Insulin (protamine zinc recombinant human insulin): what the FDA reviewed for dog products
2 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Insulin (protamine zinc recombinant human insulin), as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Cats; Dogs.
Products
- ProZinc® (NADA/ANADA 141-297)
ProZinc® NADA 141-297, Supplemental approval, February 08, 2019; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 6708; FDA PDF
Indication
Reduction of hyperglycemia and hyperglycemia-associated clinical signs in dogs with diabetes mellitus (supplement adds dogs to the existing cat indication).
Dose regimen
starting dose 0.2-0.5 IU insulin/lb (0.5-1.0 IU/kg); naive dogs at the lower end, poorly controlled/transitioning dogs at the mid to higher end, Subcutaneous, once daily (twice daily may be considered if duration of action is inadequate, each dose about 25% less than the once-daily dose), given with or right after a meal; titrated on clinical signs and blood glucose curve/fructosamine (adequate control: nadir 80-125 mg/dL, maximum <= 300 mg/dL)
The recommended starting dose for ProZinc® is 0.2-0.5 IU insulin/pound of body weight (0.5-1.0 IU/kg) once daily.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| other (onset of action) | 1 to 14 hours | 0.5 IU/kg SC single site (5 dogs); Study 2010062: single SC dose in healthy fasted adult Beagles, incomplete crossover; Table II.1 row (column order: onset of action, time to nadir, duration of action) | 0.5 IU/kg at a single site 1 to 14 hours 6 to 16 hours 16 to > 24 hours |
| other (time to glucose nadir) | 6 to 16 hours | 0.5 IU/kg SC single site (5 dogs); Study 2010062: single SC dose in healthy fasted adult Beagles, incomplete crossover; Table II.1 row (column order: onset of action, time to nadir, duration of action) | 0.5 IU/kg at a single site 1 to 14 hours 6 to 16 hours 16 to > 24 hours |
| other (duration of action) | 16 to > 24 hours | 0.5 IU/kg SC single site (5 dogs); Study 2010062: single SC dose in healthy fasted adult Beagles, incomplete crossover; Table II.1 row (column order: onset of action, time to nadir, duration of action) | 0.5 IU/kg at a single site 1 to 14 hours 6 to 16 hours 16 to > 24 hours |
| other (onset of action) | 0.5 to 10 hours | 0.8 IU/kg SC single site (10 dogs); Study 2010062: single SC dose in healthy fasted adult Beagles, incomplete crossover; Table II.1 row (column order: onset of action, time to nadir, duration of action) | 0.8 IU/kg at a single site 0.5 to 10 hours 5 to > 24 hours 16 to > 24 hours |
| other (time to glucose nadir) | 5 to > 24 hours | 0.8 IU/kg SC single site (10 dogs); Study 2010062: single SC dose in healthy fasted adult Beagles, incomplete crossover; Table II.1 row (column order: onset of action, time to nadir, duration of action) | 0.8 IU/kg at a single site 0.5 to 10 hours 5 to > 24 hours 16 to > 24 hours |
| other (duration of action) | 16 to > 24 hours | 0.8 IU/kg SC single site (10 dogs); Study 2010062: single SC dose in healthy fasted adult Beagles, incomplete crossover; Table II.1 row (column order: onset of action, time to nadir, duration of action) | 0.8 IU/kg at a single site 0.5 to 10 hours 5 to > 24 hours 16 to > 24 hours |
| other (onset of action) | 1 to 10 hours | 0.8 IU/kg SC divided at three sites (6 dogs); Study 2010062: single SC dose in healthy fasted adult Beagles, incomplete crossover; Table II.1 row (column order: onset of action, time to nadir, duration of action) | 0.8 IU/kg divided at three sites 1 to 10 hours 8 to 20 hours 18 to > 24 hours |
| other (duration of action) | 18 to > 24 hours | 0.8 IU/kg SC divided at three sites (6 dogs); Study 2010062: single SC dose in healthy fasted adult Beagles, incomplete crossover; Table II.1 row (column order: onset of action, time to nadir, duration of action) | 0.8 IU/kg divided at three sites 1 to 10 hours 8 to 20 hours 18 to > 24 hours |
Target-animal safety
duration up to 6 months (Day 182) in the field study; animals 276.
