Phenylpropanolamine hydrochloride: what the FDA reviewed for dog products
3 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Phenylpropanolamine hydrochloride, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- PROIN ER™ (NADA/ANADA 141-517)
- PROIN® Chewable Tablets (NADA/ANADA 141-324)
- Phenylpropanolamine Hydrochloride (NADA/ANADA 200-787)
PROIN® Chewable Tablets NADA 141-324, Original approval, August 04, 2011; sponsor Pegasus Laboratories, Inc.; species: Dogs; foi_id 881; FDA PDF
Indication
Control of urinary incontinence due to urethral sphincter hypotonus in dogs.
Dose regimen
2 mg/kg (0.91 mg/lb), oral (chewable tablet), twice daily, dosage calculated in half-tablet increments; long-term use (field study up to 6 months)
The total recommended dosage for oral administration is 2 mg/kg (0.91 mg/lb) of body weight twice daily. The dosage should be calculated in half-tablet increments.
Target-animal safety
dose multiples 1X, 3X, 5X; duration 182 days (2, 6 or 10 mg/kg twice daily); separate 21-day acute tolerance study at 10X (20 mg/kg twice daily) in 12 female Beagles; animals 16M, 16F (4 groups of 8).
Test Animals: Thirty-two Beagle dogs (16M, 16F), ranging in weight from 15 - 35 lbs. and 1 – 6 years of age, were randomly assigned to 4 treatment groups of 8 dogs (4M, 4F) each.
| Finding | Quote |
|---|---|
| Dose-related vomiting and loose stool, highest at 5X (under 4% of observations). | Vomiting and loose stool occurred in a dose-related fashion, with the 5X dogs having the highest incidence of both (less than 4% of the observations). |
| Anxious/restless behaviour more frequent in PPA groups: 0.5%, 7.0%, 1.6%, 3.2% of 2,912 observations for 0X, 1X, 3X, 5X (largely single dogs). | Dogs administered PPA exhibited anxious/restless behavior more frequently than the control group; total incidences out of 2,912 observations (per group) for the 0X, 1X, 3X, and 5X groups were 0.5%, 7.0%, 1.6%, and 3.2%. |
| Systolic blood pressure significantly higher in all PPA groups (means within normal range); diastolic and MAP higher at 3X, 5X and 1X males, some means hypertensive. | Systolic blood pressure was statistically significantly higher in all three PPA-dosed groups compared to the control group. Systolic means were within the normal reference range. |
| Heart rate significantly lower at 3X and 5X. | Heart rates taken from electrocardiograms, averaged over study days, were statistically significantly lower in the 3X (p=0.0187) and 5X (p=0.0392) groups compared to the control group. |
| Gallop heart sounds in one 1X and one 3X dog after treatment began. | One dog in each of the 1X and 3X groups developed gallop heart sounds that were noted after treatment began in 12 of 13 and 6 of 13 physical exams, respectively. |
| Transient elevations of platelet count (up to 1.4x ULN at 3X/5X) and serum ALT (3X, 5X; < 1.8x ULN), normal by study end. | Platelet counts were statistically significantly higher (p<0.10) in at least one of the PPA-dosed groups compared to the control group on 12 of 13 exams, with individual values up to 1.4 times the upper limit of normal (ULN) in the 3X and 5X groups. |
