Label: SEVOFLURANE liquid

  • Category: PRESCRIPTION ANIMAL DRUG LABEL

Drug Label Information

Updated February 25, 2015

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  • DESCRIPTION

    Inhalation Anesthetic For Use in Dogs

    Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.


    Sevoflurane, a volatile liquid, is a halogenated general inhalation anesthetic drug. Its chemical name is fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether, and its structural formula is:

     sevo-structure

    Sevoflurane Physical Constants are:

    Molecular weight                                       200.05

    Boiling point at 760 mm Hg                    58.6°C

    Specific gravity at 20°C                            1.520-1.525 g/mL

    Vapor pressure in mm Hg      at 20°C    157

                                                         at 25°C    197

                                                         at 36°C    317


    Distribution Partition Coefficients at 37°C:

    Blood/Gas                                                   0.63-0.69

    Water/Gas                                                   0.36

    Olive Oil/Gas                                              47-54

    Brain/Gas                                                    1.15


    Mean Component/Gas Partition Coefficients at 25°C for Polymers Used Commonly in Medical Applications:

    Conductive rubber                                    14.0

    Butyl rubber                                                7.7

    Polyvinyl chloride                                      17.4

    Polyethylene                                               1.3


    Sevoflurane is nonflammable and nonexplosive as defined by the requirements of International Electrotechnical Commission 601-2-13.


    Sevoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers. Sevoflurane is nonpungent. It is miscible with ethanol, ether, chloroform and petroleum benzene, and it is slightly soluble in water. Sevoflurane is stable when stored under normal room lighting condition according to instructions.


  • INDICATIONS

    Sevoflurane is indicated for induction and maintenance of general anesthesia in dogs.

  • DOSAGE AND ADMINISTRATION

    Inspired Concentration: The delivered concentration of Sevoflurane should be known. Since the depth of anesthesia may be altered easily and rapidly, only vaporizers producing predictable percentage concentrations of sevoflurane should be used. Sevoflurane should be vaporized using a precision vaporizer specifically calibrated for sevoflurane. Sevoflurane contains no stabilizer. Nothing in the drug product alters calibration or operation of these vaporizers. The administration of general anesthesia must be individualized based on the patient's response. WHEN USING SEVOFLURANE, PATIENTS SHOULD BE CONTINUOUSLY MONITORED AND FACILITIES FOR MAINTENANCE OF PATENT AIRWAY, ARTIFICIAL VENTILATION, AND OXYGEN SUPPLEMENTATION MUST BE IMMEDIATELY AVAILABLE.

    Replacement of Desiccated CO2 Absorbents: When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced. An exothermic reaction occurs when sevoflurane is exposed to CO2 absorbents. This reaction is increased when the CO2 absorbent becomes desiccated (see PRECAUTIONS).


    Premedication: No specific premedication is either indicated or contraindicated with sevoflurane. The necessity for and choice of premedication is left to the discretion of the veterinarian. Preanesthetic doses for premedicants may be lower than the label directions for their use as a single medication.1


    Induction: For mask induction using sevoflurane alone, inspired concentrations of up to 7% sevoflurane with oxygen are employed to induce surgical anesthesia in the healthy dog. These concentrations can be expected to produce surgical anesthesia in 3 to 14 minutes. Due to the rapid and dose dependent changes in anesthetic depth, care should be taken to prevent overdosing. Respiration must be monitored closely in the dog and supported when necessary with supplemental oxygen and/or assisted ventilation.

    Maintenance: Sevoflurane may be used for maintenance anesthesia following mask induction using sevoflurane or following injectable induction agents. The concentration of vapor necessary to maintain anesthesia is much less than that required to induce it.


    Surgical levels of anesthesia in the healthy dog may be maintained with inhaled concentrations of 3.7-4.0% sevoflurane in oxygen in the absence of premedication and 3.3-3.6% in the presence of premedication. The use of injectable induction agents without premedication has little effect on the concentrations of sevoflurane required for maintenance. Anesthetic regimens that include opioid, alpha2- agonist, benzodiazepine or phenothiazine premedication will allow the use of lower sevoflurane maintenance concentrations.