In the field study, 276 dogs received ProZinc® insulin daily for up to 6 months.
| Finding | Quote |
|---|---|
| 80 hypoglycemic episodes: 37 with clinical signs in 24 dogs, 40 without signs in 27 dogs, 3 unknown in 2 dogs | Hypoglycemia: There were 80 hypoglycemic episodes recorded during the study; 37 episodes were associated with clinical signs in 24 dogs, 40 were without clinical signs in 27 dogs, and 3 were with unknown signs in 2 dogs. |
| Two dogs euthanized when hypoglycemia did not resolve with supportive care | Although most dogs recovered after supportive care (ranging from hospitalization and intravenous dextrose to oral glucose supplementation), two dogs were euthanized when the hypoglycemia did not resolve with supportive care. |
| Mean cholesterol elevated at Day 182 (432.6 mg/dL vs 333.7 mg/dL at Day -1); no other drug-related clinical pathology changes | Clinical pathology: Mean cholesterol was elevated at Day 182 (432.6 mg/dL, normal range 131-345 mg/dL) compared to Day -1 (333.7 mg/dL). No other clinically significant, potentially drug-related changes were seen in laboratory testing. |
| Injection site reactions in seven dogs, all resolved without stopping ProZinc | Injection site reactions: Seven dogs had injection site reactions, including observations of thickened skin, swelling, bumps at the injection site, and redness. All injection site reactions resolved without cessation of ProZinc® therapy. |
| Eleven dogs with diabetic ketoacidosis (four died/euthanized); twenty-one with pancreatitis | Eleven dogs were diagnosed with diabetic ketoacidosis. Four of these 11 dogs died or were euthanized, one after one dose of ProZinc®. Twenty-one dogs were diagnosed with pancreatitis. |
| 36 deaths/euthanasias, six possibly related to ProZinc | Deaths: Thirty-six (36) dogs died or were euthanized, six of which were possibly related to ProZinc®. |
| Safety confirmed in the field study including an extended use phase; no laboratory margin-of-safety study | The safety of ProZinc® was confirmed in the field study, which included an extended use phase. |
Effectiveness
Pivotal multicenter (16 US sites), single-arm, open-label GCP field study (Study 2012028, 2013-2017) in client-owned diabetic dogs; ProZinc started at 0.5-1.0 IU/kg SC once daily and titrated to effect for up to 6 months; compared with historically derived experience per 21 CFR 514.117(b)(4)(iv); 276 dogs enrolled/treated (safety population), 224 evaluated for effectiveness; n = 224 (effectiveness analysis); primary endpoint: Treatment success at Day 84: composite of improvement in at least one laboratory variable (blood glucose curve mean, nadir, or fructosamine) and at least one clinical sign (polyuria, polydipsia, or weight loss) vs baseline; effective if lower bound of the 95% CI >= 60%; result: 162/224 (72%) treatment successes; 95% CI 61.4 to 80.9% (lower bound above the 60% criterion)
Results: Of the 224 dogs included in the effectiveness analysis, 162 (72%) were considered treatment successes. The 95% confidence interval was 61.4 to 80.9%.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Lethargy (lethargy, depression, listless, tiredness) | 45 (16.3%) | Lethargy (lethargy, depression, listless, and tiredness) 45 (16.3%) | |
| Anorexia (decreased appetite, inappetence, not eating) | 28 (10.1%) | Anorexia (anorexia, decreased appetite, inappetence, and not eating) 28 (10.1%) | |
| Hypoglycemia with clinical signs | 24 (8.9%) | Hypoglycemia with clinical signs* 24 (8.9%) | |
| Vomiting | 21 (7.6%) | Vomiting 21 (7.6%) Seizures 16 (5.8%) | |
| Seizures | 16 (5.8%) | Vomiting 21 (7.6%) Seizures 16 (5.8%) | |
| Shaking/trembling/twitching | 13 (4.7%) | Shaking/trembling/twitching 13 (4.7%) |
Extraction notes: Supplemental approval (2019) adding dogs to NADA 141-297. The pharmacokinetics entries are pharmacodynamic ranges (onset of action, time to glucose nadir, duration of action) from Table II.1 of PK/PD Study 2010062 (10 healthy fasted Beagles; 0.5 IU/kg n=5, 0.8 IU/kg single site n=10, 0.8 IU/kg divided over three sites n=6); no classical PK parameters (Cmax, AUC, half-life) are reported. A 60-day pilot field study (Study 2010025, 17 dogs, median start 0.6 IU/kg BID) also informed the dose. No laboratory margin-of-safety study: target_animal_safety is derived from the 276-dog field study. Adverse reaction percentages (Table II.3) are out of 276 treated dogs with no control group; table rows were flattened by PDF extraction (column order: reaction, number (percentage)).
ProZinc® NADA 141-297, Original approval, October 28, 2009; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Cats; foi_id 861; FDA PDF
Indication
Reduction of hyperglycemia and hyperglycemia-associated clinical signs in cats with diabetes mellitus.
