Prescription Drug Information: Sevoflurane (Page 3 of 3)

ADVERSE REACTIONS

Clinical Trials Experience

Adverse events are derived from controlled clinical studies conducted in the United States, Canada, and Europe. The reference drugs were isoflurane, enflurane, and propofol in adults and halothane in pediatric patients. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (including disease) and/or medications administered.

Of the 5182 patients enrolled in the clinical studies, 2906 were exposed to sevoflurane, including 118 adults and 507 pediatric patients who underwent mask induction. Each patient was counted once for each type of adverse event. Adverse events reported in patients in clinical studies and considered to be possibly or probably related to sevoflurane are presented within each body system in order of decreasing frequency in the following listings. One case of malignant hyperthermia was reported in pre-registration clinical studies.

Adverse Events During the Induction Period (from Onset of Anesthesia by Mask Induction to Surgical Incision) Incidence > 1%

Adult Patients (N = 118)

Cardiovascular

Bradycardia 5%, Hypotension 4%, Tachycardia 2%

Nervous System

Agitation 7%

Respiratory System

Laryngospasm 8%, Airway obstruction 8%, Breathholding 5%, Cough Increased 5%

Pediatric Patients (N = 507)

Cardiovascular

Tachycardia 6%, Hypotension 4%

Nervous System

Agitation 15%

Respiratory System

Breathholding 5%, Cough Increased 5%, Laryngospasm 3%, Apnea 2%

Digestive System

Increased salivation 2%

Adverse Events During Maintenance and Emergence Periods, Incidence > 1% (N = 2906)

Body as a whole

Fever 1%, Shivering 6%, Hypothermia 1%, Movement 1%, Headache 1%

Cardiovascular

Hypotension 11%, Hypertension 2%, Bradycardia 5%, Tachycardia 2%

Nervous System

Somnolence 9%, Agitation 9%, Dizziness 4%, Increased salivation 4%

Digestive System

Nausea 25%, Vomiting 18%

Respiratory System

Cough increased 11%, Breathholding 2%, Laryngospasm 2%

Adverse Events, All Patients in Clinical Studies (N = 2906), All Anesthetic Periods, Incidence < 1% (Reported in 3 or More Patients)

Body as a whole

Asthenia, Pain

Cardiovascular

Arrhythmia, Ventricular Extrasystoles, Supraventricular Extrasystoles, Complete AV Block, Bigeminy, Hemorrhage, Inverted T Wave, Atrial Fibrillation, Atrial Arrhythmia, Second Degree AV Block, Syncope, S-T Depressed

Nervous System

Crying, Nervousness, Confusion, Hypertonia, Dry Mouth, Insomnia

Respiratory System

Sputum Increased, Apnea, Hypoxia, Wheezing, Bronchospasm, Hyperventilation, Pharyngitis, Hiccup, Hypoventilation, Dyspnea, Stridor

Metabolism and Nutrition

Increases in LDH, AST, ALT, BUN, Alkaline Phosphatase, Creatinine, Bilirubinemia, Glycosuria, Fluorosis, Albuminuria, Hypophosphatemia, Acidosis, Hyperglycemia

Hemic and Lymphatic System

Leucocytosis, Thrombocytopenia

Skin and Special Senses

Amblyopia, Pruritus, Taste Perversion, Rash, Conjunctivitis

Urogenital

Urination Impaired, Urine Abnormality, Urinary Retention, Oliguria

See WARNINGS for information regarding malignant hyperthermia.

POSTMARKETING EXPERIENCE

The following adverse events have been identified during post-approval use of sevoflurane. Due to the spontaneous nature of these reports, the actual incidence and relationship of sevoflurane to these events cannot be established with certainty.

Central Nervous System

• Seizures — Post-marketing reports indicate that sevoflurane use has been associated with seizures. The majority of cases were in children and young adults, most of whom had no medical history of seizures. Several cases reported no concomitant medications, and at least one case was confirmed by EEG. Although many cases were single seizures that resolved spontaneously or after treatment, cases of multiple seizures have also been reported. Seizures have occurred during, or soon after sevoflurane induction, during emergence, and during post-operative recovery up to a day following anesthesia.