  • CONTRAINDICATIONS

    Sevoflurane is contraindicated in dogs with a known sensitivity to sevoflurane or other halogenated agents.

  • WARNINGS

    Sevoflurane is a profound respiratory depressant. DUE TO THE RAPIDAND DOSE DEPENDENT CHANGES IN ANESTHETIC DEPTH, RESPIRATION MUST BEMONITORED CLOSELY IN THE DOG AND SUPPORTED WHEN NECESSARY WITHSUPPLEMENTAL OXYGEN AND/OR ASSISTED VENTILATION.

    In cases of severe cardiopulmonary depression, discontinue drugadministration, ensure the existence of a patent airway and initiateassisted or controlled ventilation with pure oxygen. Cardiovasculardepression should be treated with plasma expanders, pressor agents,antiarrhythmic agents or other techniques as appropriate for theobserved abnormality.

    Due to sevoflurane's low solubility in blood, increasing theconcentration may result in rapid changes in anesthetic depth andhemodynamic changes (dose dependent decreases in respiratory rate andblood pressure) compared to other volatile anesthetics. Excessivedecreases in blood pressure or respiratory depression may be correctedby decreasing or discontinuing the inspired concentration ofsevoflurane.

    Potassium hydroxide containing CO2 absorbents (e.g. *BARALYME®) are not recommended for use with sevoflurane.

  • ADVERSE REACTIONS

    The most frequently reported adverse reactions during maintenanceanesthesia were hypotension, followed by tachypnea, muscle tenseness,excitation, apnea, muscle fasciculations and emesis.

    Infrequent adverse reactions include paddling, retching, salivation,cyanosis, premature ventricular contractions and excessivecardiopulmonary depression.

    Transient elevations in liver function tests and white blood cell countmay occur with sevoflurane, as with the use of other halogenatedanesthetic agents.

  • PRECAUTIONS

    Halogenated volatile anesthetics can react with desiccated carbon dioxide (CO2)absorbents to produce carbon monoxide (CO) that may result in elevatedcarboxyhemoglobin levels in some patients. To prevent this reaction,sevoflurane should not be passed through desiccated soda lime or bariumhydroxide lime.




    Replacement of Desiccated CO2 Absorbents:

    When a clinician suspects that the CO2 absorbent maybe desiccated, it should be replaced before administration ofsevoflurane. The exothermic reaction that occurs with sevoflurane and CO2 absorbents is increased when the CO2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2absorbent canisters. Extremely rare cases of spontaneous fire in therespiratory circuit of the anesthesia machine have been reported duringsevoflurane use in conjunction with the use of a desiccated CO2 absorbent, specifically those containing potassium hydroxide (e.g. *BARALYME). Potassium hydroxide-containing CO2absorbents are not recommended for use with sevoflurane. An unusuallydelayed rise in the inspired gas concentration (decreased delivery) ofsevoflurane compared with the vaporizer setting may indicate excessiveheating of the CO2 absorbent canister and chemical breakdown of sevoflurane. The color indicator of most CO2absorbent may not change upon desiccation. Therefore, the lack ofsignificant color change should not be taken as an assurance of adequatehydration. CO2 absorbents should be replaced routinely regardless of the state of the color indicator.


    The use of some anesthetic regimens that include sevoflurane mayresult in bradycardia that is reversible with anticholinergics. Studiesusing sevoflurane anesthetic regimens that included atropine orglycopyrrolate as premedicants showed these anticholinergics to becompatible with sevoflurane in dogs.


