Chirocaine Side Effects, and Drug Interactions - Levobupivacaine

Chirocaine Side Effects, and Drug Interactions - Levobupivacaine

SIDE EFFECTS

Reactions to Chirocaine are characteristic of those associated with other amide-type local anesthetics. A major cause of the adverse reactions to this group of drugs is associated with excessive plasma levels, or high dermatol levels, which may be due to overdose, unintentional intravascular injection, or slow metabolic degradation. The reported adverse events are derived from studies conducted in the United States and Europe. The reference drug was primarily bupivacaine. While the adverse event profile from clinical trials in patients was similar between the two drugs, their relative potency has not been established. The studies were conducted using a variety of premedications, sedatives, and surgical procedures of varying length. A total of 1220 patients were exposed to Chirocaine. Each patient was counted once for each type of adverse event.

In the Phase II/III studies, 78% of patients who received Chirocaine ^® reported at least one adverse event. Of those patients who received the 0.75% levobupivacaine concentration, 85% reported at least one adverse event.

Adverse events that occurred in >5% of all Chirocaine-treated patients in Phase II/III studies (N=1141) were hypotension (31%), nausea (21%), post-operative pain (18%), fever (17%), vomiting (14%), anemia (12%), pruritus (9%), pain (8%), headache (7%), constipation (7%), dizziness (6%), and fetal distress (5%).

The following adverse events were reported during the Chirocaine clinical program in more than one patient, occurred at an overall incidence of <1%, and were considered clinically relevant:

Body as a Whole:   asthenia, edema.

Cardiovascular Disorders, General:   postural hypotension.

Central and Peripheral Nervous System Disorders:   hypokinesia, involuntary muscle contraction, spasm (generalized), tremor, syncope.

Heart Rate and Rhythm Disorders:   arrhythmia, extrasystoles, fibrillation (atrial), cardiac arrest.

Gastrointestinal System Disorders:   ileus.

Liver and Biliary System Disorders:   elevated bilirubin.

Psychiatric Disorders:   confusion.

Respiratory System Disorders:   apnea, bronchospasm, dyspnea, pulmonary edema, respiratory insufficiency.

Skin and Appendage Disorders:   increased sweating, skin discoloration.

Chirocaine ^® should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics since the toxic effects of these drugs could be additive. In vitro studies indicate CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. Thus agents likely to be concomitantly administered with Chirocaine that are metabolized by this isoenzyme family may potentially interact with Chirocaine. Although no clinical studies have been conducted, it is likely that the metabolism of levobupivacaine may be affected by the known CYP3A4 inducers (such as phenytoin, phenobarbital, rifampin), CYP3A4 inhibitors (azole antimycotics e.g., ketoconazole; certain protease inhibitors e.g., ritanovir; macrolide antibiotics e.g., erythromycin; and calcium channel antagonists e.g., verapamil), CYP1A2 inducers (omeprazole) and CYP1A2 inhibitors (furafylline and clarithromycin). Dosage adjustment may be warranted when levobupivacaine is concurrently administered with CYP3A4 inhibitors and CYP1A2 inhibitors as systemic levobupivacaine levels may rise resulting in toxicity.