Sevoflurane

Frequency Not Defined

Malignant hyperthermia

Dose-dependent hypotension

Bradycardia

Tachycardia

Hypotension

Hypertension

Nausea/vomiting

Cough

Agitation

Increased salivation

Airway obstruction

Laryngospasm

Apnea

Increased BUN

Increased ALT

Respiratory irritation

Nephrotoxicity

Glycosuria

Proteinuria

Postmarketing Reports

Seizures (majority of cases in children and young adults, most had no medical history of seizures)

Cardiac arrest

Cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice

Malignant hyperthermia

Allergic reactions (eg, rash, urticaria, pruritus, bronchospasm, anaphylactic or anaphylactoid reactions)

Transient elevations in glucose, liver function tests, and WBC count

Sevoflurane is part of the drug class:

• Halogenated hydrocarbons

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• LABETALOL/SEVOFLURANE
• SEVOFLURANE/SODIUM OXYBATE

This is not a complete list of Sevofluranedrug interactions. Ask your doctor or pharmacist for more information.

Sevoflurane is available in the following forms:

• Inhalant Solution

• It is used to put you to sleep for surgery.
• It is used to cause sleep during care.

Use sevoflurane as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a liquid for breathing into the lungs by a doctor.
• Other drugs may be given before this medicine to help avoid side effects.

What do I do if I miss a dose?

• This medicine is given on an as needed basis.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of a high potassium level like a heartbeat that does not feel normal; change in thinking clearly and with logic; feeling weak, lightheaded, or dizzy; feel like passing out; numbness or tingling; or shortness of breath.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Very bad dizziness or passing out.
• Trouble breathing, slow breathing, or shallow breathing.
• Slow heartbeat.
• Seizures.
• Feeling agitated.
• Muscle stiffness.
• Change in color of skin to a bluish color like on the lips, nail beds, fingers, or toes.
• This medicine may cause a very bad and sometimes deadly problem called malignant hyperthermia. Call your doctor right away if you have a fast heartbeat, fast breathing, fever, or spasm or stiffness of the jaw muscles.
• A type of abnormal heartbeat (prolonged QT interval) has happened with sevoflurane. Sometimes, this has led to another type of unsafe abnormal heartbeat (torsades de pointes). Call your doctor right away if you have a fast or abnormal heartbeat, or if you pass out.

During the maintenance of anesthesia, increasing the concentration of Sevoflurane, USP produces dose-dependent decreases in blood pressure. Due to Sevoflurane, USP’s insolubility in blood, these hemodynamic changes may occur more rapidly than with other volatile anesthetics. Excessive decreases in blood pressure or respiratory depression may be related to depth of anesthesia and may be corrected by decreasing the inspired concentration of Sevoflurane, USP.

Rare cases of seizures have been reported in association with Sevoflurane, USP use (see PRECAUTIONS - Pediatric Use and ADVERSE REACTIONS).

The recovery from general anesthesia should be assessed carefully before a patient is discharged from the post-anesthesia care unit.

Information for Patients

Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs (see WARNINGS Pediatric Neurotoxicity).

Drug Interactions

In clinical trials, no significant adverse reactions occurred with other drugs commonly used in the perioperative period, including: central nervous system depressants, autonomic drugs, skeletal muscle relaxants, anti-infective agents, hormones and synthetic substitutes, blood derivatives, and cardiovascular drugs.

Sevoflurane, USP administration is compatible with barbiturates, propofol, and other commonly used intravenous anesthetics.

Benzodiazepines and opioids would be expected to decrease the MAC of Sevoflurane, USP in the same manner as with other inhalational anesthetics. Sevoflurane, USP administration is compatible with benzodiazepines and opioids as commonly used in surgical practice.

As with other halogenated volatile anesthetics, the anesthetic requirement for Sevoflurane, USP is decreased when administered in combination with nitrous oxide. Using 50% N2O, the MAC equivalent dose requirement is reduced approximately 50% in adults, and approximately 25% in pediatric patients (see DOSAGE AND ADMINISTRATION).

As is the case with other volatile anesthetics, Sevoflurane, USP increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants. When used to supplement alfentanil-N2O anesthesia, Sevoflurane, USP and isoflurane equally potentiate neuromuscular block induced with pancuronium, vecuronium or atracurium. Therefore, during Sevoflurane, USP anesthesia, the dosage adjustments for these muscle relaxants are similar to those required with isoflurane.

