Sojourn
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Questions & Answers
Side Effects & Adverse Reactions
Although data from controlled clinical studies at low flow rates are limited, findings taken from patient and animal studies suggest that there is a potential for renal injury which is presumed due to Compound A. Animal and human studies demonstrate that sevoflurane administered for more than 2 MAC·hours and at fresh gas flow rates of < 2 L/min may be associated with proteinuria and glycosuria.
While a level of Compound A exposure at which clinical nephrotoxicity might be expected to occur has not been established, it is prudent to consider all of the factors leading to Compound A exposure in humans, especially duration of exposure, fresh gas flow rate, and concentration of sevoflurane. During sevoflurane anesthesia the clinician should adjust inspired concentration and fresh gas flow rate to minimize exposure to Compound A. To minimize exposure to Compound A, sevoflurane exposure should not exceed 2 MAC·hours at flow rates of 1 to < 2 L/min. Fresh gas flow rates < 1 L/min are not recommended.
Because clinical experience in administering sevoflurane to patients with renal insufficiency (creatinine >1.5 mg/dL) is limited, its safety in these patients has not been established.
Sevoflurane may be associated with glycosuria and proteinuria when used for long procedures at low flow rates. The safety of low flow sevoflurane on renal function was evaluated in patients with normal preoperative renal function. One study compared sevoflurane (N = 98) to an active control (N = 90) administered for ≥ 2 hours at fresh gas flow rate of ≤ 1 Liter/minute. Per study defined criteria (Hou et al.) one patient in the sevoflurane group developed elevations of creatinine, in addition to glycosuria and proteinuria. This patient received sevoflurane at fresh gas flow rates of ≤ 800 mL/minute. Using these same criteria, there were no patients in the active control group who developed treatment emergent elevations in serum creatinine.
Sevoflurane may present an increased risk in patients with known sensitivity to volatile halogenated anesthetic agents. KOH containing CO2 absorbents are not recommended for use with sevoflurane.
Isolated reports of QT prolongation, very rarely associated with torsades de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering sevoflurane to susceptible patients.
Malignant Hyperthermia
In susceptible individuals, potent inhalation anesthetic agents, including sevoflurane, may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In clinical trials, one case of malignant hyperthermia was reported. In genetically susceptible pigs, sevoflurane induced malignant hyperthermia. The clinical syndrome is signaled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia, acute hypoxia, hypercapnia, and hypovolemia.
Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible.
Perioperative Hyperkalemia
Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended; as is subsequent evaluation for latent neuromuscular disease.
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FDA Labeling Changes
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Uses
Sojourn (sevoflurane, USP) is indicated for induction and maintenance of general anesthesia in adult and pediatric patients for inpatient and outpatient surgery.
Sojourn (sevoflurane, USP) should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Since level of anesthesia may be altered rapidly, only vaporizers producing predictable concentrations of sevoflurane should be used.
History
There is currently no drug history available for this drug.
Other Information
Sojourn (sevoflurane, USP), a volatile liquid for inhalation, a nonflammable and nonexplosive liquid administered by vaporization, is a halogenated general inhalation anesthetic drug. Sevoflurane is fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether, (C4H3F7O), and its structural formula is:
Sevoflurane, Physical Constants are:
Molecular weight 200.05
Boiling point at 760 mm Hg 58.6°C
Specific gravity 20°C 1.520 to 1.525 g/mL
Vapor pressure in mm Hg 157 mm Hg at 20°C
197 mm Hg at 25°C
317 mm Hg at 36°C
Distribution Partition Coefficients at 37°C:
Blood/Gas .63 to 0.69
Water/gas 0.36
Olive Oil/gas 47 to 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
Polyvinylchloride 17.4
Polyethylene 1.3
Sojourn® (sevoflurane, USP) is nonflammable and nonexplosive as defined by the requirements of International Electrotechnical Commission 601-2-13.
Sojourn® (sevoflurane, USP) is a clear, colorless, liquid containing no additives. Sojourn® (sevoflurane, USP) is not corrosive to stainless steel, brass, aluminum, nickel-plated brass, chrome-plated brass or copper beryllium. Sojourn® (sevoflurane, USP) is non-pungent. It is miscible with ethanol, ether, chloroform, and benzene, and it is slightly soluble in water. Sojourn® (sevoflurane, USP) is stable when stored under normal room lighting conditions according to instructions.
No discernible degradation of sevoflurane occurs in the presence of strong acids or heat. When in contact with alkaline CO2 absorbents (e.g. *Baralyme® and to a lesser extent soda lime) within the anesthesia machine, sevoflurane can undergo degradation under certain conditions. Degradation of sevoflurane is minimal, and degradants are either undetectable or present in non-toxic amounts when used as directed with fresh absorbents. Sevoflurane degradation and subsequent degradant formation are enhanced by increasing absorbent temperature increased sevoflurane concentration, decreased fresh gas flow and desiccated CO2 absorbents (especially with potassium hydroxide containing absorbents e.g. Baralyme®).
Sevoflurane alkaline degradation occurs by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropenyl fluoroethyl ether (PIFE, C4H2F6O), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether (PMFE, C5H6F6O), also known as Compound B. The second pathway for degradation of sevoflurane which occurs primarily in the presence of desiccated CO2 absorbents, is discussed later.
