), Cmax (pg/mL), Clast at 24 h (pg/mL), AUC 0-24 (hr*pg/mL)); n=6 healthy female Beagles, 2 mg estriol/dog orally once daily for 7 days, 15-30 min before feeding; AUC increased with repeated dosing | Mean 7 7.8 0.8 740 36 3639 |
Target-animal safety
dose multiples 1X (2 mg/dog), 3X (6 mg/dog), 5X (10 mg/dog); duration 26 weeks, once daily; animals 4 treatment groups of 6 dogs each (twenty four).
Animals: Twenty four healthy, purebred female ovariohysterectomized Beagle dogs approximately 1 year of age weighing 7.3 to 10.5 kg at the beginning of the treatment period were allocated to 4 treatment groups of 6 dogs each. Test Material: Single scored tablets containing 1 mg of estriol. Dosage: 0, 2, 6, and 10 mg of estriol per dog (0, 1X, 3X, 5X, respectively) administered once daily for 26 weeks.
| Finding | Quote |
|---|---|
| All estriol-treated dogs developed vulvar discharges vs 2 of 6 placebo dogs | All dogs in the estriol-treated groups developed vulvar discharges (often reported daily) over the course of the study, whereas only 2 of 6 placebo-treated dogs did (a single observation in 1 dog and 2 observations in a second placebo group dog). |
| Mammary hyperplasia in 5/6 dogs at 2 mg and all dogs at 6 and 10 mg (1 placebo dog) | Mammary hyperplasia was reported in 1 dog treated with placebo (2 observations), 5 of 6 dogs treated with 2 mg (2 observations for 1 dog and multiple observations for 4 dogs), and all dogs treated with 6 mg and 10 mg of estriol per day (multiple observations). |
| Higher WBC, absolute neutrophil and platelet counts at 6 and 10 mg/day than placebo | Dogs treated with 6 mg and 10 mg of estriol per day had higher white blood cell counts, absolute neutrophil counts, and platelet counts than dogs that received placebo. |
| No estriol-related bone marrow changes at 10 mg/day (M:E ratios comparable to placebo) | There were no estriol-related changes on bone marrow smears evaluated microscopically from dogs in the 10 mg group |
| Kidney: increased lymphoplasmacytic infiltrate and urothelial hyperplasia of the pelvis only in estriol-treated dogs (low incidence, not dose-related) | In the kidney, increased lymphoplasmacytic infiltrate in the pelvis and hyperplasia of the urothelium lining the pelvis were only observed in dogs treated with estriol; these findings were thought to represent an inflammatory reaction in the pelvis of the kidney. |
| Conclusion: acceptable margin of safety up to 10 mg/dog/day (5X) for 26 weeks; estrogenic effects associated with estriol | (5 times the proposed maximum daily dose) for 26 weeks to healthy, ovariohysterectomized female dogs approximately 1 year of age had an acceptable margin of safety. Estrogenic effects (swollen vulva, vulvar discharge, mammary hyperplasia) were associated with the administration of estriol. |
Effectiveness
Multi-site (27 sites), randomized, masked, placebo-controlled field study in client-owned ovariohysterectomized female dogs >=1 year with >=3 incontinence episodes/week (Study No. 2024-006-00): 14-day effectiveness phase (2 mg estriol once daily vs placebo) followed by a 28-day unmasked titration phase on estriol; 226 enrolled (115 estriol, 111 placebo; safety population), 206 evaluable for effectiveness; n = 106 estriol, 100 placebo (effectiveness analysis); primary endpoint: Treatment Success at Day 14: Investigator Response-to-Treatment score of continent or improved (Responder) AND a targeted reduction in weekly urinary incontinence episodes vs baseline (owner diary); result: Day 14 Treatment Success 66% (70/106) with estriol vs 37% (37/100) with placebo, P = 0.0038. Responders 73.6% vs 53%; target episode reduction met by 69.8% vs 40%. During titration, 51% of 191 dogs were controlled on less than 2 mg/day.
Table 4: Summary of Treatment Successes at Day 14 P-Value for Comparison of Treatment Successes Treatment Group Number of Cases Number of Successes Percent Success Estriol 106 70 66% P = 0.0038 Placebo 100 37 37%
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Anorexia | 13.0% | 3.6% | Anorexia 13.0% 3.6% |
| Emesis | 9.6% | 6.3% | Emesis 9.6% 6.3% |
| Polydipsia | 7.0% | 7.2% | Polydipsia 7.0% 7.2% |
| Swollen vulva | 4.3% | 0.0% | Swollen vulva 4.3% 0.0% |
| Anxiety | 3.5% | 2.7% | Anxiety 3.5% 2.7% |
| Sexual attractiveness | 3.5% | 1.8% | Sexual attractiveness 3.5% 1.8% |
Extraction notes: Adverse reaction rows are from Table 9 (Effectiveness phase, Day 0-14): percent of dogs, estriol n = 115 vs placebo n = 111; row format 'term treated% control%'. Titration-phase reactions (Table 10, n = 224, estriol only) not tabulated: anorexia 12.9%, emesis 7.6%, licking vulva 4.5%, swollen vulva 4.0%, vulvovaginitis 4.0%, lethargy 4.0%. PK rows quote flattened Table 1 rows; the first number in each quote is the dosing day, not a PK value. TAS n_animals is stated in words in the summary ('Twenty four'); dose multiples are as stated (0, 1X, 3X, 5X). The TAS conclusion sentence begins with a PDF-split word ('Es triol'), so the quoted finding starts mid-sentence. A European self-controlled dose-characterization field study (136 dogs; 89.8% of 118 evaluable dogs responded at day 42) is summarized in the effectiveness section but not extracted as the pivotal study. Foreign pharmacovigilance: ~20% of reports were alopecia.
Reproduce: foi_structured_search(query="estriol") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).