Potentiation of neuromuscular blocking agents requires equilibration of muscle with delivered partial pressure of Sevoflurane, USP. Reduced doses of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation.

Among available nondepolarizing agents, only vecuronium, pancuronium and atracurium interactions have been studied during Sevoflurane, USP anesthesia. In the absence of specific guidelines:

The effect of Sevoflurane, USP on the duration of depolarizing neuromuscular blockade induced by succinylcholine has not been studied.

Hepatic Function

Results of evaluations of laboratory parameters (e.g., ALT, AST, alkaline phosphatase, and total bilirubin, etc.), as well as investigator-reported incidence of adverse events relating to liver function, demonstrate that Sevoflurane, USP can be administered to patients with normal or mild-to-moderately impaired hepatic function. However, patients with severe hepatic dysfunction were not investigated.

Occasional cases of transient changes in postoperative hepatic function tests were reported with both Sevoflurane, USP and reference agents. Sevoflurane, USP was found to be comparable to isoflurane with regard to these changes in hepatic function.

Very rare cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from postmarketing experiences. Clinical judgement should be exercised when Sevoflurane, USP is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction (see ADVERSE REACTIONS).

It has been reported that previous exposure to halogenated hydrocarbon anesthetics may increase the potential for hepatic injury.

Desiccated CO2 Absorbents

An exothermic reaction occurs when Sevoflurane, USP is exposed to CO2 absorbents. This reaction is increased when the CO2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2 absorbent canisters. Rare cases of extreme heat, smoke, and/or spontaneous fire in the anesthesia breathing circuit have been reported during Sevoflurane, USP use in conjunction with the use of desiccated CO2 absorbent, specifically those containing potassium hydroxide (e.g. Baralyme). KOH containing CO2 absorbents are not recommended for use with Sevoflurane, USP. An unusually delayed rise or unexpected decline of inspired Sevoflurane, USP concentration compared to the vaporizer setting may be associated with excessive heating of the CO2 absorbent and chemical breakdown of Sevoflurane, USP.

As with other inhalational anesthetics, degradation and production of degradation products can occur when Sevoflurane, USP is exposed to desiccated absorbents. When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced. The color indicator of most CO2 absorbents may not change upon desiccation. Therefore, the lack of significant color change should not be taken as an assurance of adequate hydration. CO2 absorbents should be replaced routinely regardless of the state of the color indicator.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Studies on carcinogenesis have not been performed for either Sevoflurane, USP or Compound A.

Mutagenesis

No mutagenic effect of Sevoflurane, USP was noted in the Ames test, mouse micronucleus test, mouse lymphoma mutagenicity assay, human lymphocyte culture assay, mammalian cell transformation assay, 32P DNA adduct assay, and no chromosomal aberrations were induced in cultured mammalian cells.

Similarly, no mutagenic effect of Compound A was noted in the Ames test, the Chinese hamster chromosomal aberration assay and the in vivo mouse micronucleus assay. However, positive responses were observed in the human lymphocyte chromosome aberration assay. These responses were seen only at high concentrations and in the absence of metabolic activation (human S-9).

Impairment of Fertility

In a study in which male rats were treated with Sevoflurane (0.22%, 0.66%, 1.1%, or 2.2% equals 0.1, 0.3, 0.5, or 1.0 MAC) three hours per day every other day starting 64 days prior to mating and female rats were treated with the same dosing regimen 14 days prior to mating until Gestation Day 7, there was no clear impact on male or female fertility.

Pregnancy

Risk Summary

There are no adequate and well-controlled studies in pregnant women.In animal reproduction studies, reduced fetal weights were noted following exposure to 1 MAC Sevoflurane for three hours a day during organogenesis. Developmental and reproductive toxicity studies of Sevoflurane in animals in the presence of strong alkalies (i.e., degradation of Sevoflurane and production of Compound A) have not been conducted. 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.

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.

