Propofol: what the FDA reviewed for dog products
6 Freedom of Information summaries from the FDA Center for Veterinary Medicine for products containing Propofol, as typed records: every value below is followed by the verbatim passage it was taken from. Species as stated by each summary: Cats and Dogs; Dogs; Dogs and cats.
Products
- PropoClear™ (NADA/ANADA 141-303)
- PropoFlo™ PropoFlo™ 28 (NADA/ANADA 141-098)
- PropofolVet Multidose (NADA/ANADA 200-793)
- Rapanofal® (NADA/ANADA 141-070)
PropoFlo™ PropoFlo™ 28 NADA 141-098, Supplemental approval, February 04, 2011; sponsor Zoetis Inc.; species: Dogs; foi_id 631; FDA PDF
Indication
Induction of anesthesia; maintenance of general anesthesia by intermittent bolus injections for short procedures; induction where maintenance is provided by inhalant anesthetics.
Dose regimen
Induction 7.6 mg/kg (no preanesthetic), 4.7 mg/kg (benzodiazepine/opioid), 4.0 mg/kg (phenothiazine/opioid), 3.2 mg/kg (alpha2-agonist/opioid), over 60-90 seconds, Intravenous, Titrated to effect over 60-90 seconds; maintenance by intermittent IV injections (3.22 mg/kg none, 1.67 benzodiazepine/opioid, 2.03 phenothiazine/opioid), 10 mg propofol/mL in 20 mL multidose vials preserved with benzyl alcohol; rapid injection (≤5 seconds) may increase apnea.
None 7.6 60-90 5.0-7.6 0.50-0.76 Benzodiazepine/ opioid 4.7 60-90 3.1-4.7 0.31-0.47 Phenothiazine/ opioid 4.0 60-90 2.7-4.0 0.27-0.40 Alpha2-agonist/ opioid 3.2 60-90 2.1-3.2 0.21-0.32
Target-animal safety
dose multiples 0X (saline), 1X (6.5 mg/kg PROPOFLO 28), 3X (19.5 mg/kg PROPOFLO 28), 3X (19.5 mg/kg unpreserved PROPOFLO, active control, twice); duration Single IV bolus per treatment; each dog received all treatments with at least 7-day washout (Study Days 1, 10, 20, 27, 50); animals Two female and 2 male Beagle dogs.
b. Study Animals: Two female and 2 male Beagle dogs, young adults (5 – 6 months), 6.2 – 8.3 kg. c. Treatment Groups: Each dog received all treatments with at least a 7 day washout period between treatments.
| Finding | Quote |
|---|---|
| No unexpected serious adverse reactions at 6.5 or 19.5 mg/kg with 2% benzyl alcohol | This study demonstrated that the addition of 2% benzyl alcohol to PROPOFLO at an induction dose of 6.5 mg/kg and an exaggerated dose of 19.5 mg/kg in 4 Beagle dogs did not produce unexpected serious adverse reactions. |
| Clinically significant effects: sinus tachycardia, decreased body temperature and blood pressure, abnormal mucous membrane colour, tachypnea, increased end-tidal CO2, decreased SpO2, transient hypertension | Clinically significant effects of the PROPOFLO and PROPOFLO 28 on variables in this study include sinus tachycardia, decreases in body temperature and blood pressure, abnormal mucous membrane color, tachypnea, increased end tidal CO2, decreased SpO2, and transient hypertension. |
| PROPOFLO 28 caused dose-dependent and greater sinus tachycardia than unpreserved PROPOFLO at the same dose | Treatment with PROPOFLO 28 had a dose-dependent effect on sinus tachycardia, and induced a higher degree of sinus tachycardia compared to PROPOFLO at the same dose. |
| Abnormal observations occurred only after the high dose of PROPOFLO 28 and second high dose of PROPOFLO during recovery | All abnormal observations noted after treatment occurred with the high dose of PROPOFLO 28 and second high dose of PROPOFLO during recovery. |
Effectiveness
Clinical field effectiveness and safety study (Study 05-02-MC-D-CT-H) at 5 sites in client-owned dogs of ASA I-II, six groups (no preanesthetic; midazolam/buprenorphine; acepromazine/buprenorphine; medetomidine/buprenorphine; propofol or inhalant maintenance); each animal its own control.; n = 138; primary endpoint: Induction dose, investigator quality scores for induction/maintenance/recovery, recovery times, physiological variables, adverse reactions; result: Induction excellent in 82 (59%) and good in 47 (34%) of 138 cases; maintenance with PROPOFLO 28 good/excellent in 100%, 68% and 91% of Groups 1-3; benzyl alcohol did not affect induction or maintenance dose or the number/severity of adverse reactions.
The quality of induction was judged as excellent in 82 (59%) of 138 total cases. It was rated as good in 47 (34%) of the cases, fair in 8 (6%) of the cases and poor in 1 (1%) of the cases.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Hypotension (field study) | 16 dogs | Hypotension Cardiovascular 16 | |
| Apnea (field study) | 15 dogs | Apnea Respiratory 15 | |
| Excitation (field study) | 13 dogs | Excitation Central Nervous System 13 | |
| Bradycardia (field study) | 11 dogs | Bradycardia Cardiovascular 11 | |
| Tachypnea (field study) | 7 dogs | Tachypnea Respiratory 7 | |
| Fasciculation (field study) | 4 dogs | Fasciculation Muscular 4 |
Extraction notes: Supplement adding benzyl alcohol preservative (multidose vial); a new field study and tolerance study were conducted. Adverse reaction counts are numbers of dogs among 138 (Table 11, no control group). One dog died 3 days post-ovariohysterectomy from sepsis, judged unrelated. Tolerance study had 4 dogs (crossover); n_animals mirrors the design quote wording.
