Bupivacaine

1 INDICATIONS AND USAGE BUPIVACAINE SPINAL is indicated for subarachnoid injection in adults for the production of subarachnoid block (spinal anesthesia). BUPIVACAINE SPINAL is an amide-local anesthetic indicated in adults for subarachnoid injection for the production of subarachnoid block (spinal anesthesia). ( 1 )

2 DOSAGE AND ADMINISTRATION The dosage of BUPIVACAINE SPINAL administered varies with the anesthetic procedure, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. Administer the smallest dosage and concentration required to produce the desired result. The following are general dosage guidelines: • BUPIVACAINE SPINAL 6 mg is generally adequate for vaginal delivery. ( 2.2 ) • BUPIVACAINE SPINAL 7.5 mg is generally adequate for spinal anesthesia for lower extremity and perineal procedures. ( 2.2 ) • BUPIVACAINE SPINAL 12 mg is generally adequate for lower abdominal procedures. ( 2.2 ) • BUPIVACAINE SPINAL 7.5 mg to 10.5 mg is generally adequate for Cesarean section. ( 2.2 ) 2.1 Important Dosage and Administration Information • Visually inspect this product for particulate matter and discoloration prior to administration. BUPIVACAINE SPINAL is a clear, colorless solution. 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 SPINAL is not recommended because of insufficient data on the clinical use of such mixtures. • Discard unused portions of BUPIVACAINE SPINAL following initial use. Administration Precautions • BUPIVACAINE SPINAL 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 SPINAL 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 (5.3) , 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 SPINAL [see Warnings and Precautions (5.3) , Drug Interactions (7.1) , Overdosage (10) ]. • Aspirate for blood and cerebrospinal fluid prior to injecting BUPIVACAINE SPINAL, for both the initial dose and all subsequent doses (where applicable), to avoid intravascular injection and to confirm entry into the subarachnoid space. Aspiration of cerebrospinal fluid into a BUPIVACAINE SPINAL‐filled syringe will result in an identifiable swirl in the solution. A negative aspiration for blood does not ensure against an intravascular injection [see Warnings and Precautions (5.4) ] . • Avoid rapid injection of BUPIVACAINE SPINAL. • The patient should have an indwelling intravenous catheter to assure adequate intravenous access. The lowest dosage of BUPIVACAINE SPINAL that results in effective spinal anesthesia should be used to avoid a high motor block 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 during spinal anesthesia. Conditions Which May Preclude Use of Spinal Anesthesia The following conditions may preclude the use of spinal anesthesia, depending upon the physician’s evaluation of the patient: • Pre-existing diseases of the central nervous system (CNS), such as those attributable to pernicious anemia, poliomyelitis, syphilis, or tumor. • Hematological disorders predisposing to coagulopathies or patients on anticoagulant therapy. Trauma to a blood vessel during the conduct of spinal anesthesia may, in some instances, result in uncontrollable CNS hemorrhage, soft tissue hemorrhage, or development of a hematoma. • Chronic backache and preoperative headache. • Hypotension an …

3 DOSAGE FORMS AND STRENGTHS BUPIVACAINE SPINAL (bupivacaine hydrochloride in dextrose injection) is a clear, colorless solution available as: • 15 mg/2 mL (7.5 mg/mL) in single-dose glass ampules. Injection: 15 mg/2 mL (7.5 mg/mL) in single-dose glass ampules. ( 3 )

4 CONTRAINDICATIONS BUPIVACAINE SPINAL is contraindicated in: • intravenous regional anesthesia (Bier Block) [see Warnings and Precautions (5.8) ] . • patients with septicemia. • patients with severe hemorrhage, severe hypotension or shock, due to a reduced cardiac output. • patients with clinically significant arrhythmias, such as complete heartblock, due a reduced cardiac output. • patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of BUPIVACAINE SPINAL. • patients with local infection at the site of proposed lumbar puncture. • Intravenous regional anesthesia (Bier Block). ( 4 ) • Septicemia. ( 4 ) • Severe hemorrhage, severe hypotension or shock, and arrhythmias, such as complete heartblock, which severely reduce cardiac output. ( 4 ) • Known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of BUPIVACAINE SPINAL. ( 4 ) • Local infection at the site of proposed lumbar puncture. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions have been reported and described in other sections of the labeling: • Allergic-Type Reactions [see Contraindications (4) ] • Dose-Related Toxicity [see Warnings and Precautions (5.3) ] • Systemic Toxicities with Unintended Intravascular Injection [see Warnings and Precautions (5.4) ] • Methemoglobinemia [see Warnings and Precautions (5.5) ] • Cardiac Arrest in Obstetrical Anesthesia [see Warnings and Precautions (5.6) ] • Chondrolysis with Intra-Articular Infusion [see Warnings and Precautions (5.7) ] • Cardiac Arrest with Intravenous Regional Anesthesia Use [see Contraindications (4) , Warnings and Precautions (5.8) ] 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 SPINAL are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to BUPIVACAINE SPINAL is due to cephalad extension of the motor level of anesthesia and/or 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 following the administration of spinal anesthesia were hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia. These have led to cardiac arrest if untreated. In addition, dose-related convulsions and cardiovascular collapse have resulted from diminished tolerance, rapid absorption from the injection site, or from unintentional intravascular injection of a local anesthetic solution. Respiratory System : Respiratory paralysis or underventilation have been noted as a result of cephalad spread of spinal anesthesia and has led to secondary hypoxic cardiac arrest when untreated. Preanesthetic medication, intraoperative anesthetics, analgesics, and sedatives, as well as surgical manipulation, may contribute to underventilation. This has usually been noted within minutes of the injection of spinal anesthetic solution, but because of differing maximal onset times, differing intercurrent drug usage, and differing surgical manipulation, it may occur at any time during surgery or the immediate recovery period. Cardiac Disorders : Hypotension due to loss of sympathetic tone has been commonly encountered following spinal anesthesia. This has been more commonly observed in elderly patients, particularly those with hypertension, and patients with reduced blood volume, reduced interstitial fluid volume, cephalad spread of the local anesthetic, and/or mechanical obstruction of venous return. Nausea and vomiting have been frequently associated with hypotensive episodes following the administration of spinal anesthesia. High doses, or inadvertent intravascular injection, have led to high plasma levels and related depression of the myocardium, decreased cardiac output, bradycardia, heart block, ventricular arrhythmias, and cardiac arrest [see Warnings and Precautions (5.4) ] . Nervous System Disorders : Respiratory paralysis or underventilation secondary to cephalad spread of the level of spinal anesthesia (see Respiratory System ) and hypotension for the same reason (see Cardiac Disorders ) have been the two most commonly encountered CNS-related adverse observations which demand immediate counter-measures. High doses or inadvertent intravascular injection have led to high plasma levels and related CNS toxicity. Adverse reactions were characterized by excitation and/or depression of the CNS and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsines …

