Bupivacaine Hydrochloride

The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling: • Cardiac Arrest in Obstetrical Anesthesia [see Warnings and Precautions (5.1)] • Dose-Related Toxicity [see Warnings and Precautions (5.2)] • Methemoglobinemia [see Warnings and Precautions (5.3)] • Chondrolysis with Intra-Articular Infusion [see Warnings and Precautions (5.5)] • Cardiac Arrest with Intravenous Regional Anesthesia Use [see Contraindications (4), Warnings and Precautions (5.7)] • Systemic Toxicities with Unintended Intravascular or Intrathecal Injection [see Warnings and Precautions (5.9)] • Respiratory Arrest Following Retrobulbar Block [see Warnings and Precautions (5.15)] The following adverse reactions from voluntary reports or clinical studies have been reported with bupivacaine. Because many of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions to bupivacaine hydrochloride injection are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation. The most commonly encountered acute adverse reactions that demand immediate counter-measures were related to the CNS and the cardiovascular system. These adverse reactions were generally dose-related and due to high plasma levels which may have resulted from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional intrathecal injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) has resulted in underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia have occurred. This has led to secondary cardiac arrest when untreated. Nervous System Disorders : Adverse reactions were characterized by excitation and/or depression of the central nervous system and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, respiratory arrest, nausea, vomiting, chills, pupillary constriction. In the practice of caudal or lumbar epidural block, unintentional penetration of the subarachnoid space by the catheter or needle has occurred. Subsequent adverse effects may have depended partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia have included spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control, all of which had slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Neurologic effects following other procedures or routes of administration have included persistent anesthesia, paresthesia, weakness, paralysis, all with slow, incomplete, or no recovery. Convulsions : Incidence varied with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Cardiac Disorders : High doses or unintentional intravascular injection have led to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest [ see Warnings and Precautions (5.9) ]. Immune System Disorders : Allergic-type reactions have occurred as a result of sensitivity to bupivacaine or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials. These reactions were characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and severe hypotension. Cross sensitivity among members of the amide-type local anesthetic group has been reported [see Warnings and Precautions (5.8)]. Most common adverse reactions are related to the central nervous system and the cardiovascular system. (6) To report SUSPECTED ADVERSE REACTIONS, contact Steriscience at 1-888-278-1784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Bupivacaine hydrochloride injection is contraindicated in: • obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. • intravenous regional anesthesia (Bier Block) [ see Warnings and Precautions (5.7) ]. • patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of bupivacaine hydrochloride injection. • Obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. (4) • Intravenous regional anesthesia (Bier Block). (4) • Known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of bupivacaine hydrochloride injection. (4)

11 DESCRIPTION Bupivacaine hydrochloride injection contains bupivacaine hydrochloride, an amide local anesthetic, as the active pharmaceutical ingredient. The route of administration for bupivacaine hydrochloride injection is by injection, for infiltration, perineural, caudal, epidural, or retrobulbar use.[ 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 injection 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. Structure

2 DOSAGE AND ADMINISTRATION • Not for intrathecal use. (2.1) • Avoid use of solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia. (2.1, 5.4) • See full prescribing information for: -Recommended concentrations and dosages of bupivacaine hydrochloride injection according to type of block. (2.2) -Additional dosage and administration information pertaining to use in epidural anesthesia and use in ophthalmic surgery. (2.3, 2.4, 2.5, 2.6)

1 INDICATIONS AND USAGE Bupivacaine hydrochloride injection is indicated in adults for the production of local or regional anesthesia or analgesia for surgery and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations of bupivacaine hydrochloride injection are recommended for each type of block indicated to produce local or regional anesthesia or analgesia [ see Dosage and Administration (2.2) ]. Limitations of Use Not all blocks are indicated for use with bupivacaine hydrochloride injection given clinically significant risks associated with use [ see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions ( 5.1 , 5.4 , 5.5 , 5.7 , 5.9 ) ]. Bupivacaine hydrochloride injection contains bupivacaine, an amide local anesthetic. Bupivacaine hydrochloride injection is indicated in adults for the production of local or regional anesthesia or analgesia for surgery and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. For each type of block indicated to produce local or regional anesthesia or analgesia, specific concentrations and presentations are recommended. ( 1 , 2.2 ) Limitations of Use Not all blocks are indicated for use with bupivacaine hydrochloride injection given clinically significant risks associated with use. ( 1 , 2.2 , 4 , 5.1 , 5.4 , 5.5 , 5.7 , 5.9 )