Rapanofal® NADA 141-070, Supplemental approval, January 14, 1999; sponsor IVAOES, INC. DBA IVAOES ANIMAL HEALTH; species: Dogs and cats; foi_id 611; FDA PDF
Indication
Anesthetic injection for dogs and cats: single injection for short procedures; induction and maintenance with incremental doses; induction with inhalant maintenance. Supplement adds cats and medetomidine information for dogs.
Dose regimen
Dogs: induction 5.5 - 7.0 mg/kg without premedication; cats: induction 8.0-13.2 mg/kg without premedication, Intravenous, Single induction dose over 60-90 seconds; maintenance by intermittent injections to effect, Maintenance: dogs 1.1-3.3 mg/kg, cats 1.1-4.4 mg/kg; premedication reduces propofol requirements (dogs: medetomidine preanesthetic dose lowered to 5-10 µg/kg IM); repeated maintenance doses may be cumulative in the cat.
following the recommended induction dose (5.5 - 7.0 mg/kg for dogs without premedication or 8.0-13.2 mg/kg for cats without premedication) is generally 5 - 7 minutes for dogs
Target-animal safety
dose multiples Vehicle control, 1 induction dose only (13.2 mg/kg), 1 induction dose plus 3 maintenance doses (4.4 mg/kg each), 1 induction dose plus 6 maintenance doses; duration Treated on Days 0, 1, 2, 7, 8 and 9 (six anesthetic episodes); observed to Day 23; animals 4 M and 4 F cats per group.
Treatment groups (4 M and 4 F per group) were designated as follows: Group A (VC) Vehicle Controls Group B (IO) Propofol - 1 induction dose only Group C (I+3M) Propofol - 1 induction dose plus 3 maintenance doses Group D (I+6M) Propofol - 1 induction dose plus 6 maintenance doses
| Finding | Quote |
|---|---|
| Recovery time nearly doubled in the induction + 6 maintenance dose group (47.3 min vs 24.7 min induction-only) | Average recovery tim e for Group D (I+6M) for the entire study was 47.3 m inutes, nearly double the m ean for Group B (IO) and 18 minutes longer than the mean for Group C (I+3M). |
| Heinz bodies increased in all treated groups; remained above 10% on Day 23 in 10 of 24 treated cats, without anemia | In 10 of 24 treated cats the Heinz bodies rem ained above 10% on Day 23. |
| No consistent treatment-related clinical signs | No consistent treatment related clinical signs were noted in cats on study. |
| No treatment-related microscopic findings | There were no m icroscopic findings that were considered to be treatm ent related. |
| Acute toxicity study in cats: no apnea at 19.8 mg/kg (1.5X); apnea > 1 min in two of four cats at 26.4 mg/kg (2X), one of which died | There were no signs of apnea in cats adm inistered 19.8 m g/kg of propofol. Two cats at 26.4 mg/kg experienced apnea lasting longer th an one m inute. |
Effectiveness
Clinical field trial in cats (Peterson 1997) at 4 locations (8 investigators): propofol alone, with preanesthetics (acepromazine, butorphanol, xylazine), or with halothane/isoflurane maintenance; 212 cases (207 cats).; n = 212 cases (cats); primary endpoint: Ease of induction and anesthetic effectiveness scores, recovery times, physiological parameters, adverse reactions; result: Ease of induction excellent or good in 95.4% (propofol only), 100% (acepromazine), 96.2% (butorphanol), 96.7% (xylazine); mean induction dose 10.0 mg/kg without premedication; anesthetic effectiveness excellent or good in 92-100% of inhalant-maintained cases.
Peterson (1997) conducted a clinical field study at 4 locations (8 investigators) with 212 cases presented for surgery and / or other procedures requiring anesthesia.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Cyanosis (cat field trial) | 5 cases | Respiratory side effects during the entire study included: cyanosis (5); apnea (3); and sneezing (1). | |
| Apnea (cat field trial) | 3 cases | Respiratory side effects during the entire study included: cyanosis (5); apnea (3); and sneezing (1). | |
| Paddling (cat field trial) | 24 cases | Musculature side effects were: paddling (24); te nseness (7); fasciculations (5); and twitching (2). | |
| Excitation (cat field trial) | 8 cases | Neurological side effects included: excitation (8); opisthotonus (1); nystagmus (1); excessive depression (1); and slight delirium (1). | |
| Hypotension (cat field trial) | 9 cases | Cardiovascular side effects in cluded: hypotension (9); tachycardia (1); sinus block (1); and premature ventricular contractions (1). |
Extraction notes: Supplement adding cats; this FOI supersedes the 1996 dog summary and repeats all dog data (dose determination, compatibility, field study, toxicity, PK literature). Record focuses on the NEW feline studies: effectiveness = cat field trial (n_dogs holds cat case count), TAS = cat margin-of-safety study (young adult DSH cats, induction 13.2 mg/kg) plus acute toxicity. Cat adverse reaction counts are of 212 cases. PDF extraction inserted stray spaces inside words (e.g. 'm inutes', 'te nseness'); quotes reproduce the text as extracted. Dog PK literature values are captured in the original approval record (foi 610).
