Torsemide: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Torsemide, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- UpCard®-CA1 (NADA/ANADA 141-577)
UpCard®-CA1 NADA 141-577, Original approval, May 10, 2024; sponsor Vetoquinol USA, Inc.; species: Dogs; foi_id 15407; FDA PDF
Indication
With concurrent pimobendan, spironolactone and an ACE inhibitor, management of pulmonary edema in dogs with congestive heart failure caused by myxomatous mitral valve disease (MMVD). Conditional approval.
Dose regimen
0.05 to 0.2 mg/lb (0.11 to 0.44 mg/kg) of bodyweight, Oral (2 mg/mL solution), Once daily, Expanded conditional approval; used with concurrent pimobendan, spironolactone and an ACE inhibitor
UpCard®-CA1 should be administered orally once daily at a dose of 0.05 to 0.2 mg/lb (0.11 to 0.44 mg/kg) of bodyweight.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| tmax | 0.75 h (median; range 0.5 to 1.0) for the oral solution; 1.0 h (range 0.5 to 1.5) for torsemide tablets | PK bridging study No. 1906VP2F1; 10 fasted Beagle dogs; single 0.1 mg/kg oral dose; 2-period crossover, 14-day washout; table columns: torsemide tablets then UpCard-CA1 | Tmaxa (h) 1.0 (0.5 to 1.5) 0.75 (0.5 to 1.0) |
| cmax | 1.20 μg/mL (CL 0.840 - 1.71) for the oral solution; 1.39 μg/mL (CL 0.863 - 2.22) for torsemide tablets | Geometric mean (95% confidence limits); single 0.1 mg/kg oral dose, fasted Beagles (n=10); columns: tablets then UpCard-CA1 | Cmax (μg/mL) 1.39 (0.863 - 2.22) 1.20 (0.840 - 1.71) |
| half-life | 7.68 h (CL 4.79 - 12.3) for the oral solution; 7.43 h (CL 4.25 - 13.0) for torsemide tablets | Elimination half-life, geometric mean (95% confidence limits); single 0.1 mg/kg oral dose, fasted Beagles (n=10); columns: tablets then UpCard-CA1 | t½ (h) 7.43 (4.25 - 13.0) 7.68 (4.79 - 12.3) |
| auc | 7.17 μg*h/mL AUClast (CL 4.35 - 11.8) for the oral solution; 7.94 μg*h/mL (CL 3.93 - 16.0) for torsemide tablets | Geometric mean (95% confidence limits); single 0.1 mg/kg oral dose, fasted Beagles (n=10); columns: tablets then UpCard-CA1 | AUClast (μg*h/mL) 7.94 (3.93 - 16.0) 7.17 (4.35 - 11.8) |
| bioavailability | 100% relative bioavailability in plasma (FR; CL 62.8 - 160) of the oral solution vs torsemide tablets | Geometric mean (95% confidence limits); dose-normalised AUCinf ratio; single 0.1 mg/kg oral dose, fasted Beagles (n=10) | FR (%) - 100 (62.8 - 160) |
| bioavailability | 93.1% relative bioavailability in urine (FRu; CL 70.6 - 123) of the oral solution vs torsemide tablets | Geometric mean (95% confidence limits); ratio of total torsemide excreted in urine; single 0.1 mg/kg oral dose, fasted Beagles (n=10) | FRu (%) - 93.1 (70.6 - 123) |
| other | Percent of dose excreted in urine as parent drug: 64.0% (CL 48.8 - 83.8) for the oral solution; 68.8% (CL 54.1 - 87.5) for torsemide tablets | Geometric mean (95% confidence limits); urine collected to 72 h; single 0.1 mg/kg oral dose, fasted Beagles (n=10); columns: tablets then UpCard-CA1 | %Dose (%) 68.8 (54.1 - 87.5) 64.0 (48.8 - 83.8) |
| other | Accumulation approximately 30% at 1X with steady state by Week 4 | Six-month margin-of-safety study (No. 036327); oral solution once daily with feeding; AUC increased dose-proportionally between 0.1 and 0.6 mg/kg | At 1X, accumulation was minimal (approximately 30%) with steady state being reached by Week 4, the first sample timepoint after Day 0. |
Target-animal safety
dose multiples 0X, 0.25X (0.11 mg/kg/day), 1.0X (0.44 mg/kg/day), 1.5X (0.66 mg/kg/day); duration 6 months (184 once-daily doses) of the commercial 0.2% oral solution given by syringe concurrent with feeding; GLP (Study No. 036327); animals 32 healthy Beagle dogs (16 male and 16 female), eight per group.
