Desflurane

No clinically significant adverse interactions with commonly used preanesthetic drugs, or drugs used during anesthesia (muscle relaxants, intravenous agents, and local anesthetic agents) were reported in clinical trials. The effect of SUPRANE on the disposition of other drugs has not been determined. Similar to isoflurane, SUPRANE does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine. • Concomitant use of N 2 O, benzodiazepines and/or opioids reduces the MAC of SUPRANE. Adjust dose accordingly. ( 7.1 , 7.3 ) • SUPRANE decreases the doses of neuromuscular blocking agents required. Adjust dose accordingly. (7.2)

7.1 Benzodiazepines and Opioids (MAC Reduction) Benzodiazepines and opioids decrease the amount of desflurane (MAC) needed to produce anesthesia. This effect is shown in Table 3 for intravenous midazolam (25-50 µg/kg) and intravenous fentanyl (3-6 µg/kg) in patients of two different age groups. Table 3 SUPRANE MAC with Fentanyl or Midazolam Mean ± SD (percent reduction) Dose 18-30 years 31-65 years No fentanyl 6.4 ± 0.0 6.3 ± 0.4 3 µg/kg fentanyl 3.5 ± 1.9 (46%) 3.1 ± 0.6 (51%) 6 µg/kg fentanyl 3.0 ± 1.2 (53%) 2.3 ± 1.0 (64%) No midazolam 6.9 ± 0.1 5.9 ± 0.6 25 µg/kg midazolam - 4.9 ± 0.9 (16%) 50 µg/kg midazolam - 4.9 ± 0.5 (17%)

7.2 Neuromuscular Blocking Agents Anesthetic concentrations of desflurane at equilibrium (administered for 15 or more minutes before testing) reduced the ED 95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N 2 O/opioid anesthesia ( see Table 4 ). The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied. Table 4 Dosage of Muscle Relaxant Causing 95% Depression in Neuromuscular Blockade Desflurane Concentration Mean ED 95 (µg/kg) Pancuronium Atracurium Succinylcholine Vecuronium

0.65 MAC 60% N 2 O/O 2 26 133 - -

1.25 MAC 60% N 2 O/O 2 18 119 - -

1.25 MAC O 2 22 120 360 19 Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of SUPRANE. Among nondepolarizing drugs, pancuronium, atracurium, and vecuronium interactions have been studied. In the absence of specific guidelines: 1. For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine. 2.

During maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N 2 O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation.

7.3 Concomitant use with N 2 O Concomitant administration of N 2 O reduces the MAC of SUPRANE [ See Dosage and Administration (2), Table 1 ].

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, embryo-fetal toxicity (reduced viable fetuses and/or increased post-implantation loss) was noted in pregnant rats and rabbits administered 1 MAC desflurane for 4 hours a day (4 MAC-hours/day) during organogenesis. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [See Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively. Clinical Considerations Labor or Delivery The safety of SUPRANE during labor or delivery has not been demonstrated. SUPRANE is a uterine-relaxant.

Data Animal Data Pregnant rats were exposed to 8.2% desflurane (1 MAC; 60% oxygen) for 0.5, 1.0, or 4.0 hours (0.5, 1.0, or

4.0 MAC-hours) per day during organogenesis (Gestation Day 6-15). Embryo-fetal toxicity (increased post-implantation loss and reduced viable fetuses) was noted in the 4 hour treatment group in the presence of maternal toxicity (reduced body weight gain). There was no evidence of malformations in any group. Pregnant rabbits were exposed to 8.9% desflurane (1 MAC; 60% oxygen) for 0.5, 1.0, or 3.0 hours per day during organogenesis (Gestation Days 6-18). Fetal toxicity (reduced viable fetuses) was noted in the 3 hour treatment group in the presence of maternal toxicity (reduced body weight). There was no evidence of malformations in any group.

Pregnant rats were exposed to 8.2% desflurane (1 MAC; 60% oxygen) for 0.5, 1.0, or 4.0 hours per day from late gestation and through lactation (Gestation Day 15 to Lactation Day 21). Pup body weights were reduced in the 4 hours per day group in the presence of maternal toxicity (increased mortality and reduced body weight gain). This study did not evaluate neurobehavioral function including learning and memory or reproductive behavior in the first generation (F1) pups. In a published study in primates,…