Petrem

Piramal Critical Care Inc.
Piramal Critical Care Inc.

Petrem®(sevoflurane, USP) Inhalation Anesthetic For Use in Dogs              

FULL PRESCRIBING INFORMATION: CONTENTS*

• PETREM DESCRIPTION
• CLINICAL PHARMACOLOGY
• INDICATIONS & USAGE
• PETREM CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • General Precautions
  • Drug Interactions
• PETREM ADVERSE REACTIONS
• DOSAGE & ADMINISTRATION
• HOW SUPPLIED
• CLINICAL STUDIES
• REFERENCES
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL -Bottle Label - 250ml
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL -Carton- 250ml

FULL PRESCRIBING INFORMATION

PETREM DESCRIPTION

Petrem® (sevoflurane, USP), 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:

Sevoflurane, USP Physical Constants are:

Molecular weight 200.05

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, USP is nonflammable and nonexplosive as defined by the requirements of

International Electrotechnical Commission 601-2-13.

Sevoflurane, USP is a clear, colorless, stable liquid containing no additives or chemical stabilizers.

Sevoflurane, USP is nonpungent. It is miscible with ethanol, ether, chloroform and petroleum benzene, and it is slightly soluble in water. Sevoflurane, USP is stable when stored under normal room lighting condition according to instructions.

CLINICAL PHARMACOLOGY

Sevoflurane, USP is an inhalational anesthetic agent for induction and maintenance of general anesthesia. The Minimum Alveolar Concentration (MAC) of sevoflurane, USP 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, USP in blood (blood/gas partition coefficient at 37°C = 0.63-0.69), a minimal amount of sevoflurane, USP is required to be dissolved in the blood before the alveolar partial pressure is in equilibrium with the arterial partial pressure. During sevoflurane, USP induction, there is a rapid increase in alveolar concentration toward the inspired concentration.

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

Sevoflurane, USP is chemically stable. No discernible degradation occurs in the presence of strong acids or heat. Sevoflurane, USP reacts through direct contact with CO2 absorbents (soda lime and barium hydroxide lime) producing pentafluoroisopropenyl fluoromethyl ether (PIFE, C₄H₂F₆0), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether (PMFE, C₅H₆F₆0), 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, USP. Compound A is produced when sevoflurane, USP 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, USP concentrations and with decreasing fresh gas flow rates. Sevoflurane, USP 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, USP 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, USP 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, USP. Once formed, HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane, USP 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, USP 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, USP 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.

INDICATIONS & USAGE

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

PETREM CONTRAINDICATIONS

Petrem® is contraindicated in dogs with a known sensitivity to sevoflurane, USP or other

halogenated agents.

WARNINGS

sevoflurane, USP is a profound respiratory depressant. DUE TO THE RAPID AND DOSE DEPENDENT CHANGES IN ANESTHETIC DEPTH, RESPIRATION MUST BE MONITORED CLOSELY IN THE DOG AND SUPPORTED WHEN NECESSARY WITH SUPPLEMENTAL OXYGEN AND/OR ASSISTED VENTILATION.

In cases of severe cardiopulmonary depression, discontinue drug administration, ensure the existence of a patent airway and initiate assisted or controlled ventilation with pure oxygen. Cardiovascular depression should be treated with plasma expanders, pressor agents, antiarrhythmic agents or other techniques as appropriate for the observed abnormality. Due to sevoflurane, USP’s low solubility in blood, increasing the concentration may result in rapid hemodynamic changes (dose dependent decreases in blood pressure) compared to other volatile anesthetics. Excessive decreases in blood pressure or respiratory depression may be corrected by decreasing or discontinuing the inspired concentration of sevoflurane, USP.

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

PRECAUTIONS

Halogenated volatile anesthetics can react with desiccated carbon dioxide (CO ₂ ) absorbents to produce carbon monoxide (CO) that may result in elevated carboxyhemoglobin levels in some patients. To prevent this reaction, sevoflurane should not be passed through desiccated soda lime or barium hydroxide lime.

Replacement of Desiccated Co ₂ Absorbents:

When a clinician suspects that the CO ₂ absorbent may be desiccated, it should be replaced before administration of sevoflurane. The exothermic reaction that occurs with sevoflurane and CO ₂ absorbent is increased when the CO ₂ extended period of dry gas flow through the CO ₂ absorbent canisters. Extremely rare cases of spontaneous fire in the respiratory circuit of the anesthesia machine have been reported during sevoflurane use in conjunction with the use of desiccated CO ₂ absorbent, specifically those containing potassium hydroxide (e.g. BARALYME). Potassium hydroxide-containing CO ₂ absorbents are not recommended for use with sevoflurane. An unusually delayed rise in the inspired gas concentration (decrease delivery) of sevoflurane compared with the

vaporizer setting may indicate excessive heating of the CO ₂ absorbent canister

and chemical breakdown of sevoflurane. The color indicator of most CO2 absorbent 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.

The use of some anesthetic regimens that include sevoflurane may result in bradycardia that is reversible with anticholinergics. Studies using sevoflurane anesthetic regimens that included atropine or glycopyrrolate as premedicants showed these anticholinergics to be compatible with sevoflurane in dogs.