PropoFlo™ PropoFlo™ 28 NADA 141-098, Original approval, March 13, 1998; sponsor Zoetis Inc.; species: Dogs; foi_id 630; FDA PDF
Indication
Induction of anesthesia; maintenance of general anesthesia for up to 20 minutes; induction where maintenance is provided by inhalant anesthetics.
Dose regimen
5.5 mg/kg induction without preanesthetic, administered over 40-60 seconds (5.5-8.3 mg/kg/min), Intravenous, Titrated to effect over 30-60 seconds; maintenance by intermittent IV injections (2.2 mg/kg without preanesthetic, 1.6-1.8 mg/kg with preanesthetics), 10 mg propofol/mL emulsion; preanesthetics reduce induction dose (acepromazine 3.7, ace/oxymorphone 2.6, xylazine/butorphanol 3.1, diazepam/oxymorphone 2.4, diazepam/butorphanol 3.3 mg/kg).
Induction Dosage Guidelines Preanesthetic Propofol Induction Dose Propofol Rate of Administration mg/kg Seconds mg/kg/min mL/kg/min None 5.5 40-60 5.5-8.3 0.55-0.83
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| half-life | 2.2, 31 and 303 minutes (alpha, beta, gamma phases, bolus) | Cockshott et al. 1992 (supportive literature), three dogs, single 7 mg/kg IV bolus, three-compartment model | Half-lives for the alpha, beta and gamma elimination phases were 2.2, 31 and 303 minutes, respectively, following bolus dosing, and 7.4, 53 and 725 minutes following infusion at 28 mg/kg/hour. |
| half-life | 7.4, 53 and 725 minutes (alpha, beta, gamma phases, infusion) | Cockshott et al. 1992, 7 mg/kg bolus followed by infusion at 28 mg/kg/hour for 6 hours | Half-lives for the alpha, beta and gamma elimination phases were 2.2, 31 and 303 minutes, respectively, following bolus dosing, and 7.4, 53 and 725 minutes following infusion at 28 mg/kg/hour. |
| protein binding | 98.1% | Cockshott et al. 1992, in vitro, dog plasma | Plasma protein binding was determined to be 98.1% in the dog. |
| half-life | 75 to 91 minutes (terminal elimination) | Nolan et al. 1993, six dogs, 6.5 mg/kg IV bolus, with or without halothane/nitrous oxide maintenance | The terminal elimination half-life was 75 to 91 minutes. |
| other | 4863 to 4889 mL/kg volume of distribution at steady state | Nolan et al. 1993, six dogs, 6.5 mg/kg IV bolus | Propofol exhibited a large volume of distribution at steady state (4863 to 4889 mL/kg) and rapid clearance (56 to 58 mL/kg/min). |
| clearance | 56 to 58 mL/kg/min | Nolan et al. 1993, six dogs, 6.5 mg/kg IV bolus | Propofol exhibited a large volume of distribution at steady state (4863 to 4889 mL/kg) and rapid clearance (56 to 58 mL/kg/min). |
Target-animal safety
dose multiples Saline control, Low Dose 11.6 mg/kg total per episode (6.5 mg/kg induction + 3 x 1.7 mg/kg), High Dose 29.7 mg/kg total per episode (19.5 mg/kg induction + 6 x 1.7 mg/kg); duration Six anesthetic episodes, every other day over an 11-day period; animals 8 dogs per group (4 males and 4 females).
Two propofol groups received total doses of either 11.6 (Low Dose) or 29.7 mg/kg (High Dose) at each episode. Anesthesia was induced with doses of propofol of 6.5 or 19.5 mg/kg and maintained with three and six bolus injections of 1.7 mg/kg propofol, respectively. A third group of dogs was injected with saline (Controls) at a volume equal to that administered to the High Dose dogs. Each group included a total of 8 dogs (4 males and 4 females). Dogs were anesthetized every other day over an 11-d period (six anesthetic episodes for each dog).
| Finding | Quote |
|---|---|
| Apnea after induction averaged 28 s (6.5 mg/kg) and 70 s (19.5 mg/kg) and did not increase with repeated episodes; no oxygen or assisted ventilation required | The duration of apnea averaged 28 and 70 s after induction doses of 6.5 and 19.5 mg/kg, respectively, and did not increase with repeated episodes of propofol administration. |
| No adverse effect on body weight, food consumption, respiration rate, temperature or clinical observations | Propofol did not adversely affect body weight, food consumption, daily respiration rate, temperature or daily clinical observations. |
| Hematology/clinical chemistry findings incidental; no organ weight differences | Hematology and clinical chemistry findings were incidental and not attributed to the administration of propofol. No differences in organ weights or organ weight ratios were observed. |
| Conclusion: 29.7 mg/kg total dose produced no toxicological effects on repeated administration | The results of this Target Animal Safety Study indicate that propofol at a total dose of 29.7 mg/kg body weight produced no toxicological effects upon repeated administration in the dog. |
| Tolerance study (4 Beagles, escalating single bolus doses): apnea > 90 s defined the toxic dose at 16.5-21.5 mg/kg | A dose of 16.5 mg/kg for one dog, 19.0 mg/kg for two dogs and 21.5 mg/kg for one dog produced apnea of > 90 s duration. |
| Mean toxic dose 19.0 mg/kg is about 3.5 times the 5.5 mg/kg average anesthetic dose | These data indicate that propofol is well tolerated by the dog and that the mean toxic dose of 19.0 mg/kg is approximately 3.5 times the average dose required to produce acceptable anesthesia in the non-premedicated dog (5.5 mg/kg). |
Effectiveness
Multi-site clinical field study (4 university sites) in client-owned dogs of ASA status I-III, 11 treatment groups (propofol with/without preanesthetics, maintained with propofol or isoflurane/halothane); animals served as their own controls; descriptive statistics only.; n = 419; primary endpoint: Investigator quality scores for induction, maintenance and recovery; propofol dose requirements; physiological variables; side effects; result: Induction excellent or good in 396 of 419 (94%); maintenance good/excellent in 81% of propofol-maintained and 89% of inhalant-maintained cases; recovery excellent/good in 92% and 93% respectively; preanesthetics reduced induction dose by 33-56%.