Data

Animal Data

Pregnant rats were treated with Sevoflurane, USP (0.22%, 0.66%, or 2.2% equals 0.1, 0.3, or 1.0 MAC) without CO2 absorbent for three hours per day during organogenesis (from Gestation Day 7 to 17). Fetuses obtained by Cesarean section were examined on Gestation Day 20 while some animals were maintained for littering and pups were examined for adverse effects. There were no adverse effects on fetuses at 0.3 MAC. Reduced fetal body weights and increased skeletal variations such as delayed ossifications in the presence of maternal toxicity (reduced food and water intake and body weight of the dams) were noted at 1 MAC. In dams allowed to litter, reduced pup bodyweight gain and evidence of developmental delays (slight delay in eyelid opening and increased incidence of nonreactive animals in the visual placing reflex test) were noted in the 1.0 MAC treatment group.

Pregnant rabbits were treated with Sevoflurane, USP (0.1, 0.3, or 1.0 MAC) without CO2 absorbent for three hours per day during organogenesis (from Gestation Day 6 to 18). There were no adverse effects on the fetus at any dose; the mid-and high-dose produced a 5% and 6% decrease in maternal body weight, respectively.

In another study, pregnant rats were administered Sevoflurane (0.1, 0.3, or 1.0 MAC) from Gestation Day 17 to Postnatal Day 21. Pup body weights were reduced in the 1.0 MAC treatment group in the absence of maternal toxicity. There was no effect of Sevoflurane, USP on sensory function (visual, auditory, nociception, righting reflexes), motor (roto-rod), open field test, or learning tasks (shuttle box avoidance and water T-maze).

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 -Pediatric Neurotoxicity, PRECAUTIONS -Pediatric Use, and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).

Labor and Delivery

Sevoflurane, USP has been used as part of general anesthesia for elective cesarean section in 29 women. There were no untoward effects in mother or neonate. (See PHARMACODYNAMICS-Clinical Trials). The safety of Sevoflurane, USP in labor and delivery has not been demonstrated.

Nursing Mothers

The concentrations of Sevoflurane, USP in milk are probably of no clinical importance 24 hours after anesthesia. Because of rapid washout, Sevoflurane, USP concentrations in milk are predicted to be below those found with many other volatile anesthetics.

Geriatric Use

MAC decreases with increasing age. The average concentration of Sevoflurane, USP to achieve MAC in an 80 year old is approximately 50% of that required in a 20 year old.

Pediatric Use

Induction and maintenance of general anesthesia with Sevoflurane, USP have been established in controlled clinical trials in pediatric patients aged 1 to 18 years (see PHARMACODYNAMICS – Clinical Trials and ADVERSE REACTIONS). Sevoflurane, USP has a nonpungent odor and is suitable for mask induction in pediatric patients.

The concentration of Sevoflurane, USP required for maintenance of general anesthesia is age dependent. When used in combination with nitrous oxide, the MAC equivalent dose of Sevoflurane, USP should be reduced in pediatric patients. MAC in premature infants has not been determined. (See PRECAUTIONS - Drug Interactions and DOSAGE AND ADMINISTRATION for recommendations in pediatric patients 1 day of age and older.)

The use of Sevoflurane, USP has been associated with seizures (see PRECAUTIONS and ADVERSE REACTIONS). The majority of these have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors. Clinical judgement should be exercised when using Sevoflurane, USP in patients who may be at risk for seizures.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Sevoflurane, USP, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see WARNINGS -Pediatric Neurotoxicity, PRECAUTIONS -Pregnancy, and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).

Sevoflurane, USP, Volatile Liquid for Inhalation, is available as:

NDC 10019-651-64 - Aluminum bottle containing 250 mL Sevoflurane, USP.

SAFETY AND HANDLING

There is no specific work exposure limit established for Sevoflurane, USP. However, the National Institute for Occupational Safety and Health has recommended an 8 hour time-weighted average limit of 2 ppm for halogenated anesthetic agents in general (0.5 ppm when coupled with exposure to N2O) (see ADVERSE REACTIONS).

Store at controlled room temperature 15°-30°C (59°-86°F) [see USP].

The bottle cap should be replaced securely after each use of Sevoflurane, USP.

Published studies in animals demonstrate that the use of anesthetic agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures against the potential risks suggested by the nonclinical data (see WARNINGS -Pediatric Neurotoxicity, PRECAUTIONS - Pregnancy, and PRECAUTIONS -Pediatric Use).

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Revised: June 2017
07-19-00-0027