Alfaxalone: what the FDA reviewed for dog products

Alfaxan® Multidose NADA 141-342, Supplemental approval, August 01, 2014; sponsor Zoetis Inc.; species: Cats and Dogs; foi_id 899; FDA PDF

Indication

Induction and maintenance of anesthesia, and induction of anesthesia followed by maintenance with an inhalant anesthetic, in cats and dogs

Dose regimen

1.5 – 4.5 mg/kg (dogs with no preanesthetic); 0.2 – 3.5 mg/kg (preanesthetized dogs), Intravenous, Single induction dose titrated to effect; intermittent IV maintenance boluses as needed, Induction of general anesthesia in dogs; dose guidelines unchanged from original approval

Induction of general anesthesia in dogs: Induction dose guidelines are based on data from the field study (see EFFECTIVENESS) and range between 1.5 – 4.5 mg/kg for dogs that did not receive a preanesthetic, and between 0.2 – 3.5 mg/kg for dogs that received a preanesthetic.

Extraction notes: Supplemental approval for revised labeling only (placement of alfaxalone into DEA Schedule IV). CVM did not require effectiveness or target animal safety studies; the summary refers to the original approval FOI summary dated September 6, 2012. No PK, safety or effectiveness content to extract.

Alfaxan® Multidose NADA 141-342, Supplemental approval, June 06, 2018; sponsor Zoetis Inc.; species: Cats and Dogs; foi_id 3739; FDA PDF

Indication

Induction and maintenance of anesthesia, and induction of anesthesia followed by maintenance with an inhalant anesthetic, in cats and dogs

Dose regimen

2.2 mg/kg average (range 1.5 - 4.5 mg/kg) for induction in dogs with no preanesthetic, Intravenous, Single induction dose to effect; intermittent IV maintenance boluses as needed, Preanesthetized dogs 0.2 - 3.5 mg/kg; maintenance boluses 1.2 - 1.4 mg/kg (preanesthetized) or 1.5 - 2.2 mg/kg (unpreanesthetized) give an additional 6 - 8 minutes of anesthesia; dosage range unchanged from unpreserved Alfaxan®

No preanesthetic 2.2 (1.5 - 4.5) 17

Pharmacokinetics

Target-animal safety

dose multiples 1X; duration Single 2 mg/kg IV dose per period; randomized 2-period crossover with 6 days washout (preserved vs unpreserved formulation); animals Twelve.

Study Animals: Twelve adult, healthy dogs were used during the study. Dogs had an average body weight of 18 kg (range 12.6 – 22.4 kg). Experimental Design: The experimental design was a randomized, 2 period, crossover with 6 days of washout between treatments. Drug Administration: Each dog was administered alfaxalone intravenously at a dose rate of 2 mg/kg over a period of 60 seconds, using either the preserved or unpreserved formulation.

Effectiveness

Bioequivalence study (JX9604.08-L026), labelled as such: randomized two-treatment, two-period crossover with 7-day washout of Alfaxan® Multidose (test) vs Alfaxan® (reference) at 3 mg/kg IV over 60 s in healthy male Beagles; plasma alfaxalone PK plus pharmacodynamic/anesthetic quality (VAS) comparison; no new field effectiveness study conducted; n = 24; primary endpoint: Cmax and AUClast 90% CI within 80-125%; anesthetic induction, effectiveness and recovery VAS scores; result: Bioequivalent: Cmax T/R 1.07 (100.26% - 114.57%), AUClast T/R 1.06 (101.52% - 109.72%); no VAS or anesthetic event time differences except a non-clinically-relevant pulse rate difference (175 vs 164 beats/min, p=0.072)

Study Animals: Twenty-four (24), healthy, adult, male Beagle dogs weighing 7.8 to 10.5 kg.

Adverse reactions

Extraction notes: Supplement adds preservatives (ethanol, chlorocresol, benzethonium chloride) and multidose vial; effectiveness and safety bridged by bioequivalence (dogs 3 mg/kg, cats 5 mg/kg). Dose quote is the dog induction guideline table row (columns: preanesthetic, average dose (range) mg/kg, number of dogs) because the prose sentence is garbled in extraction ('1.5 –4 .5'). TAS n_animals given as 'Twelve' verbatim (12 dogs, 24 dog-periods) since the design quote carries no digit 12. TAS entry is the dog clinical safety study JX9604.08-K013 with a non-final preserved formulation at the label dose (no dose-multiple margin-of-safety study in this supplement). Cat studies (bioequivalence, induction and maintenance safety) not extracted apart from two cat PK entries. Adverse reaction rows have no control arm (crossover).