| Conclusion: dose-dependent increase in blood pressure and decrease in heart rate; no ophthalmic or histologic evidence of target-organ damage from chronic hypertension. | The most pronounced effects were a dose-dependent increase in blood pressure and a dose-dependent decrease in heart rate. There were no findings in ophthalmic examinations or histologic evaluation of tissues collected at necropsy indicative of target organ damage caused by chronic hypertension. |
Effectiveness
Multi-center (21 sites), masked, randomized (2:1), placebo-controlled 28-day clinical field study PLI-CL001 in client-owned dogs with urinary incontinence due to sphincter hypotonus (minimum four accidents/week); PROIN 2 mg/kg or placebo orally twice daily; followed by a 6-month open-label continuation (PLI-CL002, 157 dogs); n = 184 enrolled (35 male, remainder female); 100 females and 27 males evaluated for effectiveness; primary endpoint: Reduction in owner-recorded urinary accidents per week from pre-treatment to day 28 (analysed in females); result: Significant (p< 0.0064) decrease in urinary accidents per week in females: PROIN (N=66) mean 9.0 pre-treatment to 1.6 at week 4 vs placebo (N=34) 7.8 to 2.8; effectiveness not demonstrated in males (N=20 vs 7). Open-label study: 91.3% owner satisfaction at one month rising to 98.1% by day 180
Study Animals: The study enrolled 184 client-owned dogs diagnosed with urinary incontinence due to sphincter hypotonus. One hundred forty-nine female dogs (6 intact, 143 spayed) and 35 male dogs (4 intact, 31 castrated) were enrolled. The dogs ranged in age from 1 to 17 years old, represented 50 breeds including mixed breeds, and weighed 11.7 to 130.8 pounds. A total of 100 female dogs and 27 male dogs completed the study and were evaluated for effectiveness.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Emesis (28-day placebo-controlled study; PROIN N=123, placebo N=61) | 20.3% | 8.2% | Emesis 20.3% 8.2% |
| Hypertension (>= 160 mm Hg, one or more readings) | 19.5% | 14.7% | Hypertension (≥ 160 mm Hg)1 19.5% 14.7% |
| Anorexia | 16.3% | 3.3% | Anorexia 16.3% 3.3% |
| Body weight loss (>= 5%) (N=118 vs 59 with final weights) | 16.1% | 6.8% | Body weight loss (≥5%)2 16.1% 6.8% |
| Proteinuria | 13.0% | 8.2% | Proteinuria 13.0% 8.2% |
| Anxiety/aggression/behavior change | 9.7% | 3.2% | Anxiety/aggression/behavior change 9.7% 3.2% |
Extraction notes: Original approval (2011). No PK study in the summary; dosage characterization is literature-based (White & Pomeroy, Richter & Lang, Scott et al.). TAS n_animals given as '16M, 16F' because 'Thirty-two' is spelled out in the design quote. Adverse reaction quotes are flattened Table 6 rows (term, PROIN %, placebo %). Other Table 6 rows: diarrhea 7.3% vs 9.8%, polydipsia 6.5% vs 9.8%, lethargy 5.7% vs 1.6%. In the 6-month open-label study (N=125) hypertension 34.6%, weight loss >= 5% 24.8%, emesis 19.7%, proteinuria 15.3%, anorexia 10.2%; two deaths in the 28-day study (one PROIN dog with abdominal mass, relation unknown; one placebo dog with hepatitis).
Phenylpropanolamine Hydrochloride NADA 200-787, Original approval, June 11, 2024; sponsor ZyVet Animal Health, Inc.; species: Dogs; foi_id 15526; FDA PDF
Indication
Control of urinary incontinence due to urethral sphincter hypotonus in dogs.