Induction was judged as Excellent or Good in 396 of 419 cases (94%).
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Apnea (field study) | n=110 | Respiratory Apnea (n=110) Tachypnea (n=180) Labored Breathing (n=3) | |
| Tachypnea (field study) | n=180 | Respiratory Apnea (n=110) Tachypnea (n=180) Labored Breathing (n=3) | |
| Hypotension (field study) | n=98 | Cardiovascular Hypotension (n=98) Membrane Cyanosis (n=14) Bradycardia (n=72) Tachycardia (n=45) Arrhythmias (n=18) | |
| Bradycardia (field study) | n=72 | Cardiovascular Hypotension (n=98) Membrane Cyanosis (n=14) Bradycardia (n=72) Tachycardia (n=45) Arrhythmias (n=18) | |
| Fasciculations (field study) | n=68 | Muscular Fasciculations (n=68) Muscle Tenseness (n=18) Paddling (n=12) | |
| Excitation (field study) | n=31 | Central Nervous System Excitation (n=31) Excessive Depression (n=2) |
Extraction notes: Original NADA. Adverse reaction counts are numbers of dogs among 419 enrolled (no control group). PK values come from supportive published studies summarised in section 7, not a sponsor PK study. Target animal safety comprised a tolerance (dose escalation) study and the exaggerated-dose repeat study recorded above.
PropoClear™ NADA 141-303, Original approval, May 21, 2010; sponsor Zoetis Inc.; species: Cats and Dogs; foi_id 867; FDA PDF
Indication
Induction and maintenance of anesthesia and induction followed by maintenance with an inhalant anesthetic, in cats and dogs.
Dose regimen
Dogs: induction 4.0 - 6.5 mg/kg without a preanesthetic; 1.4 - 6.5 mg/kg with a preanesthetic, Intravenous injection, Single induction dose; maintenance by intermittent IV injections (dogs mean 1.7-1.8 mg/kg, range 0.4-3.3 mg/kg; duration approximately 3-5 minutes per dose), Cats: induction 4.1-8.0 mg/kg without and 2.7-8.0 mg/kg with a preanesthetic; maintenance 0.6-5.0 mg/kg. Sighthounds may need lower maintenance doses and longer recovery.
Induction of General Anesthesia in Dogs: Induction dose guidelines are 4.0 - 6.5 mg/kg in dogs that do not receive a preanesthetic, and 1.4 - 6.5 mg/kg in dogs that receive a preanesthetic.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| cmax | 5746 (1763) ng/mL (TPI-213M) | Canine PK study MDSPS 030214: six male Beagle dogs (7.7-11.5 kg), 6.0 mg/kg IV over ~60 seconds, two-treatment two-period crossover of precursor formulation TPI-213M vs RAPINOVET; Table 18 columns: Cmax (±1SD), Tmax (±1SD), AUC0-inf (±1SD), half-life (±1SD) | TPI-213M 5746 (1763) ng/mL 1 (0) minutes 928 (128) hours·ng/mL 0.4 (0.1) hours |
| tmax | 1 (0) minutes (TPI-213M) | Canine PK study MDSPS 030214: six male Beagle dogs (7.7-11.5 kg), 6.0 mg/kg IV over ~60 seconds, two-treatment two-period crossover of precursor formulation TPI-213M vs RAPINOVET; Table 18 columns: Cmax (±1SD), Tmax (±1SD), AUC0-inf (±1SD), half-life (±1SD) | TPI-213M 5746 (1763) ng/mL 1 (0) minutes 928 (128) hours·ng/mL 0.4 (0.1) hours |
| auc | 928 (128) hours·ng/mL AUC0-inf (TPI-213M) | Canine PK study MDSPS 030214: six male Beagle dogs (7.7-11.5 kg), 6.0 mg/kg IV over ~60 seconds, two-treatment two-period crossover of precursor formulation TPI-213M vs RAPINOVET; Table 18 columns: Cmax (±1SD), Tmax (±1SD), AUC0-inf (±1SD), half-life (±1SD) | TPI-213M 5746 (1763) ng/mL 1 (0) minutes 928 (128) hours·ng/mL 0.4 (0.1) hours |
| half-life | 0.4 (0.1) hours (TPI-213M) | Canine PK study MDSPS 030214: six male Beagle dogs (7.7-11.5 kg), 6.0 mg/kg IV over ~60 seconds, two-treatment two-period crossover of precursor formulation TPI-213M vs RAPINOVET; Table 18 columns: Cmax (±1SD), Tmax (±1SD), AUC0-inf (±1SD), half-life (±1SD) | TPI-213M 5746 (1763) ng/mL 1 (0) minutes 928 (128) hours·ng/mL 0.4 (0.1) hours |
| cmax | 8590 (5895) ng/mL (RAPINOVET) | Canine PK study MDSPS 030214: six male Beagle dogs (7.7-11.5 kg), 6.0 mg/kg IV over ~60 seconds, two-treatment two-period crossover of precursor formulation TPI-213M vs RAPINOVET; Table 18 columns: Cmax (±1SD), Tmax (±1SD), AUC0-inf (±1SD), half-life (±1SD) | RAPINOVET 8590 (5895) ng/mL 1 (0) minutes 1064 (269) hours·ng/mL 0.4 (0.3) hours |