• Delirium

Cardiac

• Cardiac arrest

• QT prolongation associated with Torsade de Pointe

• Bradycardia in patients with Down syndrome

Hepatic

• Cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported. Histological evidence was not provided for any of the reported hepatitis cases. In most of these cases, patients had underlying hepatic conditions or were under treatment with drugs known to cause hepatic dysfunction. Most of the reported events were transient and resolved spontaneously (see PRECAUTIONS).

• Hepatic necrosis

• Hepatic failure

Other

• Malignant hyperthermia (see CONTRAINDICATIONS, WARNINGS)

• Allergic reactions, such as rash, urticaria, pruritus, bronchospasm, and anaphylactic reactions (see CONTRAINDICATIONS)

• Reports of hypersensitivity (including contact dermatitis, rash, dyspnea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, particularly in association with long-term occupational exposure to inhaled anesthetic agents, including sevoflurane (see SAFETY AND HANDLING — Occupational Caution).

Laboratory Findings

• Transient elevations in glucose, liver function tests, and white blood cell count may occur as with use of other anesthetic agents.

OVERDOSAGE

In the event of overdosage, or what may appear to be overdosage, the following action should be taken: discontinue administration of sevoflurane, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.

DOSAGE AND ADMINISTRATION

The concentration of sevoflurane being delivered from a vaporizer should be known. This may be accomplished by using a vaporizer calibrated specifically for sevoflurane. The administration of general anesthesia must be individualized based on the patient’s response.

Replacement of Desiccated CO 2 Absorbents

When a clinician suspects that the CO 2 absorbent may be desiccated, it should be replaced. The exothermic reaction that occurs with sevoflurane and CO 2 absorbents is increased when the CO 2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO 2 absorbent canisters (see PRECAUTIONS).

Pre-anesthetic Medication

No specific premedication is either indicated or contraindicated with sevoflurane. The decision as to whether or not to premedicate and the choice of premedication is left to the discretion of the anesthesiologist.

Induction

Sevoflurane has a nonpungent odor and does not cause respiratory irritability; it is suitable for mask induction in pediatrics and adults.

Maintenance

Surgical levels of anesthesia can usually be achieved with concentrations of 0.5 — 3% sevoflurane with or without the concomitant use of nitrous oxide. Sevoflurane can be administered with any type of anesthesia circuit.

Table 9. MAC Values for Adults and Pediatric Patients According to Age

Age of Patient (years)

Sevoflurane in Oxygen

Sevoflurane in 65% N 2 O/35% O 2

0 — 1 months #

3.3%

1 — < 6 months

3.0%

6 months — < 3 years

2.8%

2.0%@

3 — 12

2.5%

25

2.6%

1.4%

40

2.1%

1.1%

60

1.7%

0.9%

80

1.4%

0.7%

# Neonates are full-term gestational age. MAC in premature infants has not been determined.

@ In 1 — < 3 year old pediatric patients, 60% N 2 O/40% O 2 was used.

HOW SUPPLIED

Sevoflurane, USP, Volatile Liquid for Inhalation, is packaged in amber colored bottles containing 250 mL Sevoflurane, USP, NDC # 66794-022-25.

SAFETY AND HANDLING

Occupational Caution

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 (0.5 ppm when coupled with exposure to N 2 O) (see ADVERSE REACTIONS).

Storage

Store at controlled room temperature, 15° — 30°C (59° — 86°F). See USP.

ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY

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 pregnant women, neonates and young children who require procedures against the potential risks suggested by the nonclinical data (see WARNINGS — Pediatric Neurotoxicity, PRECAUTIONS — Pregnancy, PRECAUTIONS — Pediatric Use).

Manufactured by:

Piramal Critical Care, Inc.

3950 Schelden Circle

Bethlehem, PA 18017

(888) 822-8431

Last Revised: May 2022

© 2022 Piramal Critical Care, Inc.

label
(click image for full-size original)

SEVOFLURANE
sevoflurane liquid
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:66794-022
Route of Administration RESPIRATORY (INHALATION) DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
SEVOFLURANE (SEVOFLURANE) SEVOFLURANE 1 mL in 1 mL
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:66794-022-25 250 mL in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077867 10/01/2020
Labeler — Piramal Critical Care Inc (805600439)
Establishment
Name Address ID/FEI Operations
Piramal Critical Care Inc 805600439 analysis (66794-022), api manufacture (66794-022), label (66794-022), manufacture (66794-022), pack (66794-022)

Revised: 06/2022 Piramal Critical Care Inc

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