Study Animals: The study included 32 healthy Beagle dogs (16 male and 16 female), non-pregnant, non-lactating, approximately 6 months of age and weighing between 4.95 and 7.50 kg at the beginning of the treatment period. Experimental Design: The study was a masked, randomized, controlled margin of safety laboratory study. Dogs were randomly allocated to four treatment groups (0X, 0.25X, 1.0X, 1.5X) of eight dogs each. UpCard®-CA1 (0.2% torsemide oral solution) was administered once daily for 6 months (184 doses) at 0.25X, 1.0X, and 1.5X the maximum daily recommended therapeutic dose (0.11, 0.44, 0.66 mg/kg/day, respectively).
| Finding | Quote |
|---|---|
| Body weight decreased in torsemide groups: up to 4.6% at 0.25X (not significant); up to 9.4% (1X) and 11.8% (1.5X), significant at sporadic timepoints | Body weight decreased in the groups administered torsemide. In the 0.25X group, mean weekly body weights decreased up to 4.6%, but the differences were not statistically significant in comparison to the control group. |
| Increased water consumption at 1.5X (about twice control) from Days 28-29 in males and Days 56-57 in females; no apparent effect at 0.25X or 1X | The 1.5X group had increased daily mean water consumption starting on Days 28-29 in male dogs and on Days 56-57 in female dogs. |
| 1X and 1.5X: increased red cell mass (hemoconcentration), increased albumin, BUN and creatinine, decreased chloride and potassium | In the 1X and 1.5X groups, erythroid changes consisted of increased red cell mass parameters (red blood cell count, hemoglobin, and hematocrit) and were consistent with hemoconcentration as a result of dehydration secondary to diuresis. Serum chemistry changes in these groups consisted of increased albumin, BUN, and creatinine; and decreased chloride and potassium. |
| No clinical pathology effect at 0.25X | Torsemide administration in the 0.25X group had no effect on clinical pathology parameters. |
| No mortality, moribundity or serious adverse reactions; clinical signs were reduced fecal amounts, thin body condition, lethargy in one 1.5X male, and dehydration in 1X and 1.5X dogs | There was no mortality, moribundity, or serious adverse reactions observed during the study. Torsemide-related clinical observations included reduced fecal amounts in 1X and 1.5X group dogs and, in individual animals, general body conditions or activity level findings including thin body appearance in 1X and 1.5X group dogs, reduced activity or lethargy in one 1.5X male dog, and dehydration in 1X and 1.5X male and 1.5X female dogs. |
| Study conclusion: adequate margin of safety up to 0.66 mg/kg (1.5X) for 6 months; observations consistent with loop-diuretic pharmacology | Conclusion: The study demonstrated that UpCard®-CA1 Oral Solution (torsemide oral solution) has an adequate margin of safety for management of pulmonary edema related to congestive heart failure in dogs with MMVD when administered at doses up to 0.66 mg/kg or 1.5X the maximum labeled dose for 6 months. |
| Supportive 13-week tablet study (No. 521868; 0.1/0.3/0.6 mg/kg/day = 0.23X/0.68X/1.36X): kidneys enlarged in all 0.6 mg/kg/day dogs with tubular histopathology attributed to torsemide pharmacology | The kidneys of all dogs that received 0.6 mg/kg/day were enlarged, with microscopic correlates of basophilic tubular epithelial cells in the renal cortex and outer medulla, tubular dilation of the proximal and distal tubules, mononuclear cell infiltration, and tubular mineralization observed in several animals. |
Effectiveness