| auc | 1064 (269) hours·ng/mL AUC0-inf (RAPINOVET) | Canine PK study MDSPS 030214: six male Beagle dogs (7.7-11.5 kg), 6.0 mg/kg IV over ~60 seconds, two-treatment two-period crossover of precursor formulation TPI-213M vs RAPINOVET; Table 18 columns: Cmax (±1SD), Tmax (±1SD), AUC0-inf (±1SD), half-life (±1SD) | RAPINOVET 8590 (5895) ng/mL 1 (0) minutes 1064 (269) hours·ng/mL 0.4 (0.3) hours |
| half-life | 0.4 (0.3) hours (RAPINOVET) | Canine PK study MDSPS 030214: six male Beagle dogs (7.7-11.5 kg), 6.0 mg/kg IV over ~60 seconds, two-treatment two-period crossover of precursor formulation TPI-213M vs RAPINOVET; Table 18 columns: Cmax (±1SD), Tmax (±1SD), AUC0-inf (±1SD), half-life (±1SD) | RAPINOVET 8590 (5895) ng/mL 1 (0) minutes 1064 (269) hours·ng/mL 0.4 (0.3) hours |
| other | Cmax ratio 0.85 (90% CI 0.47-1.53) TPI-213M vs RAPINOVET | Same study; log-transformed data; AUC ratio 0.93 (90% CI 0.72-1.20); not equivalent by 0.80-1.25 criterion | The estimated ratio for mean Cmax values (based on log-transformed data) of TPI-213M relative to RAPINOVET was 0.85 and the 90% Confidence Interval Limits about the ratio were 0.47 and 1.53. |
Target-animal safety
dose multiples 0X (saline 2.1 mL/kg), 1X (7.0 mg/kg induction + 3 maintenance doses of 3.3 mg/kg), 3X (21.0 mg/kg induction + 6 maintenance doses of 3.3 mg/kg); duration Every other day for 6 doses (Study Days 0-10); entire dose administered, not to effect; animals 24 purpose-bred Beagle dogs.
The study utilized 24 purpose-bred Beagle dogs, aged 7.5 to 8.5 months old, weighing 10.0 to 12.4 kg on Study Day 0.
| Finding | Quote |
|---|---|
| Two deaths on Day 0: one 3X dog after induction (21 mg/kg) and one 1X dog after the second maintenance dose | One dog in the 3X group (21 mg/kg) died after administration of the induction dose on Study Day 0, and one dog in the 1X group (7 mg/kg) died after administration of the second maintenance dose on Study Day 0. |
| Deaths followed propofol-induced apnea, hypotension, bradycardia, hypoxia and arrhythmias; administration time then increased from 1 to 2 minutes | Both dogs developed propofol-induced apnea, followed by hypotension, bradycardia, hypoxia, arrhythmias, and death. |
| Apnea in one 1X dog and seven 3X dogs; mean duration 22 minutes (range 1-55) | Apnea occurred in one 1X dog, and seven 3X group dogs. |
| Dose- and time-dependent decrease in body temperature, normal within 4 hours | Body temperature decreased in a dose and time dependent manner in both treated groups, and returned to normal within 4 hours post anesthesia, or sooner. |
| No effect on body weights, organ weights, clinical chemistry, coagulation or urinalysis | administration of PROPOCLEAR did not affect body weights, organ weights, clinical chemistry, coagulation, or urinalysis. |
| Conclusion: full induction (7.0 mg/kg) and maintenance (3.3 mg/kg) doses safest when administered over 2 minutes | Under the conditions of the study where the entire dose was administered, propofol 1% w/v administered for anesthesia induction (7.0 mg/kg) and maintenance (3.3 mg/kg) was safest when dose administration occurred over a 2-minute interval. |
Effectiveness
Multicentric GCP field study in dogs (Study 0989-C-US-03-06, 7 sites, 2007): client-owned dogs of ASA I-II assigned to 8 groups (no preanesthetic, acepromazine+butorphanol, medetomidine, or midazolam+butorphanol; propofol or isoflurane maintenance); propofol to effect up to 6.5 mg/kg over ~60 seconds.; n = One hundred sixty-one enrolled; primary endpoint: Time to onset of recumbency/anesthesia, duration of anesthesia and recumbency, time to standing recovery, quality of anesthesia scores; result: Induction and maintenance quality excellent or acceptable in 100% of dogs in all groups; recovery excellent/acceptable in 100% except Group 8 (85%); mean induction dose 6.2 mg/kg without and 4.6 mg/kg with a preanesthetic (20-30% sparing); mean maintenance dose 1.8 mg/kg.