    During the induction and maintenance of anesthesia, increasingthe concentration of sevoflurane produces dose dependent decreases inblood pressure and respiratory rate. Due to sevoflurane's low solubilityin blood, these changes may occur more rapidly than with other volatileanesthetics. Excessive decreases in blood pressure or respiratorydepression may be related to depth of anesthesia and may be corrected bydecreasing the inspired concentration of sevoflurane. RESPIRATIONMUST BE MONITORED CLOSELY IN THE DOG AND SUPPORTED WHEN NECESSARY WITHSUPPLEMENTAL OXYGEN AND/OR ASSISTED VENTILATION. The low solubility of sevoflurane also facilitates rapid elimination by the lungs.


    The use of sevoflurane in humans increases both the intensity andduration of neuromuscular blockade induced by nondepolarizing musclerelaxants. The use of sevoflurane with nondepolarizing muscle relaxantshas not been evaluated in dogs.


    Compromised or debilitated dogs: Doses may need adjustment forgeriatric or debilitated dogs. Because clinical experience inadministering sevoflurane to dogs with renal, hepatic and cardiovascularinsufficiency is limited, its safety in these dogs has not beenestablished.


    Breeding dogs: The safety of sevoflurane in dogs used for breedingpurposes, during pregnancy, or in lactating bitches, has not beenevaluated.


    Neonates: The safety of sevoflurane in young dogs (less than 12 weeks of age) has not been evaluated.


    HUMAN SAFETY:

    Not for human use. Keep out of reach of children.


    Operating rooms and animal recovery areas should be provided withadequate ventilation to prevent the accumulation of anesthetic vapors.

    There is no specific work exposure limit established for sevoflurane.However, the National Institute for Occupational Safety and Health hasrecommended an 8 hour time-weighted average limit of 2 ppm forhalogenated anesthetic agents in general.


    Direct exposure to eyes, may result in mild irritation. If eyeexposure occurs, flush with plenty of water for 15 minutes. Seek medicalattention if irritation persists.


    Symptoms of human overexposure (inhalation) to sevoflurane vaporsinclude respiratory depression, hypotension, bradycardia, shivering,nausea and headache. If these symptoms occur, remove the individual fromthe source of exposure and seek medical attention.


    The material safety data sheet (MSDS) contains more detailed occupational safety information. For customer service, adverse effects reporting, and/or a copy of the MSDS, call (888) 822-8431.

  • CLINICAL PHARMACOLOGY

    Sevoflurane is an inhalational anesthetic agent for induction and maintenance of general anesthesia. The Minimum Alveolar Concentration (MAC) of sevoflurane as determined in 18 dogs is 2.36%.2 MAC is defined as that alveolar concentration at which 50% of healthy patients fail to respond to noxious stimuli. Multiples of MAC are used as a guide for surgical levels of anesthesia, which are typically 1.3 to 1.5 times the MAC value.


    Because of the low solubility of sevoflurane in blood (blood/gas partition coefficient at 37°C = 0.63-0.69), a minimal amount of sevoflurane is required to be dissolved in the blood before the alveolar partial pressure is in equilibrium with the arterial partial pressure. During sevoflurane induction, there is a rapid increase in alveolar concentration toward the inspired concentration.


    Sevoflurane produces only modest increases in cerebral blood flow and metabolic rate, and has little or no ability to potentiate seizures.3 Sevoflurane has a variable effect on heart rate, producing increases or decreases depending on experimental conditions.4,5 Sevoflurane produces dose-dependent decreases in mean arterial pressure, cardiac output and myocardial contraction.6 Among inhalation anesthetics, sevoflurane has low arrhythmogenic potential.7


    Sevoflurane is chemically stable. No discernible degradation occurs in the presence of strong acids or heat. Sevoflurane reacts through direct contact with CO2 absorbents (soda lime and barium hydroxide lime) producing pentafluoroisopropenyl fluoromethyl ether (PIFE, C4H2F6O), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether (PMFE, C5H6F6O), also known as Compound B.


    Compound A:

    The production of degradants in the anesthesia circuit results from the extraction of the acidic proton in the presence of a strong base (potassium hydroxide and/or NaOH) forming an alkene (Compound A) from sevoflurane.


