Ormetoprim, Sulfadimethoxine: what the FDA reviewed for dog products
2 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Ormetoprim, Sulfadimethoxine, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Dogs.
Products
- Primor® Tablets (NADA/ANADA 100-929)
Primor® Tablets NADA 100-929, Supplemental approval, August 05, 1996; sponsor Zoetis Inc.; species: Dogs; foi_id 1689; FDA PDF
Indication
Skin and soft tissue infections (wounds and abscesses) caused by susceptible Staphylococcus aureus and Escherichia coli, and (added by this supplement) urinary tract infections caused by Escherichia coli, Staphylococcus spp. and Proteus mirabilis susceptible to sulfadimethoxine/ormetoprim, in dogs.
Dose regimen
25 mg/lb (55 mg/kg) initial dose on the first day, then 12.5 mg/lb (27.5 mg/kg), oral (tablet), once daily, continue at least two days after remission of clinical signs; not more than 21 consecutive days
Administer an initial oral dose of 25 mg/lb (55 mg/kg) of body weight on the first day of treatment. Administer subsequent daily doses at the rate of 12.5 mg/lb (27.5 mg/kg) of body weight. Continue treatment for at least two days after remission of clinical signs. Do not extend treatment for more than 21 consecutive days.
Effectiveness
Well-controlled, blinded, multicentered (nine investigators, three geographic regions) positive-controlled field study vs Tribrissen (sulfadiazine/trimethoprim 12 mg/lb once daily) in dogs with acute naturally occurring bacterial urinary tract infections; Primor 25 mg/lb day 1 then 12.5 mg/lb once daily for 10-14 days; n = 75; primary endpoint: Investigator clinical response grade (excellent/good = positive) and bacteriological elimination on post-treatment urine culture; result: Bacteriological elimination table: Primor 39/43 isolates (91%) vs Tribrissen 29/33 (88%) (narrative gives 93% vs 90%); E. coli 87% vs 86%, Proteus mirabilis 92% vs 100%, Staphylococcus spp. 100% vs 83%. Clinical response for E. coli cases: excellent 65%, good 13%, fair 18%, poor 4% with Primor (n=23) vs 72%/9%/5%/14% with Tribrissen (n=22)
This study was conducted as a multicentered trial involving nine investigators. There were 75 dogs with urinary tract infections that were treated with either experimental or control drug and completed the study protocol.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Adverse reactions reported (all types, field study) | 3 | 4 | A total of 7 adverse reactions were reported, 3 with Primor and 4 with Tribrissen. |
| Notable changes in hematology and clinical chemistry parameters | 7 | 9 | There were also 10 cases with a total of 16 notable changes in hematology and clinical chemistry parameters, 7 with Primor and 9 with Tribrissen. |
Extraction notes: Supplemental approval (1996) adding the urinary tract infection claim. Animal safety cross-references the original FOI summary (same species and dosage); no PK data. Of the 75 dogs, 42 received Primor and 33 Tribrissen (per the clinical response section). Narrative elimination rates (93% vs 90%) differ from the table totals (91% vs 88%); both are as printed.
Primor® Tablets NADA 100-929, Original approval, November 24, 1989; sponsor Zoetis Inc.; species: Dogs; foi_id 1774; FDA PDF
Indication
Treatment of skin and soft tissue infections (wounds and abscesses) in dogs caused by strains of Staphylococcus aureus and Escherichia coli susceptible to sulfadimethoxine/ormetoprim.
Dose regimen
25 mg/lb (55 mg/kg) initial dose on the first day, then 12.5 mg/lb (27.5 mg/kg), oral (tablet), once daily, continue at least two days after remission of clinical signs; not more than 21 consecutive days
Administer an initial oral dose of 25 mg/lb (55 mg/kg) of body weight on the first day of treatment. Administer subsequent daily doses at the rate of 12.5 mg/lb (27.5 mg/kg) of body weight. Continue treatment for at least two days after remission of clinical signs. Do not extend treatment for more than 21 consecutive days.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| other | SDM 23, 41, 39, 85, 36 mcg/mL (recommended regimen) vs 16, 22, 12, 28, 14 mcg/mL (half regimen) | sulfadimethoxine blood levels at 2, 8, 24 (pre-second-dose), 28 and 48 h; recommended regimen 25 mg/lb day 1 then 12.5 mg/lb at 24 h in 2 male + 2 female dogs vs half regimen (12.5 then 6.25 mg/lb) in eight dogs; Table 5 row columns alternate Rec / half-Rec per time point | SDM 23 16 41 22 39 12 85 28 36 14 |
| other | OMP 1.04, 0.55, 0.09, 0.96, 0.03 mcg/mL (recommended regimen) vs 0.94, 0.52, ND, 0.45, ND (half regimen) | ormetoprim blood levels at 2, 8, 24, 28 and 48 h, same design as above; ND = not detected; ormetoprim not detectable 24 h after the half dose | OMP 1.04 0.94 0.55 0.52 0.09 ND+ 0.96 0.45 0.03 ND |
Target-animal safety
dose multiples 1x, 3x, 5x; duration eight weeks (about 3 times the maximum 21-day label duration) at 27.5, 82.5 or 137.5 mg/kg/day; 12-week recovery for high-dose and control subgroups; plus acute pyramiding-dose study (up to 320 mg/kg) and 13-week SDM/OMP 5:3 chronic study.