One hundred sixty-one dogs enrolled in the study.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Apnea after propofol (dog field study) | 6 dogs (3.7%) | After administration of propofol, apnea occurred at least once during anesthesia in 6 dogs (3.7%). | |
| Hypotension (SBP ≤ 70 mm Hg) after propofol | 12 dogs (7.5%) | A total of 12 dogs (7.5%) experienced hypotension (systolic blood pressure ≤ 70 mm Hg) following propofol administration. | |
| Hypoxia (SpO2 < 85%) after propofol (vs 7 dogs, 4.3%, before propofol) | 14 dogs (8.7%) | 14 dogs (8.7%) experienced hypoxia following propofol administration versus 7 dogs before (4.3%). | |
| Bradycardia (≤ 70 bpm), all groups (Table 31: after preanesthetics / after propofol) | 90 after propofol | Bradycardia (≤ 70 bpm) 12 90 | |
| Pain on injection (Table 31: after preanesthetics / after propofol) | 13 after propofol | Pain on Injection 0 13 | |
| Bradycardia in medetomidine-preanesthetized dogs (Groups 5 and 6) after propofol | 27/41 dogs (66%) | Bradycardia was documented in 14/41 dogs (34%) in Groups 5 and 6 prior to the start of propofol infusion, and 27/41 dogs (66%) following propofol administration. |
Extraction notes: Summary covers cats and dogs (species stated 'Cats and Dogs'); this record captures the DOG sections (IV-VI); the feline field study and safety studies are not extracted. Dog field study: 161 enrolled, 158 evaluated for effectiveness (number spelled out in the summary text, so n_dogs is given in words). Adverse reaction 'treated' counts are event counts among the enrolled dogs, with no untreated control group (Table 31 compares after-preanesthetic vs after-propofol). PK values are from a precursor formulation (TPI-213M) crossover with RAPINOVET; ±1SD in parentheses.
Rapanofal® NADA 141-070, Original approval, November 07, 1996; sponsor IVAOES, INC. DBA IVAOES ANIMAL HEALTH; species: Dogs; foi_id 610; FDA PDF
Indication
Anesthetic injection for dogs: single injection for general anesthesia for procedures up to five minutes; induction and maintenance with incremental doses; induction where maintenance is by inhalant anesthetics.
Dose regimen
Induction 5.5 - 7.0 mg/kg without premedication (administered over 60-90 seconds); maintenance 1.1 to 3.3 mg/kg, Intravenous, Single induction dose; maintenance by intermittent injections to effect, 10 mg/mL emulsion; premedicants markedly reduce requirements (e.g. acepromazine 4.0-4.4, xylazine 2.2-3.3, oxymorphone 2.2-3.3, medetomidine 2.2-2.8, butorphanol 4.4-5.0 mg/kg induction); use without available supplemental oxygen and ventilation not recommended.
Induction of anesthesia will usually be observed within 30-60 seconds after the end of administration (administration should take 60 -90 seconds). The duration of anesthesia following the recommended induction dose (5.5 - 7.0 mg/kg without premedication) is generally 5 - 7 minutes. The duration of anesthesia following maintenance doses varies depending upon the dose; generally 2 - 6 minutes after 1.1 mg/kg and 6 - 10 minutes after 3.3 mg/kg.
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| half-life | 27 minutes (elimination) | Cockshott 1983 (supportive literature/sponsor study), bolus doses of 5 or 10 mg/kg IV, two-compartment model | Following bolus doses of 5 or 10 mg/kg, propofol was rapidly distributed into a large apparent volume of distribution (81 L). Propofol clearance was characterized by an elimination half-life of 27 minutes. |
| other | 81 L apparent volume of distribution | Cockshott 1983, bolus 5 or 10 mg/kg IV | Following bolus doses of 5 or 10 mg/kg, propofol was rapidly distributed into a large apparent volume of distribution (81 L). |
| half-life | 35 minutes (elimination, after induction plus maintenance infusion) | Cockshott 1983, induction dose followed by maintenance infusion; steady state within 25 minutes | The elimination half life was 35 minutes. |
| clearance | 76 mL/kg/min total body clearance (single injection) | Cockshott et al. 1992, 3 dogs, 7 mg/kg single IV dose, three-compartment model | Following a single injection, there was a large initial volume of distribution (1.4 L/kg), and extensive redistribution (11.4 L/kg). The total body clearance was rapid (76 mL/kg/min). |
| other | 1.4 L/kg initial volume of distribution; 11.4 L/kg redistribution | Cockshott et al. 1992, single 7 mg/kg IV injection | Following a single injection, there was a large initial volume of distribution (1.4 L/kg), and extensive redistribution (11.4 L/kg). |
| clearance | 34 mL/kg/min total body clearance (after infusion) | Cockshott et al. 1992, 7 mg/kg followed by infusion at 0.47 mg/kg/min for 6 hours | The total body clearance rate was slower (34 mL/kg/min). |
| half-life | approximately 24 minutes (apparent elimination from plasma) | Simons 1983, 14C propofol 9.7 mg/kg IV, 3 male and 3 female dogs | The apparent elimination half-life of propofol from plasma was approximately 24 minutes. |
Target-animal safety
dose multiples 3X (20 mg/kg), 4.5X (30 mg/kg), 6X (40 mg/kg); duration Single IV injection at 0.5 mg/sec; 14-day observation; animals 2 male, 2 female beagles per group (3 groups).