Reasonable expectation of effectiveness (conditional approval) from a multi-center European GCP field study (No. 182VC1F2; France, Spain, Germany; 2011-2014) of torsemide TABLETS 0.1-0.6 mg/kg once daily vs furosemide tablets 1-5 mg/kg twice daily for 3 months in 251 dogs with congestive heart failure (safety population 126 torsemide / 125 furosemide); primary analysis restricted to clinically stable MMVD dogs on furosemide for at least 10 days before enrollment. PK bridging study showed similar bioavailability of the oral solution.; n = 251 enrolled; 61 MMVD dogs evaluated for the primary endpoint (25 torsemide, 36 furosemide); primary endpoint: Response rate at Day 84: dog clinically stable and pulmonary edema/pleural effusion/ascites not worsened compared with Day 0; result: Success 96.0% (24/25) torsemide vs 80.6% (29/36) furosemide; torsemide judged non-inferior to furosemide. More adverse events with torsemide (184 vs 104 events), mainly urinary/renal and electrolyte disturbances; 30 deaths (12 torsemide, 18 furosemide).
Results: Of the 251 dogs that were enrolled in the study, 61 dogs with MMVD were considered appropriate for evaluation of the primary endpoint to support reasonable expectation of effectiveness because they were clinically stable and had received furosemide for at least 10 days prior to enrollment. After enrollment, 25 of these dogs were transitioned to torsemide tablets, and 36 dogs continued to be treated with furosemide. The primary endpoint was response rate at Day 84; a dog was considered to have a successful response to treatment if pulmonary edema and/or pleural effusion or ascites had not worsened compared to Day 0. The success rates were 96.0% (24/25) for the torsemide group and 80.6% (29/36) for the furosemide group.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| All adverse events (event counts, field study 182VC1F2; torsemide n=126 vs furosemide n=125 dogs) | 184 events | 104 events | A greater overall frequency of adverse events was recorded in the torsemide group (n = 184 events) compared with the furosemide treatment group (n = 104 events). |
| Death (all causes, mostly euthanasia) | 12 | 18 | A total of 30 dogs died during the study, 12 in the torsemide group and 18 in the furosemide group. |
| Renal insufficiency / increased BUN and creatinine / renal failure (serious adverse events) | A relative increase in the risk of serious adverse events due to renal insufficiency (including increased BUN and serum creatinine and renal failure) was observed among torsemide-treated dogs compared with furosemide-treated dogs. | ||
| Electrolyte disturbances (hypokalemia, hypochloremia, hypercalcemia, hypomagnesemia) | Electrolyte disturbances, including hypokalemia, hypochloremia, hypercalcemia, and hypomagnesemia, were also associated with torsemide therapy. |
Extraction notes: Application for (expanded) conditional approval, not a full NADA; effectiveness is a 'reasonable expectation of effectiveness'. The field study used a tablet formulation at 0.1-0.6 mg/kg; UpCard-CA1 is a 2 mg/mL oral solution bridged by PK study 1906VP2F1 (Table II.3 rows quoted as flattened: parameter (unit), tablet value, then UpCard-CA1 value; Tmax median (range), other parameters geometric mean (95% confidence limits)). Adverse reactions in the field study are given as event counts and qualitative statements only, no per-term incidence table. Food effect: feeding increased torsemide exposure by 24% (solution) and 39% (tablets) in separate studies (sentences span page breaks so not quoted). Pilot field study 182VC1F1 (176 dogs, torsemide 0.2-0.8 mg/kg/day) showed non-inferiority (response 68.7% vs 63.1%) but more renal adverse events, prompting the lower dose.
Reproduce: foi_structured_search(query="Torsemide") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).