Tiletamine Hydrochloride, Zolazepam Hydrochloride: what the FDA reviewed for dog products

ZOLETIL® NADA 200-618, Supplemental approval, August 16, 2021; sponsor Virbac AH, Inc.; species: Dogs; foi_id 11186; FDA PDF

Indication

Intravenous induction of anesthesia in dogs followed by maintenance with an inhalant anesthetic (new indication added by this supplement).

Dose regimen

1-2 mg/lb (2.2-4.4 mg/kg) body weight, to effect; total dose not to exceed 2 mg/lb (4.4 mg/kg), Intravenous injection, Single induction dose given slowly over 30-45 seconds; additional drug may be given if intubation is not possible after 60 seconds, Induction of anesthesia followed by maintenance with an inhalant anesthetic

In dogs, for induction of anesthesia, administer Zoletil™ for Injection intravenously at 1-2 mg/lb (2.2-4.4 mg/kg) body weight to effect.

Extraction notes: Supplemental ANADA adding the IV induction indication. No new studies: 'CVM did not require additional bioequivalence information for this supplemental approval'; refers to the original ANADA 200-618 FOI summary (June 23, 2017; foi 1541). RLNAD Telazol NADA 106-111 (its IV-induction supplement is foi 2525).

ZOLETIL® NADA 200-618, Original approval, June 23, 2017; sponsor Virbac AH, Inc.; species: Dogs and cats; foi_id 1541; FDA PDF

Indication

Cats: restraint or anesthesia with muscle relaxation; dogs: restraint and minor procedures of short duration (about 30 min) requiring mild to moderate analgesia.

Dose regimen

Dogs: 3 to 4.5 mg/lb (6.6 to 9.9 mg/kg) for diagnostic purposes; 4.5 to 6 mg/lb (9.9 to 13.2 mg/kg) for minor procedures; total dose not to exceed 12 mg/lb (26.4 mg/kg); maximum safe dose 13.6 mg/lb (29.92 mg/kg), Intramuscular injection, Initial dose; supplemental doses, if required, each less than the initial dose, Healthy dogs; cats have a separate dosage schedule (4.4-7.2 mg/lb initial depending on procedure; maximum 32.7 mg/lb)

Dogs: In healthy dogs, an initial intramuscular dosage of 3 to 4.5 mg/lb (6.6 to 9.9 mg/kg) Zoletil® for Injection is recommended for diagnostic purposes; 4.5 to 6 mg/lb (9.9 to 13.2 mg/kg) for minor procedures of short duration, such as treatment of lacerations and wounds, castrations and other procedures requiring mild to moderate analgesia. When supplemental doses of Zoletil® for Injection are required, such individual supplemental doses should be less than the initial dose, and the total dose given (initial dose plus supplemental dose or doses) should not exceed 12 mg/lb (26.4 mg/kg). The maximum safe dose is 13.6 mg/lb (29.92 mg/kg).

Effectiveness

Bioequivalence waiver (generic ANADA; no in vivo study). RLNAD: Telazol®, NADA 106-111 (Zoetis); result: Waiver from demonstrating bioequivalence granted on formulation characteristics (same active ingredients, concentration and dosage form as the RLNAD). CVM did not require effectiveness or target animal safety studies.

Based on the formulation characteristics of the generic product, Virbac AH, Inc. was granted a waiver from the requirement to demonstrate bioequivalence for the generic product Zoletil® for Injection (tiletamine HCl and zolazepam HCl) injectable solution.

Extraction notes: Generic (ANADA) original approval of Zoletil® for Injection (Virbac). No PK, safety or effectiveness studies; the effectiveness entry records the bioequivalence waiver only. Dose regimen given for dogs; cat dosages are in the same section.

Tzed™ NADA 200-557, Original approval, March 26, 2015; sponsor Dechra Veterinary Products LLC; species: Dogs and cats; foi_id 1238; FDA PDF

Indication

Cats: restraint or anesthesia with muscle relaxation; dogs: restraint and minor procedures of short duration (about 30 min) requiring mild to moderate analgesia.

Dose regimen

Dogs: 3 to 4.5 mg/lb (6.6 to 9.9 mg/kg) for diagnostic purposes; 4.5 to 6 mg/lb (9.9 to 13.2 mg/kg) for minor procedures; total dose not to exceed 12 mg/lb (26.4 mg/kg); maximum safe dose 13.6 mg/lb (29.92 mg/kg), Intramuscular injection, Initial dose; supplemental doses, if required, each less than the initial dose, Cats have a separate dosage schedule (4.4-7.2 mg/lb initial depending on procedure; maximum 32.7 mg/lb)

Dogs: an initial intramuscular dosage of 3 to 4.5 mg/lb (6.6 to 9.9 mg/kg) is recommended for diagnostic purposes; 4.5 to 6 mg/lb (9.9 to 13.2 mg/kg) for minor procedures of short duration, such as treatment of lacerations and wounds, castrations and other procedures requiring mild to moderate analgesia. When supplemental doses are required, such individual supplemental doses should be less than the initial dose, and the total dose given (initial dose plus supplemental dose or doses) should not exceed 12 mg/lb (26.4 mg/kg). The maximum safe dose is 13.6 mg/lb (29.92 mg/kg).

Effectiveness

Bioequivalence waiver (generic ANADA; no in vivo study). RLNAD: TELAZOL, NADA 106-111 (Zoetis); result: Waiver from demonstrating bioequivalence granted on formulation characteristics (same active ingredients, concentration and dosage form as the RLNAD; no inactive ingredients affecting bioavailability). CVM did not require effectiveness or target animal safety studies.