Dose regimen
initial 0.1 - 0.3 IU insulin/lb (0.2 - 0.7 IU/kg), Subcutaneous (back of the neck or side of the cat, U-40 insulin syringe), every 12 hours, given concurrently with or right after a meal; dose adjusted on clinical signs and glucose nadirs until adequate glycemic control (nadir 80-150 mg/dL on a 9-hour curve)
The initial recommended PROZINC dose is 0.1 - 0.3 IU insulin/pound of body weight (0.2 - 0.7 IU/kg) every 12 hours. The dose should be given concurrently with or right after a meal.
Target-animal safety
duration 45 days (field study) and 136 days (extended use field study); animals 176.
Adverse Reactions: In the field study, 176 cats received PROZINC insulin.
| Finding | Quote |
|---|---|
| Hypoglycemia (blood glucose < 50 mg/dL) in seventy-one of the treated cats, mostly without clinical signs | Seventy-one cats experienced hypoglycemia (defined as a blood glucose value of < 50 mg/dL on the blood glucose curve). |
| One serious hypoglycemic event (stupor, recumbency, hypothermia, seizures) that resolved with supportive therapy | One cat had a serious hypoglycemic event associated with stupor, lateral recumbency, hypothermia and seizures. The cat fully recovered after supportive therapy and finished the study. |
| Seven cats euthanized during the 45-day study (one for hypoglycemia, two ketoacidosis, four for concurrent conditions) | Deaths: Seven cats were euthanized during the study. One was euthanized by the referring veterinarian for hypoglycemia. Two had ketoacidosis. Four cats were euthanized after receiving PROZINC for less than 1 week due to worsening of concurrent medical conditions. |
| No unusual clinical pathology changes Day 0 to Day 45 | Serum chemistry and hematology results from blood samples collected on Day 0 were compared to those from Day 45. No unusual changes were seen. |
| Fourteen cats died or were euthanized in the extended use study; insulin continued despite anorexia/hypoglycemia contributed in two | Fourteen cats died or were euthanized during the extended use study. In two cases, continued use of insulin despite anorexia and signs of hypoglycemia contributed to the deaths. |
| Safety was based on the field studies; no laboratory margin-of-safety study | The safety of protamine zinc recombinant human insulin was confirmed in the field study and the extended use field study. |
Effectiveness
Multicenter (19 investigators), single-arm, open-label 45-day field study (IPI-PZI-0106) in client-owned diabetic cats; all cats received PROZINC and were compared with historically derived experience per 21 CFR 514.117(b)(4)(iv); 187 cats enrolled, 176 treated (safety population); n = 151 cats (effectiveness analysis); primary endpoint: Treatment success at Day 45: improvement in at least one blood glucose variable (curve mean, nadir or fructosamine) and at least one clinical sign (polyuria, polydipsia, body weight); effective if lower bound of the 90% CI for success > 66%; result: 115/151 (76.2%) treatment successes, 90% CI 70.5% to 81.9%; six cats transiently diabetic and off insulin at study end
Results: Of the 151 cats included in the effectiveness analysis, 115 (76.2%) were considered treatment successes. The 90% confidence interval was 70.5% to 81.9%.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Vomiting (Table 5, No. of cases) | 23 cases | Vomiting 23 Lethargy 22 Diarrhea, loose stool 10 Cystitis, hematuria 6 Upper respiratory infection 3 | |
| Lethargy (Table 5) | 22 cases | Vomiting 23 Lethargy 22 Diarrhea, loose stool 10 Cystitis, hematuria 6 Upper respiratory infection 3 | |
| Diarrhea, loose stool (Table 5) | 10 cases | Vomiting 23 Lethargy 22 Diarrhea, loose stool 10 Cystitis, hematuria 6 Upper respiratory infection 3 | |
| Cystitis, hematuria (Table 5) | 6 cases | Vomiting 23 Lethargy 22 Diarrhea, loose stool 10 Cystitis, hematuria 6 Upper respiratory infection 3 | |
| Hypoglycemia (blood glucose < 50 mg/dL) | seventy-one cats | Seventy-one cats experienced hypoglycemia (defined as a blood glucose value of < 50 mg/dL on the blood glucose curve). | |
| Injection site reactions | three cats | Injection site reactions: Three cats had injection site reactions. |
Extraction notes: Species is CATS: this is the original NADA 141-297 approval (2009); the dog indication was added by the 2019 supplement (foi 6708). The n_dogs field holds the cat count. Adverse reaction counts are cases among 176 treated cats with no control group (single-arm design); the Table 5 row quote was flattened into one line by PDF extraction (column order: reaction, number of cases). Extended use study IPI-PZI-0206 (145 cats enrolled, 113 completed, 136 days; fructosamine and body weight continued to improve; 12 cats went into remission) not captured as a separate effectiveness entry. No PK data and no laboratory target animal safety study; TAS section relies on the field studies and literature.
Reproduce: foi_structured_search(query="Insulin (protamine zinc recombinant human insulin)") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).