Alfaxan® Multidose NADA 141-342, Original approval, September 06, 2012; sponsor Zoetis Inc.; species: Cats and Dogs; foi_id 898; FDA PDF

Indication

Induction and maintenance of anesthesia, and induction of anesthesia followed by maintenance with an inhalant anesthetic, in cats and dogs

Dose regimen

1.5 – 4.5 mg/kg (dogs with no preanesthetic); 0.2 – 3.5 mg/kg (preanesthetized dogs), Intravenous (over approximately 60 seconds), Single induction dose titrated to effect; intermittent IV maintenance boluses as needed, Induction of general anesthesia in dogs; maintenance boluses of 1.2 - 1.4 mg/kg (preanesthetized) or 1.5 - 2.2 mg/kg (unpreanesthetized) provide an additional 6 - 8 minutes of anesthesia

Induction of general anesthesia in dogs: Induction dose guidelines are based on data from the field study (see EFFECTIVENESS) and range between 1.5 – 4.5 mg/kg for dogs that did not receive a preanesthetic, and between 0.2 – 3.5 mg/kg for dogs that received a preanesthetic.

Target-animal safety

dose multiples 0X, 1X, 3X, 5X; duration 3 IV treatments every 48 hours (Days 1, 3 and 5); 8-day study; animals 24.

The 24 dogs were randomly assigned to 4 treatment groups of 6 animals (3 male, 3 female) each. A control group received 0.9% saline. ALFAXAN (or saline) was administered every 48 hours (Days 1, 3, and 5) for 3 treatments at the following rates:

Effectiveness

Multicenter Australian field study (JX9604.03-C009), 9 clinics, October 2003 to August 2004; 4 treatment groups (no preanesthetic + ALFAXAN maintenance n=17; preanesthetic + ALFAXAN maintenance n=47; preanesthetic + halothane n=28; preanesthetic + isoflurane n=90); ALFAXAN 10 mg/mL IV over ~60 s to effect up to 2.0 mg/kg, maintenance increments ~0.5-0.7 mg/kg; n = 182; primary endpoint: Time to onset of anesthesia (intubation), induction/anesthetic/recovery quality scores, induction and maintenance doses, apnea, physiological variables (descriptive statistics; no control group); result: All 182 dogs successfully anesthetized; intubation within 1-2 minutes in all dogs (87 s unpreanesthetized vs 72 s preanesthetized); average induction dose 2.2 mg/kg unpreanesthetized (range 1.5-4.5) and 1.6 mg/kg preanesthetized (range 0.2-3.5); induction scores acceptable in >90% of dogs; anesthesia score excellent in 149/182; post-induction apnea (>=30 s) in 46/123 preanesthetized and 9/14 unpreanesthetized dogs with data

Of the 182 dogs in the study, 159 treated dogs received one or more preanesthetics and 23 dogs received no preanesthetic. No incompatibilities were noted when ALFAXAN was used in the presence of preanesthetics.

Adverse reactions

Extraction notes: Section parser lumped the whole summary into general_information; extracted from raw text. Summary covers cats and dogs; only the dog sections (III Effectiveness: Dogs, V Target Animal Safety: Dogs) are extracted here. Adverse reaction counts are number of dogs (of 182; apnea of 137 with data) in the uncontrolled field study (Table 37); additional table rows: Apnea >=60 s 34 (of 137), Bradycardia 24, Hypoxia 4, Unacceptable anesthesia quality 1, Emesis 1. TAS margin-of-safety study is the 8-day multidose study (JX9604.03-H005, 24 Beagles, 2/6/10 mg/kg = 1X/3X/5X); tolerance study (JX9604.03-H004) used 8 dogs at 2, 6, 20 mg/kg (1X, 3X, 10X) in a 4-way crossover; preanesthetic compatibility study (48 Beagles) and Cesarean section study (48 bitches) also summarized. No pharmacokinetic data in this summary. Product named ALFAXAN (10 mL single-use vials) in this 2012 summary; catalogue lists it under Alfaxan® Multidose.