Dose regimen
2 mg/kg (0.91 mg/lb), oral (chewable tablet), twice daily, scored tablets; dosage calculated in half-tablet increments
The total recommended dosage for oral administration is 2 mg/kg (0.91 mg/lb) of body weight twice daily. Phenylpropanolamine Hydrochloride is scored and dosage should be calculated in half-tablet increments.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| auc | 4133 (generic) vs 4137 (RLNAD) (ng/mL)*hour; ratio 99.9% (CI 95.9-104.1) | geometric means with 90% confidence interval, single oral 25 mg tablet, 30 fasted male Beagles, three-period crossover | AUC (ng/mL)*hour 4133† 4137† 99.9 95.9 104.1 |
| cmax | 658 (generic) vs 609 (RLNAD) ng/mL; ratio 108.1% (CI 102.9-113.5) | geometric means with 90% confidence interval, single oral 25 mg tablet, fasted, n=30 | CMAX (ng/mL) 658† 609† 108.1 102.9 113.5 |
| tmax | 1.47 (0.46) h generic vs 1.49 (0.51) h RLNAD | arithmetic mean (SD), single oral 25 mg tablet, fasted, n=30 | TMAX (hours) (SD)‡ 1.47 (0.46)‡ 1.49 (0.51)‡ NE NE NE |
Effectiveness
Bioequivalence: masked, randomized, three-period, two-sequence, single-dose crossover blood-level study (113-BC-1921) of generic 25 mg vs PROIN 25 mg chewable tablets in fasted dogs; 7- and 14-day washouts; biowaiver for 50 and 75 mg strengths on dissolution (f2 82.2 and 66.3); n = 30; primary endpoint: 90% confidence interval of generic:RLNAD geometric mean ratios for CMAX and AUC within 0.80-1.25; result: Bioequivalence demonstrated: AUC ratio 99.9% (95.9-104.1), CMAX ratio 108.1% (102.9-113.5); no serious adverse events
The in vivo blood-level study was conducted in 30 healthy, fasted beagle dogs.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| No serious adverse events (bioequivalence study) | There were no serious adverse events reported during the study. |
Extraction notes: Generic (ANADA) approval (2024), first generic phenylpropanolamine chewable tablet; RLNAD PROIN (NADA 141-324). Only a bioequivalence study is reported; effectiveness field records that study. Table II.1 rows are quoted with their dagger footnote markers as extracted.
PROIN ER™ NADA 141-517, Original approval, March 29, 2019; sponsor Pegasus Laboratories, Inc.; species: Dogs; foi_id 6907; FDA PDF
Indication
Control of urinary incontinence due to urethral sphincter hypotonus in dogs.
Dose regimen
2 to 4 mg/kg (0.9 to 1.8 mg/lb), oral (extended-release tablet, 18/38/74/145 mg by body-weight band), once daily, administer with food; do not split or crush; dogs under 10 lb cannot be safely dosed
The recommended dosage is 2 to 4 mg/kg (0.9 to 1.8 mg/lb) of body weight once daily according to Table I.1 below. Administer PROIN ERTM with food. Do not split or crush tablets.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | 626.72 ng/mL (ER) vs 861.52 ng/mL (IR); ratio 0.73 (CI 62.11-85.21%) | steady-state Cmax, 90% confidence interval; postprandial, 38 mg PROIN ER once daily (observed, study PLI-CL015) vs 50 mg PROIN chewable twice daily (simulated from single dose, PLI-CL012); same 12 female Beagles; geometric means | Cmaxss ng/mL 861.52 626.72 0.73 62.11 85.21 |
| auc | 5158.03 h*ng/mL (ER) vs 7650.59 (IR); ratio 0.67 (CI 58.20-78.10%) | AUC 0-24, 90% confidence interval; postprandial, 38 mg ER once daily vs 50 mg IR twice daily, n=12 | AUC 0-24 h*ng/mL 7650.59 5158.03 0.67 58.20 78.10 |
| auc | 5297.33 h*ng/mL (ER) vs 7998.56 (IR); ratio 0.66 (CI 56.68-77.38%) | AUCss, 90% confidence interval; postprandial, 38 mg ER once daily vs 50 mg IR twice daily, n=12 | AUCss h*ng/mL 7998.56 5297.33 0.66 56.68 77.38 |
| cmax | 726.63 ng/mL (ER) vs 707.30 (IR); ratio 1.03 (CI 88.41-119.38%) | steady-state Cmax with 90% confidence interval from non-parametric superposition simulation of label doses (ER 4 mg/kg every 24 h vs IR 2 mg/kg every 12 h), postprandial, n=12 | Cmaxss ng/mL 707.30 726.63 1.03 88.41 119.38 |
| auc | 5980.33 h*ng/mL (ER) vs 6492.18 (IR); ratio 0.92 (CI 85.08-99.74%) | AUC 0-24 with 90% confidence interval from superposition simulation of label doses (ER 4 mg/kg every 24 h vs IR 2 mg/kg every 12 h), n=12 | AUC 0-24 h*ng/mL 6492.18 5980.33 0.92 85.08 99.74 |
| other | accumulation ratios 1.0 - 1.19 | PROIN chewable tablets simulated every 12 hours to steady state (4 doses), per dog | There was minor accumulation at steady state for each dog, with accumulation ratios ranging from 1.0 - 1.19. |
Target-animal safety
duration no margin-of-safety study; safety bridged to PROIN Chewable Tablets (NADA 141-324) through two single-dose crossover PK studies in the same twelve female Beagle dogs.