In the first pathway, the defluorination pathway, the production of degradants in the anesthesia circuit results from the extraction of the acidic proton in the presence of a strong base (KOH and/or NaOH) forming an alkene (Compound A) from sevoflurane similar to formation of 2-bromo-2-chloro-1,1-difluoro ethylene (BCDFE) from halothane. Laboratory simulations have shown that the concentration of these degradants is inversely correlated with the fresh gas flow rate (See Figure 1).
Since the reaction of carbon dioxide with absorbents is exothermic, the temperature increase will be determined by quantities of CO2 absorbed, which in turn will depend on fresh gas flow in the anesthesia circle system, metabolic status of the patient, and ventilation. The relationship of temperature produced by varying levels of CO2 and Compound A production is illustrated in the following in vitro simulation where CO2 was added to a circle absorber system.
Compound A
Compound A concentration in a circle absorber system increases as a function of increasing CO2 absorbent temperature and composition (Baralyme® producing higher levels than soda lime), increased body temperature, and increased minute ventilation, and decreasing fresh gas flow rates. It has been reported that the concentration of Compound A increases significantly with prolonged dehydration of Baralyme®. Compound A exposure in patients also has been shown to rise with increased sevoflurane concentrations and duration of anesthesia. In a clinical study in which sevoflurane was administered to patients under low flow conditions for ≥ 2 hours at flow rates of 1 Liter/minute, Compound A levels were measured in an effort to determine the relationship between MAC hours and Compound A levels produced. The relationship between Compound A levels and sevoflurane exposure are shown in Figure 2a.
Compound A has been shown to be nephrotoxic in rats after exposures that have varied duration from one to three hours. No histopathologic change was seen at a concentration of up to 270 ppm for one hour. Sporadic single cell necrosis of proximal tubule cells has been reported at a concentration of 114 ppm after a 3-hour exposure to Compound A in rats. The LC50 reported at 1 hour is 1050 to1090 ppm (male-female) and, at 3 hours, 350 to 490 ppm (male-female).
An experiment was performed comparing sevoflurane plus 75 or 100 ppm Compound A with an active control to evaluate the potential nephrotoxicity of Compound A in non-human primates. A single 8-hour exposure of sevoflurane in the presence of Compound A produced single-cell renal tubular degeneration and single-cell necrosis in cynomolgus monkeys. These changes are consistent with the increased urinary protein, glucose level and enzymatic activity noted on days one and three on the clinical pathology evaluation. This nephrotoxicity produced by Compound A is dose and duration of exposure dependent.
At a fresh gas flow rate of 1 L/min, mean maximum concentrations of Compound A in the anesthesia circuit in clinical settings are approximately 20 ppm (0.002%) with soda lime and 30 ppm (0.003%) with Baralyme® in adult patients; mean maximum concentrations in pediatric patients with soda lime are about half those found in adults. The highest concentration observed in a single patient with Baralyme® was 61 ppm (0.0061%) and 32 ppm (0.0032%) with soda lime. The level of Compound A at which toxicity occurs in humans is not known.
The second pathway for degradation of sevoflurane occurs primarily in the presence of desiccated CO2 absorbents and leads to the dissociation of sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic, rapidly glucuronidated and cleared by the liver. Formaldehyde is present during normal metabolic processes. Upon exposure to a highly desiccated absorbent, formaldehyde can further degrade into methanol and formate. Formate can contribute to the formation of carbon monoxide in the presence of high temperature that can be associated with desiccated Baralyme®. Methanol can react with Compound A to form the methoxy addition product Compound B. Compound B can undergo further HF elimination to form Compounds C, D, and E.
Sevoflurane degradants were observed in the respiratory circuit of an experimental anesthesia machine using desiccated CO2 absorbents and maximum sevoflurane concentrations (8%) for extended periods of time (> 2 hours). Concentrations of formaldehyde observed with desiccated soda lime in this experimental anesthesia respiratory circuit were consistent with levels that could potentially result in respiratory irritation. Although KOH containing CO2 absorbents are no longer commercially available, in the laboratory experiments, exposure of sevoflurane to the desiccated KOH containing CO2 absorbent, Baralyme®, resulted in the detection of substantially greater degradant levels.
Sources
Sojourn Manufacturers
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Piramal Critical Care Inc
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Sojourn | Zydus Pharmaceuticals (usa) Inc.
2.1 EpilepsyDivalproex sodium delayed-release capsules (sprinkle) are administered orally. As divalproex sodium dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see DRUG INTERACTIONS (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Divalproex sodium has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of divalproex sodium therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Divalproex sodium may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see CLINICAL STUDIES 14]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see DRUG INTERACTIONS (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures are considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see CLINICAL PHARMACOLOGY (12.3)].
As the divalproex sodium delayed-release capsules (sprinkle) dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see DRUG INTERACTIONS (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving valproic acid therapy, divalproex sodium delayed-release capsules (sprinkle) should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on divalproex sodium delayed-release capsules (sprinkle), a dosing schedule of two or three times a day may be elected in selected patients.
2.2 General Dosing AdviceDosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see WARNINGS AND PRECAUTIONS (5.14), USE IN SPECIFIC POPULATIONS (8.5) and CLINICAL PHARMACOLOGY (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see WARNINGS AND PRECAUTIONS (5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.
Administration of Sprinkle Capsules
Divalproex sodium delayed-release capsules (sprinkle) may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoonful) of soft food such as applesauce or pudding. The drug/food mixture should be swallowed immediately (avoid chewing) and not stored for future use. Each capsule is oversized to allow ease of opening.
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