During the maintenance of anesthesia, increasing the concentration of sevoflurane produces dose dependent decreases in blood pressure. Due to sevoflurane's low solubility 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. RESPIRATION MUST BE MONITORED CLOSELY IN THE DOG AND SUPPORTED WHEN NECESSARY WITH SUPPLEMENTAL 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 and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants. The use of sevoflurane with nondepolarizing muscle relaxants has not been evaluated in dogs.

Compromised or debilitated dogs: Doses may need adjustment for geriatric or debilitated dogs. Because clinical experience in administering sevoflurane to dogs with renal, hepatic and cardiovascular insufficiency is limited, its safety in these dogs has not been established.

Breeding dogs: The safety of sevoflurane in dogs used for breeding purposes, during pregnancy, or in lactating bitches, has not been evaluated.

General Precautions

Operating rooms and animal recovery areas should be provided with adequate 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 has recommended an 8 hour time-weighted average limit of 2 ppm for halogenated anesthetic agents in general.

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

Symptoms of human overexposure (inhalation) to sevoflurane, USP vapors include respiratory depression, hypotension, bradycardia, shivering, nausea and headache. If these symptoms occur, remove the individual from the 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 (610) 974-9760.

Drug Interactions

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

Phenothiazines and Alpha₂-Agonists: Sevoflurane, USP is compatible with  phenothiazines and alpha ₂ -agonists as commonly used in surgical practice.

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

STORAGE CONDITIONS:

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

PETREM ADVERSE REACTIONS

The most frequently reported adverse reactions during maintenance anesthesia 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 excessive cardiopulmonary depression. Transient elevations in liver function tests and white blood cell count may occur with sevoflurane, USP, as with the use of other halogenated anesthetic agents.

DOSAGE & ADMINISTRATION

Inspired Concentration: The delivered concentration of Petrem® should be known. Since the depth of anesthesia may be altered easily and rapidly, only vaporizers producing predictable percentage concentrations of sevoflurane, USP should be used. Sevoflurane, USP should be vaporized using a precision vaporizer specifically calibrated for sevoflurane. Sevoflurane, USP 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, USP PATIENTS SHOULD BE CONTINUOSLY 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 CO ₂ absorbent may be desiccated, it should be replaced. An exothermic reaction occurs when sevoflurane, USP is exposed to CO ₂ absorbents. This reaction is increased when the CO2 absorbent becomes desiccated (see PRECAUTIONS).

Premedication: No specific premedication is either indicated or contraindicated with sevoflurane, USP. 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, USP alone, inspired concentrations of up to 7% sevoflurane, USP 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: Petrem® may be used for maintenance anesthesia following mask induction using sevoflurane, USP 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, USP 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, USP required for maintenance. Anesthetic regimens that include opioid, alpha₂- agonist, benzodiazepine or phenothiazine premedication will allow the use of lower sevoflurane, USP maintenance concentrations.

HOW SUPPLIED

Petrem® (sevoflurane, USP) is packaged in amber colored bottles containing 250 mL

sevoflurane, USP, NDC 66794-018-25.

CLINICAL STUDIES

CLINICAL EFFECTIVENESS:

The effectiveness of sevoflurane, USP was investigated in a clinical study involving 196 dogs. Thirty dogs were mask-induced with sevoflurane, USP using anesthetic regimens that included various premedicants. During the clinical study, one hundred sixty-six dogs received sevoflurane, USP maintenance anesthesia as part of several anesthetic regimens that used injectable induction agents and various premedicants. The duration of anesthesia and the choice of anesthetic regimens were dependent upon the procedures that were performed. Duration of anesthesia ranged from 16 to 424 minutes among the

individual dogs. Sevoflurane, USP vaporizer concentrations during the first 30 minutes of maintenance anesthesia were similar among the various anesthetic regimens. The quality of maintenance anesthesia was considered good or excellent in 169 out of 196 dogs.

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

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Average Vaporizer      Average Vaporizer       Average                         Average

Concentrations            Concentrations             Oxygen Flow                 Oxygen Flow

among Anesthetic       among Individual         Rates among                  Rates among

Regimens                    Dogs                             Anesthetic Regimens     Individual Dogs

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3.31 -3.63%                       1.6-5.1%                  0.97-1.31 L/minute     0.5-3.0 L/minute                                                                                                                                             

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During the clinical trial, when a barbiturate was used for induction, the times to extubation, sternal recumbency and standing recovery were longer for dogs that received anesthetic regimens containing two preanesthetics compared to regimens containing one preanesthetic. Recovery times were shorter when anesthetic regimens used sevoflurane, USP or propofol for induction. The quality of recovery was considered good or excellent in 184 out of 196 dogs. Anesthetic regimen drug dosages, physiological responses, and the quality of induction, maintenance and recovery were comparable between 10 sighthounds and other breeds evaluated in the study. During the clinical study there was no indication of prolonged recovery times in the sighthounds.

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).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL -Bottle Label - 250ml

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL -Carton- 250ml