Rabacfosadine: what the FDA reviewed for dog products
1 Freedom of Information summary from the FDA Center for Veterinary Medicine for products containing Rabacfosadine, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dog.
Products
- TANOVEA™ (NADA/ANADA 141-545)
TANOVEA™ NADA 141-545, Original approval, July 15, 2021; sponsor Elanco US Inc.; species: Dog; foi_id 11083; FDA PDF
Indication
Treatment of lymphoma in dogs.
Dose regimen
1.0 mg/kg body weight (stepwise reductions to 0.8 mg/kg and 0.66 mg/kg allowed), intravenous, 30-minute infusion, once every three weeks, up to five doses; dose reductions or dose delays may be used to manage adverse reactions
Administer TANOVEA® at 1.0 mg/kg body weight as a 30-minute intravenous infusion, once every three weeks, for up to five doses. Stepwise dose reductions to 0.8 mg/kg and 0.66 mg/kg or dose delays may be used to manage adverse reactions.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| half-life | <0.5 hours (rabacfosadine, plasma) | eight dogs with lymphoma, IV infusion, pilot study PC-193-2001 (not commercial formulation) | Rabacfosadine was rapidly eliminated from plasma with a half-life of <0.5 hours. |
| half-life | six hours (primary metabolite cPrPMEDAP, plasma) | eight dogs with lymphoma, pilot study PC-193-2001 | The primary metabolite, 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cPrPMEDAP), had a plasma half-life of six hours. |
| other | PMEG (cytotoxic metabolite) not detected in plasma; high levels in PBMCs within 24 hours of dosing | peripheral blood mononuclear cells, pilot study PC-193-2001 | The cytotoxic metabolite 9- (2-phosphonylmethoxyethyl) guanine (PMEG) was not detected in plasma samples but was detected in high levels in peripheral blood mononuclear cells (PBMCs) within 24 hours of dosing and persisted with subsequent dosing in a similar manner in all dosage groups. |
| other | PBMC concentrations 131 nM (cPrPMEDAP) and 1,420 nM (PMEG), median | 0.82 mg/kg once every two or three weeks; median of five dogs; pilot study PC-193-2001 | The PBMC concentrations in the group treated with rabacfosadine doses of 0.82 mg/kg once every two weeks or once every three weeks were 131 and 1,420 nM for cPrPMEDAP and PMEG, respectively (median values from five dogs). |
Target-animal safety
dose multiples 0 (vehicle), 0.25 mg/kg, 0.82 mg/kg, 2.5 mg/kg, 8.2 mg/kg (single IV dose; label dose is 1.0 mg/kg); duration single 30-minute IV infusion (Day 1); necropsy Day 3 (main study) or Day 21 (recovery group); animals 30 male and 30 female.
The acute toxicity study with a recovery period was conducted in 30 male and 30 female Beagle dogs.
| Finding | Quote |
|---|---|
| Single doses of 0, 0.25, 0.82 and 2.5 mg/kg were tolerated | A single IV dose of 0, 0.25, 0.82, and 2.5 mg/kg were tolerated. |
| 8.2 mg/kg caused mortality from GI toxicity and severe neutropenia | A dose of 8.2 mg/kg resulted in mortality due to gastrointestinal toxicity and severe neutropenia. |
| All 8.2 mg/kg recovery-group dogs died or were euthanized on Days 6-7 | All recovery dogs administered 8.2 mg/kg were either found dead or preterminally euthanized due to poor and deteriorating condition on Days 6 or 7. |
| Dose-dependent leukopenia/neutropenia at 0.82 mg/kg and above (nadir Days 6-9, recovery by Day 12) | There was a dose-dependent decrease in white blood cell (WBC) parameters in dogs administered 0.82, 2.5, and 8.2 mg/kg. |
| Lymphoid atrophy/necrosis at 2.5 and 8.2 mg/kg | Lymphoid atrophy and necrosis were noted in the thymus, spleen, mesenteric lymph node, and gut associated lymphoid tissue (GALT) in dogs administered 2.5 and 8.2 mg/kg. |
| Renal tubular degeneration/necrosis persisted after 21-day recovery | Dose-dependent renal tubular degeneration/necrosis was still observed. |
| 3-cycle weekly study: 0.25, 0.50 and 1.0 mg/kg weekly x3 tolerated | Weekly IV doses of 0, 0.25, 0.50, and 1.0 were tolerated. |
| Overall: narrow margin of safety | Rabacfosadine has a narrow margin of safety. |
Effectiveness
Multi-center, prospective, randomized (3:1), masked, placebo (saline)-controlled field study VC-014 in dogs with multicentric lymphoma (naive or previously treated); 1.0 mg/kg IV every 21 days for up to 5 cycles; 158 enrolled (120 TANOVEA, 38 placebo); n = 148 evaluable for effectiveness (112 TANOVEA, 36 placebo); primary endpoint: progression free survival (PFS), Cox regression; result: Median PFS 82 days (95% CI 63-140) vs 21 days (11-21); hazard ratio 6.265 (95% CI 3.947-9.945), p<0.0001. Best overall response rate 73.2% (50.9% CR) vs 5.6% placebo; 33% progression-free at Day 112 vs 0
Results: Effectiveness was evaluated in 148 dogs (112 in the TANOVEA® group and 36 in the Placebo group). TANOVEA® demonstrated a statistically significant improvement in PFS compared to Placebo (82 days vs. 21 days, p < 0.0001).
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Diarrhea | 105 (87.5%) | 19 (50%) | Diarrhea 105 87.5 19 50 |
| Decreased appetite | 82 (68.3%) | 15 (39.5%) | Decreased appetite 82 68.3 15 39.5 |
| Emesis | 82 (68.3%) | 9 (23.7%) | Emesis 82 68.3 9 23.7 |
| Lethargy | 76 (63.3%) | 24 (63.2%) | Lethargy 76 63.3 24 63.2 |
| Weight loss | 58 (48.3%) | 4 (10.5%) | Weight loss 58 48.3 4 10.5 |
| Neutropenia | 55 (45.8%) | 0 | Neutropeniaa 55 45.8 0 |
Extraction notes: Adverse-reaction rows quoted as extracted from Table II.11 (field study; column order: term, n TANOVEA, % TANOVEA (n=120), n placebo, % placebo (n=38)); 'Neutropeniaa' carries a footnote letter. Target animal safety: no X-multiple margin-of-safety study; the acute single-dose toxicity study TX-193-2009 (0.25-8.2 mg/kg, 12 dogs/group) is recorded, with findings also drawn from the 5-day, 3-cycle weekly and overall conclusions. Serious adverse events in 20% (24/120) of TANOVEA dogs including pulmonary fibrosis (5 dogs, all fatal) and dermatopathy; 29 dogs had dose reductions. PK values come from the pilot study, not a dedicated PK study.
Reproduce: foi_structured_search(query="Rabacfosadine") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).