Prescription Drug Information: Desflurane (Page 3 of 7)

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of desflurane. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Coagulopathy

Metabolism and Nutrition Disorders: Hyperkalemia, Hypokalemia, metabolic acidosis

Nervous System Disorders: Convulsion, Post-operative agitation in children

Eye Disorders: Ocular icterus

Cardiac Disorders: Cardiac arrest, QTc prolongation, torsade de pointes, ventricular failure, ventricular hypokinesia, atrial fibrillation

Vascular Disorders: Malignant hypertension, hemorrhage, hypotension, shock

Respiratory, Thoracic and Mediastinal Disorders: Respiratory arrest, respiratory failure, respiratory distress, bronchospasm, hemoptysis

Gastrointestinal Disorders: Pancreatitis acute, abdominal pain

Hepatobiliary Disorders: Hepatic failure, hepatic necrosis, hepatitis, cytolytic hepatitis, cholestasis, jaundice, hepatic function abnormal, liver disorder

Skin and Subcutaneous Tissue Disorder: Urticaria, erythema

Musculoskeletal, Connective Tissue and Bone Disorders: Rhabdomyolysis

General Disorders and Administration Site Conditions: Hyperthermia malignant, asthenia, malaise

Investigations: Electrocardiogram ST-T change, electrocardiogram T-wave inversion, tranaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, coagulation test abnormal, ammonia increased

Injury, Poisoning, and Procedural Complications*: Tachyarrhythmia, palpitations, eye burns, blindness transient, encephalopathy, ulcerative keratitis, ocular hyperemia, visual acuity reduced, eye irritation, eye pain, dizziness, migraine, fatigue, accidental exposure, skin burning sensation, drug administration error

*Reactions categorized within this System Organ Class (SOC) were accidental exposures to non-patients.

7 DRUG INTERACTIONS

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 desflurane on the disposition of other drugs has not been determined. Similar to isoflurane, desflurane does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine.

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 mcg/kg to 50 mcg/kg) and intravenous fentanyl (3 mcg/kg to 6 mcg/kg) in patients of two different age groups.

Table 3

Desflurane MAC with Fentanyl or Midazolam Mean ± SD (percent reduction)

Dose

18 to 30 years

31 to 65 years

No fentanyl

6.4 ± 0

6.3 ± 0.4

3 mcg/kg fentanyl

3.5 ± 1.9 (46%)

3.1 ± 0.6 (51%)

6 mcg/kg fentanyl

3 ± 1.2 (53%)

2.3 ± 1 (64%)

No midazolam

6.9 ± 0.1

5.9 ± 0.6

25 mcg/kg midazolam

4.9 ± 0.9 (16%)

50 mcg/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 (mcg/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 desflurane.

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 desflurane [See Dosage and Administration (2), Table 1] .

8 USE IN SPECIFIC POPULATIONS

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% to 4% and 15% to 20%, respectively.

Clinical Considerations

Labor or Delivery

The safety of desflurane during labor or delivery has not been demonstrated. Desflurane is a uterine-relaxant.

Data

Animal Data

Pregnant rats were exposed to 8.2% desflurane (1 MAC; 60% oxygen) for 0.5, 1, or 4 hours (0.5, 1, or 4 MAC-hours) per day during organogenesis (Gestation Day 6 to 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, or 3 hours per day during organogenesis (Gestation Days 6 to 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, or 4 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, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [See Warnings and Precautions (5.7), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)] .

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