10 OVERDOSAGE Clinical Presentation Acute emergencies from use of bupivacaine hydrochloride 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 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, 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 Advance Cardiac Life Support measures.

7 DRUG INTERACTIONS • Local Anesthetics: The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. (7.1) • Drugs Associated with Methemoglobinemia: Patients are at increased risk of developing methemoglobinemia when concurrently exposed to nitrates, nitrites, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other drugs. (7.5)

12.1 Mechanism of Action Bupivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

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3 DOSAGE FORMS AND STRENGTHS Bupivacaine hydrochloride injection is a clear, colorless solution available as: • 0.25% (25 mg/10 mL) (2.5 mg/mL) in single-dose vials. • 0.25% (75 mg/30 mL) (2.5 mg/mL) in single-dose vials. • 0.5% (50 mg/10 mL) (5 mg/mL) in single-dose vials. • 0.5% (150 mg/30 mL) (5 mg/mL) in single-dose vials. • 0.75% (75 mg/10 mL) (7.5 mg/mL) in single-dose vials. • 0.75% (225 mg/30 mL) (7.5 mg/mL) in single-dose vials. Bupivacaine hydrochloride injection is available in multiple concentrations. See full prescribing information for detailed description of each formulation. (3)

Bupivacaine Hydrochloride Bupivacaine Hydrochloride SODIUM HYDROXIDE HYDROCHLORIC ACID BUPIVACAINE HYDROCHLORIDE BUPIVACAINE SODIUM CHLORIDE Bupivacaine Hydrochloride Bupivacaine Hydrochloride SODIUM CHLORIDE SODIUM HYDROXIDE HYDROCHLORIC ACID BUPIVACAINE HYDROCHLORIDE BUPIVACAINE Bupivacaine Hydrochloride Bupivacaine Hydrochloride SODIUM CHLORIDE SODIUM HYDROXIDE HYDROCHLORIC ACID BUPIVACAINE HYDROCHLORIDE BUPIVACAINE Bupivacaine Hydrochloride Bupivacaine Hydrochloride SODIUM CHLORIDE SODIUM HYDROXIDE HYDROCHLORIC ACID BUPIVACAINE HYDROCHLORIDE BUPIVACAINE Bupivacaine Hydrochloride Bupivacaine Hydrochloride SODIUM CHLORIDE SODIUM HYDROXIDE HYDROCHLORIC ACID BUPIVACAINE HYDROCHLORIDE BUPIVACAINE Bupivacaine Hydrochloride Bupivacaine Hydrochloride SODIUM CHLORIDE SODIUM HYDROXIDE HYDROCHLORIC ACID BUPIVACAINE HYDROCHLORIDE BUPIVACAINE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted. Mutagenesis The mutagenic potential of bupivacaine hydrochloride has not been determined. Impairment of Fertility The effect of bupivacaine on fertility has not been determined.

ANDA091487

Bupivacaine Hydrochloride

Bupivacaine Hydrochloride

82449-228

HUMAN PRESCRIPTION DRUG

EPIDURAL,RETROBULBAR

Principal Display Panel - 0.25% Vial label - 25 mg/10 mL: NDC XXXXX- XXX -XX Rx only Preservative-Free Bupivacaine HCl Injection, USP 0.25% 25 mg/10 mL (2.5 mg/mL) For INFILTRATION, NERVE BLOCK, CAUDAL and EPIDURAL ANESTHESIA NOT FOR INTRATHECAL ANESTHESIA 10 mL Single-dose Vial Carton Label - 25 mg/10 mL: NDC XXXXX- XXX -XX Rx only LATEX-FREE Preservative-Free Bupivacaine HCl Injection, USP 0.25% 25 mg/10 mL (2.5 mg/mL) For INFILTRATION, NERVE BLOCK, CAUDAL and EPIDURAL ANESTHESIA NOT FOR INTRATHECAL ANESTHESIA 10 x 10 mL Single-dose Vials 25mg-10ml-label 25mg-10ml-carton