Based on the formulation characteristics of the generic product, Putney, Inc. was granted a waiver from the requirement to demonstrate bioequivalence for the generic product Tiletamine-Zolazepam (tiletamine HCl and zolazepam HCl) injectable solution.

Extraction notes: Generic (ANADA) original approval; the summary names the product 'Tiletamine-Zolazepam' sponsored by Putney, Inc. (catalogue name Tzed™, now Dechra). No PK, safety or effectiveness studies; the effectiveness entry records the bioequivalence waiver only. Dose regimen given for dogs; cat dosages are in the same section.

Telazol® NADA 106-111, Supplemental approval, November 09, 2017; sponsor Zoetis Inc.; species: Dogs; foi_id 2525; FDA PDF

Indication

Intravenous induction of anesthesia in dogs followed by maintenance with an inhalant anesthetic (new indication added by this supplement).

Dose regimen

1-2 mg/lb (2.2-4.4 mg/kg) body weight, to effect; total dose not to exceed 2 mg/lb (4.4 mg/kg), Intravenous injection, Single induction dose given slowly over 30-45 seconds; additional TELAZOL may be given if intubation is not possible after waiting 60 seconds, Induction of anesthesia followed by maintenance with an inhalant anesthetic

In dogs, for induction of anesthesia, administer TELAZOL intravenously at 1-2 mg/lb (2.2-4.4 mg/kg) body weight to effect.

Pharmacokinetics

Target-animal safety

dose multiples 2.2 mg/kg IV (low end of the 2.2-4.4 mg/kg label range); an additional 2.2 mg/kg IV permitted to achieve intubation; duration Six-period crossover, one IV induction per period with at least a 7-day washout; dogs preanesthetized IM with saline, acepromazine (0.11 or 1.1 mg/kg), dexmedetomidine (125 or 375 mcg/m2) or butorphanol (0.4 mg/kg), then maintained on isoflurane (Study No. A360N-US-15-554, GLP); animals 6 healthy Beagle dogs (3 males and 3 females) per group.

Study Animals: There were 6 healthy Beagle dogs (3 males and 3 females) per group. The dogs were greater than 8 months of age and weighed 5.6 to 9.4 kg.

Effectiveness

Multi-site (6 US sites) open-label (no masking) field study (Study No. A161C-US-14-481, April-July 2015); 144 client-owned dogs assigned by the investigator to three preanesthetic groups (acepromazine + opioid, opioid alone, dexmedetomidine + opioid) and maintained on isoflurane or sevoflurane (2:1); Telazol® IV 2.2-4.4 mg/kg 'to effect' for induction; no untreated control; n = 144 enrolled; 142/144 successfully intubated; primary endpoint: Successful endotracheal intubation (yes/no) without the need for mask inhalant induction; result: Successful intubation in 142/144 dogs (98.6%); both failures were premedicated with an opioid alone. Induction quality acceptable in 131/143 (91.6%); mean time to intubation 2 minutes; overall anesthesia quality excellent or good in 128/144 (88.9%); post-induction apnea in 49.3% of dogs (mean 1 minute).

Results: Primary Variable of Effectiveness = Intubation: Successful intubation was achieved with Telazol® administered intravenously at a dosage of 2.2-4.4 mg/kg in 142/144 dogs (98.6%). The two dogs that could not be intubated were both pre-medicated with an opioid alone.

Adverse reactions

Extraction notes: Supplemental approval adding an IV induction indication; contains new studies. PK table (Table 1) quoted as flattened rows: parameter (unit) then Mean then Standard Deviation; 12 Beagles given 2.2 mg/kg Telazol IV. The target-animal-safety study is a cardiorespiratory/PK crossover interaction study with preanesthetics at the 2.2 mg/kg label dose, not a dose-multiple margin-of-safety study; the label dose range is otherwise supported by three published studies (Tracy 1988, Donaldson 1989, Hellyer 1989). Adverse-reaction counts are from the uncontrolled field study (Table 6 lists them by treatment group T01-T06); treated column gives number of dogs out of 144. Mean IV dose required by group ranged 2.012-3.855 mg/kg (Table 4). Lowest dose intubated 0.592 mg/kg; one 3.65 kg dog received 5.5 mg/kg.

Tzed™ NADA 200-557, Supplemental approval, November 25, 2020; sponsor Dechra Veterinary Products LLC; species: Dogs; foi_id 10029; FDA PDF

Indication

Intravenous induction of anesthesia in dogs followed by maintenance with an inhalant anesthetic (new indication added by this supplement).

Dose regimen

1-2 mg/lb (2.2-4.4 mg/kg) body weight, to effect; total dose not to exceed 2 mg/lb (4.4 mg/kg), Intravenous injection, Single induction dose given slowly over 30-45 seconds; additional drug may be given if intubation is not possible after 60 seconds, Induction of anesthesia followed by maintenance with an inhalant anesthetic

In dogs, for induction of anesthesia, administer Tzed™ intravenously at 1-2 mg/lb (2.2-4.4 mg/kg) body weight to effect.

Extraction notes: Supplemental ANADA adding the IV induction indication, a proprietary-name change (to Tzed™) and trade-dress change. No new studies: 'CVM did not require additional bioequivalence information for this supplemental approval'; refers to the original ANADA 200-557 FOI summary (March 26, 2015; foi 1238). RLNAD Telazol NADA 106-111 (its IV-induction supplement is foi 2525).