Four beagle dogs (2 male, 2 female/9-10 months) were chosen for each of the following 3 groups: 20 mg/kg (2 mL/kg) = 3X 30 mg/kg (3 mL/kg) = 4.5X 40 mg/kg (4 mL/kg) = 6X A single injection of propofol was administered into the cephalic vein at 0.5 mg/sec. The dogs were observed for 14 days following the injection.
| Finding | Quote |
|---|---|
| All four dogs at 40 mg/kg (6X) died within one minute of the end of administration; one female at 30 mg/kg died shortly after dosing | When all four of those dogs died within one minute after the end of propofol administration, the 30 mg/kg group was added to the study. One female at 30 mg/kg died shortly after dosing. |
| Surviving dogs recovered within 45-60 min (30 mg/kg) or 20-30 min (20 mg/kg); no adverse effects over 14 days | All other animals were anesthetized; recovery occurred within 45-60 minutes (30 mg/kg dose) or 20-30 minutes (20 mg/kg dose) after dosing. Over the following 14 days, no adverse effects were noted in the surviving dogs. |
| Conclusion: propofol without respiratory support may be lethal or cause severe respiratory depression at 3X or greater (>20 mg/kg) | The administration of propofol without respiratory support (oxygen supplementation, ventilation) may be lethal or result in severe respiratory depression at doses equivalent to 3X or greater (>20 mg/kg) than the recommended induction dose. |
| 30-day IV toxicity study (5 mg/kg = 0.76X and 10 mg/kg = 1.5X daily; 30 mg/kg/day = 4.5X three times weekly): recovery times lengthened with repeated dosing, significant for Groups IV and V | As the study progressed, the recovery times lengthened for dogs from Groups III, IV, and V. This increase was statistically significant for Groups IV and V (p<0.01). |
| 30-day study: no propofol-attributed changes in organ weights or macroscopic/microscopic tissues | At necropsy, there were no changes in organ weights or any macroscopic or microscopic tissue changes that were attributed to propofol. |
| Injection site study (10 mg/kg = 1.5X, three consecutive days): no venous irritation | Propofol did not produce local irritation when injected into the cephalic vein. |
Effectiveness
Clinical trial under field conditions (Peterson 1995) at 11 sites, April-September 1995: dogs presented for surgery or other procedures, three treatment classifications (propofol sole anesthetic; propofol with preanesthetics; propofol induction with halothane or isoflurane maintenance); 325 anesthetic episodes.; n = 325; primary endpoint: Ease of induction, anesthetic effectiveness and recovery scores (excellent/good/fair/poor), physiological parameters, adverse reactions; result: Induction mostly excellent or good (propofol only 93% excellent); anesthetic effectiveness excellent or good in 85-100% per regimen; recoveries excellent or good in 93% (114 of 123) of propofol-maintained and 95% (184 of 194) of inhalant-maintained dogs; repeated maintenance doses did not prolong recovery (non-cumulative).
The study included 325 dogs that were presented to veterinarians in private practice or at veterinary teaching hospitals for surgery and/or other procedures that required anesthesia.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Induction apnea (within 10 min of induction), all regimens | 20% | Induction apnea (within 10 minutes of induction) was the most common side effect of propofol administration (20%). | |
| Apnea after oxymorphone premedication | 17/48 (35 %) | Propofol induction after oxymorphone premedication had the highest incidence of apnea (17/48; 35 %). | |
| Musculoskeletal side effects (paddling, tremors, tenseness etc.) | n = 35; 10.8% | 3. Musculoskeletal (n = 35; 10.8%): | |
| Neurological side effects (excitation, opisthotonus, nystagmus, seizure-like activity etc.) | n = 18; 5.5% | 2. Neurological (n = 18; 5.5%): | |
| Respiratory side effects other than apnea (reverse sneezing, panting etc.) | n = 16; 4.9% | 1. Respiratory (n = 16; 4.9%, excluding apnea): | |
| Cardiovascular side effects (bradycardia 8, tachycardia, cyanosis, hypotension) | n = 11; 3.4% | 5. Cardiovascular (n = 11; 3.4%): |
Extraction notes: Original NADA. Field study n = 325 anesthetic episodes (313 dogs once, five dogs used more than once). Target animal safety comprised an acute IV toxicity study (recorded above with dose multiples), a 30-day IV toxicity study and an injection-site study; dose-determination studies (30 dogs each) also reported apnea at 9.9 mg/kg induction and 5.5 mg/kg maintenance. PK values are from supportive literature/sponsor studies, not a pivotal PK study. Percentages in adverse reactions are of 325 cases; no control group. One death 8 hours after anesthesia not attributed to propofol.
PropofolVet Multidose NADA 200-793, Original approval, November 18, 2024; sponsor Parnell Technologies Pty. Ltd.; species: Dogs; foi_id 16265; FDA PDF
Indication
Induction of anesthesia; maintenance of general anesthesia by intermittent bolus injections for short procedures; induction where maintenance is provided by inhalant anesthetics.