2.1 Important Dosage and Administration Information • Bupivacaine hydrochloride injection is not for intrathecal use. • Avoid use of bupivacaine hydrochloride injection solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [ see Warnings and Precautions (5.4) ]. • Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use. • Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit. Bupivacaine hydrochloride injection is clear, colorless solutions. Do not administer solutions which are discolored or contain particulate matter. • Mixing or the prior or intercurrent use of any other local anesthetic with bupivacaine hydrochloride injection is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions • Bupivacaine hydrochloride injection is to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed. • Use bupivacaine hydrochloride injection only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies [ see Warnings and Precautions (5.2), Adverse Reactions (6), Overdosage (10) ]. • The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with bupivacaine hydrochloride injection [ see Warnings and Precautions (5.2), Drug Interactions (7.1), Overdosage (10) ]. • Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting bupivacaine hydrochloride injection the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection [ see Warnings and Precautions (5.9) ]. • Avoid rapid injection of a large volume of bupivacaine hydrochloride injection and use fractional (incremental) doses when feasible. • During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access. The lowest dosage of bupivacaine hydrochloride injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions. • Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient’s level of consciousness after each local anesthetic injection.

• Pediatric Use : Administration of bupivacaine hydrochloride injection in pediatric patients younger than 12 years is not recommended. (8.4) • 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. (8.5) • Moderate to Severe Hepatic Impairment : Consider increased monitoring for bupivacaine systemic toxicity. (8.6)

16 HOW SUPPLIED/STORAGE AND HANDLING Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 ° F to 86 °F). [See USP Controlled Room Temperature.] Protect from light. This product is clear and colorless. Do not use the solution if it is discolored or if it contains a precipitate. Unit of Sale Concentration Each 0.25% Contains 2.5 mg bupivacaine hydrochloride per mL. NDC 82449-223-02 Carton of 10 25 mg/10 mL (2.5 mg/mL) NDC 82449-223-01 single-dose vial NDC 82449-224-01 Carton of 1 75 mg/30 mL (2.5 mg/mL) NDC 82449-224-01 single-dose vial 0.5% Contains 5 mg bupivacaine hydrochloride per mL. NDC 82449-225-02 Carton of 10 50 mg/10 mL (5 mg/mL) NDC 82449-225-01 single-dose vial NDC 82449-226-01 Carton of 1 150 mg/30 mL (5 mg/mL) NDC 82449-226-01 single-dose vial 0.75% Contains 7.5 mg bupivacaine hydrochloride per mL. NDC 82449-227-02 Carton of 10 75 mg/10 mL (7.5 mg/mL) NDC 82449-227-01 single-dose vial NDC 82449-228-01 Carton of 1 225 mg/30 mL (7.5 mg/mL) NDC 82449-228-01 single-dose vial For single-dose vials: Discard unused portion.

WARNING: RISK OF CARDIAC ARREST WITH USE OF BUPIVACAINE HYDROCHLORIDE INJECTION IN OBSTETRICAL ANESTHESIA There have been reports of cardiac arrest with difficult resuscitation or death during use of bupivacaine hydrochloride injection for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of bupivacaine hydrochloride injection is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary [ see Warnings and Precautions (5.1) ]. WARNING: RISK OF CARDIAC ARREST WITH USE OF BUPIVACAINE HYDROCHLORIDE INJECTION IN OBSTETRICAL ANESTHESIA See Full prescribing information for complete boxed warning. There have been reports of cardiac arrest with difficult resuscitation or death during use of bupivacaine hydrochloride injection for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of bupivacaine hydrochloride injection is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary (5.1).