An eight week oral toxicity study was conducted in forty two beagle dogs with Primor (sulfadimethoxine + ormetoprim, 5:1). The compounds were administered together in the market dosage form designed for clinical veterinary use. Dosages were 0 (control), 0 (excipient), 27.5, 82.5, or 137.5 mg/kg (12.5, 37.5, or 62.5 mg/lb)b.w./day. The drug levels used represent at least 1x, 3x and 5x the label dose level, administered for approximately three times the maximum 21 day duration provided by label direction.
| Finding | Quote |
|---|---|
| 5x (137.5 mg/kg/day) for 8 weeks: mild clinical signs, minimal corneal and lens opacities, reduced heart rate and R-wave amplitude, decreased hemoglobin/hematocrit, decreased T3, T4 and folate, elevated cholesterol, increased thyroid, pituitary, liver and prostate weights, thyroid hyperplasia, pituitary basophil enlargement, thymic involution, adrenal and hepatic changes, focal testicular atrophy. | Treatment of dogs with Primor at 137.5 mg/kg (62.5 mg/lb) b.w./day for eight weeks resulted in a low incidence of mild clinical signs; minimal corneal and lens opacities; reduced heart rate and R wave amplitude; decreased hemoglobin and hematocrit; decreased serum T3, T4, and folate; elevated serum cholesterol; increased thyroid, pituitary, liver and prostate weights; parenchymatous thyroid hyperplasia; enlarged basophilic cells in the pituitary; involution of the thymic cortex, slight histologic changes in the adrenal cortex; areas of vacuolization and rarefication of hepatocytes limited, focal testicular atrophy. |
| After 12-week recovery thyroids decreased but remained heavier than controls; lens opacities persisted in one of two affected dogs; all other changes reversible. | At the end of a 12 week recovery period, the enlarged thyroids had markedly decreased in average weight but were still heavier than the control thyroids, diffuse colloidal goiter was present indicating recovery of function, and treatment related lens opacities were still present in one of two dogs that exhibited this change at the end of the treatment period. All other changes were totally reversible. |
| 1x (27.5 mg/kg/day) for 8 weeks: elevated cholesterol, increased thyroid and liver weights, pituitary basophil enlargement, mild follicular thyroid hyperplasia. | Treatment of dogs with Primor at 27.5 mg.kg (12.5 mg.lb)b.w./day for eight weeks resulted in elevated serum cholesterol, increased thyroid and liver weights, enlarged basophilic cells in the pituitary and mild follicular thyroid hyperplasia. |
| Principal effect of extended or excessive use is hypothyroidism, a known sulfonamide effect. | Based on reversal of virtually all treatment related effects observed with the high dose dogs, it is concluded that the principal treatment related effects of extended or excessive Primor usage is hypothyroidism. |
| Acute pyramiding study: up to 320 mg/kg (about 5x initial / 10x maintenance dose) survived with depression, tremors and, in one dog, convulsions; no lasting effects. | The 320 mg/kg dose is approximately five times the proposed initial dose for Primor and ten times the maintenance dose. No sustaining long term effects were observed following the pyramiding doses. |
| 13-week study: ormetoprim 60 mg/kg alone or with 1000 mg sulfadimethoxine caused GI disturbance, weight loss, brief seizures, hyperactivity, tremors and salivation; one high-dose SDM/OMP dog died in week six. | Ormetoprim at 60 mg/kg alone or in combination with 1000 mg sulfadimethoxine produced toxic reactions characterized by gastrointestinal disturbances and weight loss, brief seizures, hyperactivity and muscle tremors and salivation. |
Effectiveness
Double-blind, positive-controlled (sulfadiazine/trimethoprim 5:1 at 14 mg/lb/day) clinical study in three US geographic areas in dogs with bacterial skin and soft tissue infections; Primor 55 mg/kg day 1 then 27.5 mg/kg/day for 5-11 days; qualifying S. aureus and E. coli cases; n = 26 (Primor); 25 (control); primary endpoint: Clinical evaluation excellent + good (% improved); result: Primor 96% improved overall (S. aureus 94% of 16, E. coli 100% of 10) vs 84% for sulfadiazine/trimethoprim (77% of 13, 92% of 12); judged at least as effective as the positive control (not amenable to statistical analysis)
S. aureus 16 94 13 77 E. coli 10 100 12 92 Total 26 96 25 84
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| No treatment-related side effects (experimental UTI dose-titration study) | Animals were monitored daily for clinical manifestations of infection and for possible side effects. No side effects related to treatment were observed. |
Extraction notes: Original approval (1989). No Species/Class field; 'Dogs' from indication. Table 6 (effectiveness) was flattened by extraction; the quoted row reads organism, Primor no. treated, % improved, control no. treated, % improved. Table 5 blood-level rows are quoted whole; per-time-point columns alternate recommended / half-recommended regimen at 2, 8, 24, 28 and 48 h. The subacute study size is spelled out ('forty two beagle dogs') so n_animals is null; groups were 6 dogs/sex (high dose, control) and 3 dogs/sex (mid, low, excipient). Corroborative effectiveness: 217 clinical cases (87% cured, 94% cured + improved), an experimental E. coli soft tissue model in 20 Beagles, and an experimental UTI dose-titration study (5/6 cleared at label dose vs 0/7 placebo).
Reproduce: foi_structured_search(query="Ormetoprim, Sulfadimethoxine") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).