Dose regimen
Induction 7.6 mg/kg (no preanesthetic), 4.7 mg/kg (benzodiazepine/opioid), 4.0 mg/kg (phenothiazine/opioid), 3.2 mg/kg (alpha2-agonist/opioid), over 60 to 90 seconds, Intravenous, Titrated to effect over 60 to 90 seconds; maintenance by intermittent IV injections (3.2 mg/kg none, 1.7 benzodiazepine/opioid, 2.0 phenothiazine/opioid), 10 mg/mL preserved emulsion in 20 mL multidose vials; rapid injection (≤5 seconds) may increase apnea.
None 7.6 60 to 90 5.0 to 7.6 0.50 to 0.76 Benzodiazepine/Opioid 4.7 60 to 90 3.1 to 4.7 0.31 to 0.47 Phenothiazine/Opioid 4.0 60 to 90 2.7 to 4.0 0.27 to 0.40 Alpha2-agonist/Opioid 3.2 60 to 90 2.1 to 3.2 0.21 to 0.32
Pharmacokinetics
| Parameter | Value | Conditions | Quote |
|---|---|---|---|
| auc | 1757.89 (ng/mL)*hour (generic, geometric mean) | Single IV dose 7.6 mg/kg, 22 fasted intact male Beagles, two-period crossover, generic vs RLNAD PropoFlo 28; Table II.1 columns: generic mean, RLNAD mean, ratio, lower 90% CI, upper 90% CI (geometric means; AUC from 1 minute post-dose) | AUC^ (ng/mL)*hour 1757.89† 1766.65† 1.00 0.96 1.03 |
| auc | 1766.65 (ng/mL)*hour (RLNAD, geometric mean) | Single IV dose 7.6 mg/kg, 22 fasted intact male Beagles, two-period crossover, generic vs RLNAD PropoFlo 28; Table II.1 columns: generic mean, RLNAD mean, ratio, lower 90% CI, upper 90% CI (geometric means; AUC from 1 minute post-dose) | AUC^ (ng/mL)*hour 1757.89† 1766.65† 1.00 0.96 1.03 |
| cmax | 10159.63 ng/mL (generic, geometric mean) | Single IV dose 7.6 mg/kg, 22 fasted intact male Beagles, two-period crossover, generic vs RLNAD PropoFlo 28; Table II.1 columns: generic mean, RLNAD mean, ratio, lower 90% CI, upper 90% CI (geometric means; AUC from 1 minute post-dose) | CMAX (ng/mL) 10159.63† 9728.37† 1.04 0.97 1.12 |
| cmax | 9728.37 ng/mL (RLNAD, geometric mean) | Single IV dose 7.6 mg/kg, 22 fasted intact male Beagles, two-period crossover, generic vs RLNAD PropoFlo 28; Table II.1 columns: generic mean, RLNAD mean, ratio, lower 90% CI, upper 90% CI (geometric means; AUC from 1 minute post-dose) | CMAX (ng/mL) 10159.63† 9728.37† 1.04 0.97 1.12 |
| tmax | 1.02 (0.05) min (generic, arithmetic mean (SD)) | Single IV dose 7.6 mg/kg, 22 fasted intact male Beagles, two-period crossover, generic vs RLNAD PropoFlo 28; Table II.1 columns: generic mean, RLNAD mean, ratio, lower 90% CI, upper 90% CI (geometric means; AUC from 1 minute post-dose) | TMAX (min) (SD)‡ 1.02 (0.05)‡ 1.05 (0.17)‡ NE NE NE |
| tmax | 1.05 (0.17) min (RLNAD, arithmetic mean (SD)) | Single IV dose 7.6 mg/kg, 22 fasted intact male Beagles, two-period crossover, generic vs RLNAD PropoFlo 28; Table II.1 columns: generic mean, RLNAD mean, ratio, lower 90% CI, upper 90% CI (geometric means; AUC from 1 minute post-dose) | TMAX (min) (SD)‡ 1.02 (0.05)‡ 1.05 (0.17)‡ NE NE NE |
Effectiveness
Pivotal blood-level bioequivalence study (Study No. 116-BC-0521): randomized, masked, two-period, two-sequence, single-dose crossover in fasted intact male Beagles, 7.6 mg/kg IV generic vs RLNAD PropoFlo 28, 7-day washout.; n = 22; primary endpoint: CMAX and AUC (90% CI of geometric mean ratio within 0.80-1.25); result: Bioequivalence demonstrated: AUC ratio 1.00 (90% CI 0.96-1.03), CMAX ratio 1.04 (90% CI 0.97-1.12).
The laboratory study was conducted as a randomized, masked, two-period, two-sequence, two-treatment, single-dose crossover design using 22 dogs with a 7-day washout between periods.
Adverse reactions
| Term | Treated | Control | Quote |
|---|---|---|---|
| Serious adverse events (bioequivalence study) | There were no serious adverse events reported during the study. |
Extraction notes: First generic propofol injectable emulsion for dogs; the bioequivalence study is recorded as effectiveness. No target animal safety or field studies required. PK rows quoted from Table II.1 as flattened by PDF extraction.
Reproduce: foi_structured_search(query="Propofol") and foi_summary_get(foi_id=...) in dog-geroscience-mcp; dataset foi-summaries-dog (config structured).