Annotation of FDA Label for desflurane and CACNA1S, RYR1

Summary

Desflurane (SUPRANE) is a potent (volatile) inhalational anesthetic used to induce or maintain general anesthesia. The FDA-approved label warns that individuals with a genetic predisposition to malignant hyperthermia, or patients with Duchenne Muscular Dystrophy, are at greater risk of developing malignant hyperthermia, or hyperkaelemia, respectively, if administered desflurane.

Prescribing

Excerpt from the FDA-approved desflurane (SUPRANE) drug label:

The use of SUPRANE is contraindicated in the following conditions... Malignant Hyperthermia: Malignant hyperthermia may occur, especially in individuals with known or suspected susceptibility based on genetic factors or family history. Discontinue triggering agents, administer intravenous dantrolene sodium, and apply supportive therapies.

Annotation

Specific variants in the RYR1 and CACNA1S genes are associated with risk of malignant hyperthermia in individuals administered potent inhalational anesthetics, including desflurane. The FDA-approved label for desflurane (SUPRANE) contraindicates it for individuals with known, or suspected, genetic predisposition to malignant hyperthermia.

Excerpts from the FDA-approved desflurane (SUPRANE) drug label:

The use of SUPRANE is contraindicated in the following conditions...Malignant Hyperthermia: Malignant hyperthermia may occur, especially in individuals with known or suspected susceptibility based on genetic factors or family history. Discontinue triggering agents, administer intravenous dantrolene sodium, and apply supportive therapies.

In susceptible individuals, volatile anesthetic agents, including desflurane, may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand. Fatal outcomes of malignant hyperthermia have been reported.

The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. SUPRANE can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants.

Pharmacogenomics: RYR1 and CACNA1S are polymorphic genes and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (MHS) in patients receiving volatile anesthetic agents, including SUPRANE. Case reports as well as exvivo studies have identified multiple variants in RYR1 and CACNA1S associated with MHS. Variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence (see Contraindications (4), Warnings and Precautions (5.1)).

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the desflurane drug label

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Evidence for Clinical Annotations

This annotation has been used as evidence for the following clinical annotations.

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