The safety of PROIN ERTM was demonstrated using data from two pharmacokinetic studies (Studies PL-CL012 and PL-CL015, described below). Analysis of the data from these two studies determined that the systemic phenylpropanolamine exposure was similar for dogs administered PROIN ERTM when compared to dogs administered PROIN® Chewable Tablets.
| Finding | Quote |
|---|---|
| Steady-state exposure of 38 mg ER once daily was similar to or lower than 50 mg IR twice daily, so PROIN Chewable Tablet safety data apply. | Because the systemic phenylpropanolamine exposure in dogs administered 38 mg PROIN ERTM once daily was similar to dogs administered 50 mg PROIN® Chewable Tablets twice daily, the safety of PROIN ERTM is supported by the safety data for PROIN® Chewable Tablets (NADA 141-324). |
| Only clinically relevant findings in the PK studies were emesis and ventral abdominal hyperemia (one dorsal midline piloerection). | Clinical Observations: The only clinically relevant findings were emesis and ventral abdominal hyperemia. There was one incident of dorsal midline piloerection. |
| Fasted dosing of PROIN chewable tablets caused emesis in 14 of 24 dogs, so fed-state periods were added. | However, 14 of 24 dogs developed emesis in the fasted state in Period I, so the study was modified to include dosing in a fed state in Period II. |
Effectiveness
Multicenter (9 sites), prospective, open-label clinical field study PLI-CL016 in client-owned dogs with urinary incontinence due to USMI already controlled on PROIN Chewable Tablets, transitioned to PROIN ER 2-4 mg/kg once daily for 180 days; baseline (Day -7 to -1 on chewable tablets) compared with Day 21-27 on PROIN ER; n = 119 enrolled (104 evaluated for effectiveness); primary endpoint: Ratio of average daily incidence of urinary incontinence during baseline (chewable tablets) to Day 21-27 (PROIN ER) per dog; result: 75 (72.1%) dogs ratio of 1 (no difference), 19 (18.3%) better, 10 (9.6%) worse; mean daily UI incidence 0.21 (baseline) vs 0.18 (PROIN ER); owner assessment improved or same in 103 (99.0%) dogs (p < 0.0001 vs 80%); level of control did not differ after transition
A total of 104 dogs completed the study and were evaluated for effectiveness. All 119 dogs were evaluated for safety.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Emesis (180-day open-label study, N=119) | 39 (32.8%) | Emesis 39 (32.8%) | |
| Body weight loss (>= 5%) | 34 (28.6%) | Body weight loss (≥5%) 34 (28.6%) | |
| Hypertension (>= 160 mmHg) developed during study (21 further dogs were hypertensive at enrolment and throughout) | 15 (12.6%) | Hypertension (≥160 mmHg) developed during studya 15 (12.6%) | |
| Diarrhea | 20 (16.8%) | Diarrhea 20 (16.8%) | |
| Proteinuria | 16 (13.4%) | Proteinuria 16 (13.4%) | |
| Tachycardia (>= 160 bpm) | 11 (9.2%) | Tachycardia (≥160 bpm) 11 (9.2%) |
Extraction notes: Original approval (2019) of an extended-release phenylpropanolamine tablet. The batch plan counted 0 PK sentences, but the target animal safety section is entirely comparative PK (Tables III.1 and III.2, quoted as flattened rows: parameter, units, IR geometric mean, ER geometric mean, ER/IR ratio, lower and upper 90% CI). No margin-of-safety study; dose_multiples left empty. Additional Table II.4 adverse reactions: lethargy 11 (9.2%), decreased appetite 10 (8.4%), urinary tract infection 10 (8.4%), elevated ALP/ALT 7 (6%). Four deaths during the field study (two unrelated, two of undetermined cause).
Reproduce: foi_structured_search(query="Phenylpropanolamine hydrochloride") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).