    Compound A is produced when sevoflurane interacts with soda lime or barium hydroxide lime. Reaction with barium hydroxide lime results in a greater production of Compound A than does reaction with soda lime. Its concentration in a circle absorber system increases with increasing sevoflurane concentrations and with decreasing fresh gas flow rates. Sevoflurane degradation in soda lime has been shown to increase with temperature. Since the reaction of carbon dioxide with absorbents is exothermic, this temperature increase will be determined by the quantities of CO2 absorbed, which in turn will depend on fresh gas flow in the anesthetic circle system, metabolic status of the patient and ventilation. Although Compound A is a dose-dependent nephrotoxin in rats, the mechanism of this renal toxicity is unknown. Two spontaneously breathing dogs under sevoflurane anesthesia showed increases in concentrations of Compound A as the oxygen flow rate was decreased at hourly intervals, from 500 mL/min (36 and 18 ppm Compound A) to 250 mL/min (43 and 31 ppm) to 50 mL/min (61 and 48 ppm).8


    Fluoride ion metabolite:

    Sevoflurane is metabolized to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Fluoride ion concentrations are influenced by the duration of anesthesia and the concentration of sevoflurane. Once formed, HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. In humans, the fluoride ion half-life was prolonged in patients with renal impairment, but human clinical trials contained no reports of toxicity associated with elevated fluoride ion levels. In a study in which 4 dogs were exposed to 4% sevoflurane for 3 hours, maximum serum fluoride concentrations of 17.0-27.0 mcmole/L were observed after 3 hours of anesthesia. Serum fluoride fell quickly after anesthesia ended, and had returned to baseline by 24 hours post-anesthesia.


    In a safety study, eight healthy dogs were exposed to sevoflurane for 3 hours/day, 5 days/week for 2 weeks (total 30 hours exposure) at a flow rate of 500 mL/min in a semi-closed, rebreathing system with soda lime. Renal toxicity was not observed in the study evaluation of clinical signs, hematology, serum chemistry, urinalysis, or gross or microscopic pathology.


    DRUG INTERACTIONS:

    In the clinical trial, sevoflurane was used safely in dogs that received frequently used veterinary products including steroids and heartworm and flea preventative products.


    Intravenous Anesthetics: Sevoflurane administration is compatible with barbiturates, propofol and other commonly used intravenous anesthetics.

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


    Phenothiazines and Alpha2-Agonists: Sevoflurane is compatible with phenothiazines and alpha2-agonists as commonly used in surgical practice.


    In a laboratory study, the use of the acepromazine/oxymorphone/thiopental/sevoflurane anesthetic regimen resulted in prolonged recoveries in eight (of 8) dogs compared to recoveries from sevoflurane alone.


  • CLINICAL EFFECTIVENESS

    The effectiveness of sevoflurane was investigated in a clinicalstudy involving 196 dogs. Thirty dogs were mask-induced with sevofluraneusing anesthetic regimens that included various premedicants. Duringthe clinical study, one hundred sixty-six dogs received sevofluranemaintenance anesthesia as part of several anesthetic regimens that usedinjectable induction agents and various premedicants.

    The duration of anesthesia and the choice of anesthetic regimens weredependent upon the procedures that were performed. Duration ofanesthesia ranged from 16 to 424 minutes among the individual dogs.Sevoflurane vaporizer concentrations during the first 30 minutes ofmaintenance anesthesia were similar among the various anestheticregimens. The quality of maintenance anesthesia was considered good orexcellent in 169
    out of 196 dogs.

