BUPIVACAINE HYDROCHLORIDE (Page 6 of 8)

8.2 Lactation

Risk Summary

Lactation studies have not been conducted with bupivacaine. Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection should be administered to lactating women only if clearly indicated. Studies assessing the effects of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in breastfed children have not been performed. Studies to assess the effect of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection on milk production or excretion have not been performed. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for bupivacaine and any potential adverse effects on the breastfed child from bupivacaine or from the underlying maternal condition.

8.4 Pediatric Use

Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is approved for use in adults. Administration of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pediatric patients younger than 12 years is not recommended.

Continuous infusions of bupivacaine in pediatric patients have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities.

8.5 Geriatric Use

Patients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

In clinical studies of bupivacaine, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger adult patients.

Differences in various pharmacokinetic parameters have been observed between elderly and younger adult patients [see Clinical Pharmacology (12.3)].

This product is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients may require lower doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

8.6 Hepatic Impairment

Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment treated with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, especially with repeat doses [see Warnings and Precautions (5.10)].

8.7 Renal Impairment

Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. This should be considered when selecting the Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection dosage [see Use in Specific Populations (8.5)].

10 OVERDOSAGE

Clinical Presentation

Acute emergencies from use of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection are generally related to high plasma levels encountered during therapeutic use or to unintended intrathecal injection [see Warnings and Precautions (5.2, 5.9), Adverse Reactions (6)].

If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of bupivacaine may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Hypoventilation or apnea due to unintentional intrathecal injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts.

Management

The first step in the management of systemic toxic reactions, as well as hypoventilation or apnea due to unintentional intrathecal injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated.

If necessary, use drugs to manage the convulsions. A bolus intravenous dose of a benzodiazepine will counteract CNS stimulation related to Bupivacaine Hydrochloride Injection. Immediately after the institution of ventilatory measures, evaluate the adequacy of the circulation. Supportive treatment of circulatory depression may require Advanced Cardiac Life Support measures.

11 DESCRIPTION

Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection contains bupivacaine hydrochloride, an amide local anesthetic, as the active pharmaceutical ingredient. The route of administration for Bupivacaine Hydrochloride Injection (without epinephrine) is by injection, for infiltration, perineural, caudal, epidural, or retrobulbar use. The route of administration for Bupivacaine Hydrochloride and Epinephrine Injection is by injection, for infiltration, perineural, caudal, or epidural use. Multiple-dose vials contain methylparaben [see Warnings and Precautions (5.4)].

Bupivacaine hydrochloride is 2-piperidinecarboxamide, 1-butyl-N -(2,6-dimethylphenyl)-, monohydrochloride, monohydrate. It is a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula:

Bupivacaine hydrochloride with 1:200,000 epinephrine, contains bupivacaine hydrochloride and epinephrine (an alpha and beta-adrenergic agonist) as active pharmaceutical ingredients. This product is for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. Multiple-dose vials contain methylparaben and they should not be used for caudal and lumbar epidural blocks.

Epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol. Epinephrine is a vasoconstrictor. It has the following structural formula:

Bupivacaine Hydrochloride Injection, USP is a clear and colorless sterile isotonic solution. Each mL of single-dose vial contains 2.5 mg, 5 mg, or 7.5 mg of bupivacaine hydrochloride (equivalent to 2.22 mg, 4.44 mg, or 6.66 mg of bupivacaine, respectively), sodium chloride for isotonicity, sodium hydroxide or hydrochloric acid to adjust the pH between 4 and 6.5, in water for injection.

For the multiple-dose vials, each mL also contains 1 mg methylparaben as preservative.

Bupivacaine Hydrochloride and Epinephrine Injection, USP is a clear and colorless sterile isotonic solution. Each mL contains 2.5 mg or 5 mg bupivacaine hydrochloride (equivalent to 2.22 mg or 4.44 mg of bupivacaine, respectively), and 0.005 mg of epinephrine, with sodium chloride for isotonicity, 0.1 mg sodium metabisulfite as antioxidant, and 0.1 mg edetate calcium disodium anhydrous as stabilizer. The pH of these solutions is adjusted to between 3.3 and 5.5 with sodium hydroxide or hydrochloric acid.

For the multiple-dose vials, each mL also contains 1 mg methylparaben as preservative.

The specific gravity of Bupivacaine Hydrochloride and Epinephrine Injection [0.5% (5 mg/mL) of bupivacaine] at 25 °C is 1.007.