    The table shows the average vaporizer concentrations and oxygen flow rates during thefirst 30 minutes for all sevoflurane maintenance anesthesia regimens:



    Average Vaporizer
    Concentrations
    among Anesthetic
    Regimens
    Average Vaporizer Concentrations among Individual
    Dogs
    Average Oxygen Flow Rates among
    Anesthetic Regimens
    Average Oxygen Flow Rates among
    Individual Dogs
    3.31-3.63%
    1.6-5.1%
    0.97-1.31
    L/minute
    0.5-3.0
    L/minute

    During the clinical trial, when a barbituratewas used for induction, the times to extubation, sterna recumbency and standingrecovery were longer for dogs that received anesthetic regimens containing twopreanesthetics compared to regimens containing one preanesthetic. Recoverytimes were shorter when anesthetic regimens used sevoflurane or propofol forinduction. The quality of recovery was considered good or excellent in 184 outof 196 dogs.


    Anesthetic regimen drug dosages,physiological responses, and the quality of induction, maintenance and recoverywere comparable between 10 sighthounds and other breeds evaluated in the study.During the clinical study there was no indication of prolonged recovery timesin the sighthounds.

  • HOW SUPPLIED

    Sevoflurane is packaged in 250 mL amber-colored bottles.
    250 ML - NDC 14043-110-25

    STORAGE CONDITIONS

    Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C-30°C (59°F-86°F) [See USP Controlled Room Temperature].

  • REFERENCES

    1. Plumb, D.C. ed., Veterinary Drug Handbook, Second Edition, University of Iowa Press, Ames, IA: p. 424 (1995).
    2. Kazama, T. and Ikeda, K., Comparison of MAC and the rate of rise of alveolar concentration of sevoflurane with halothane and isoflurane in the dog. Anesthesiology. 68: 435-437 (1988).
    3. Scheller, M.S., Nakakimura, K., Fleischer, J.E. and Zornow, M.H., Cerebral effects of sevoflurane in the dog: Comparison with isoflurane and enflurane. Brit. J. Anesthesia 65: 388-392 (1990).
    4. Frink, E.J., Morgan, S.E., Coetzee, A., Conzen, P.F. and Brown, B.R., Effects of sevoflurane, halothane, enflurane and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs. Anesthesiology 76: 85-90 (1992).
    5. Kazama, T. and Ikeda, K., The comparative cardiovascular effects of sevoflurane with halothane and isoflurane. J. Anesthesiology 2: 63-8 (1988).
    6. Bernard, J. M., Wouters, P.F., Doursout, M.F., Florence, B., Chelly, J.E. and Merin, R.G., Effects of sevoflurane on cardiac and coronary dynamics in chronically instrumented dogs. Anesthesiology 72: 659-662 (1990).
    7. Hayaski, Y., Sumikawa, K., Tashiro, C., Yamatodani, A. and Yoshiya, I., Arrhythmogenic threshold of epinephrine during sevoflurane, enflurane and isoflurane anesthesia in dogs. Anesthesiology 69: 145-147 (1988).
    8. Muir, W.W. and Gadawski, J., Cardiorespiratory effects of low-flow and closed circuit inhalation anesthesia, using sevoflurane delivered with an in-circuit vaporizer and concentrations of compound A. Amer. J. Vet. Res. 59 (5): 603-608 (1998).

    ANADA 200-438, Approved by FDA

    *Baralyme® is a registered trademark of Allied Healthcare Products, Inc.

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    250ml label

    Prinicpal Display Panel

    250ml carton
  • INGREDIENTS AND APPEARANCE
    SEVOFLURANE 
    sevoflurane liquid
    Product Information
    Product TypePRESCRIPTION ANIMAL DRUGItem Code (Source)NDC:14043-110
    Route of AdministrationRESPIRATORY (INHALATION)
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    SEVOFLURANE (UNII: 38LVP0K73A) (SEVOFLURANE - UNII:38LVP0K73A) SEVOFLURANE1 mL  in 1 mL
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:14043-110-251 in 1 CARTON
    1250 mL in 1 BOTTLE
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANADAANADA20043809/11/2014
    Labeler - Patterson Veterinary (006962500)
    Establishment
    NameAddressID/FEIBusiness Operations
    Piramal Critical Care Inc805600439ANALYSIS, API MANUFACTURE, LABEL, MANUFACTURE, PACK