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. ( 7.2 ) 7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with BUPIVACAINE SPINAL cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration (2.1) , Warnings and Precautions (5.3) ] . 7.2 Drugs Associated with Methemoglobinemia Patients who are administered BUPIVACAINE SPINAL are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions (5.5) ] . Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

8 USE IN SPECIFIC POPULATIONS • Pediatric Use : Administration of BUPIVACAINE SPINAL in patients younger than 18 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 spinal anesthesia with BUPIVACAINE SPINAL. ( 8.5 ) • Moderate to Severe Hepatic Impairment : Consider increased monitoring for bupivacaine systemic toxicity. ( 8.6 ) 8.1 Pregnancy Risk Summary The available data on the use of BUPIVACAINE SPINAL in pregnant women do not establish the presence or absence of developmental toxicity related to the use of BUPIVACAINE SPINAL. In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis and decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning). These effects were observed at dose levels approximately 30 times the daily maximum recommended human dose (MRHD) on a body surface area (BSA) basis. Based on animal data, advise pregnant women of the potential risk to a fetus ( see Data ) . Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity [see Clinical Pharmacology (12.3) ]. The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the CNS, peripheral vascular tone, and cardiac function. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Maternal Adverse Reactions Maternal hypotension has resulted from regional and neuraxial anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional or neuraxial block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient’s legs and right-side-up positioning will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. Labor or Delivery Spinal anesthesia is commonly used during labor and delivery. Bupivacaine hydrochloride, when administered properly, via the epidural route in doses 10 to 12 times the amount used in spinal anesthesia has been used for obstetrical analgesia and anesthesia without evidence of adverse effects on the fetus. Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine. It is extremely important to avoid aortocaval compression by the gravid uterus during administrations of regional or neuraxial block to …

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.

11 DESCRIPTION BUPIVACAINE SPINAL (bupivacaine hydrochloride in dextrose injection) is an amide-local anesthetic and sterile hyperbaric aqueous solution. The route of administration for BUPIVACAINE SPINAL is by subarachnoid injection. BUPIVACAINE SPINAL contains bupivacaine hydrochloride, as the active pharmaceutical ingredient and also contains Dextrose, as baricity agent. Bupivacaine Hydrochloride (monohydrate) chemical name is 2-piperidinecarboxamide, 1-butyl- N -(2,6-dimethylphenyl)-, monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. Bupivacaine Hydrochloride (monohydrate) has a molecular formula of C 18 H 28 N 2 O·HCl·H 2 O and molecular weight of 342.90 g/mol and has the following structural formula: Dextrose chemical name is D-glucopyranose. Dextrose (anhydrous) has a molecular formula of C 6 H 12 O 6 , molecular weight of 180.16 g/mol and has the following structural formula: BUPIVACAINE SPINAL (bupivacaine hydrochloride in dextrose injection) is a clear and colorless sterile hyperbaric solution. Each mL of BUPIVACAINE SPINAL contains 7.5 mg bupivacaine hydrochloride (anhydrous) (equivalent to 7.9 mg of bupivacaine hydrochloride monohydrate), 82.5 mg dextrose (anhydrous) as baricity agent, and sodium hydroxide and hydrochloric acid as pH adjusters in water for injection. BUPIVACAINE SPINAL pH is between 4.0 and 6.5. The specific gravity of BUPIVACAINE SPINAL is between 1.030 and 1.035 at 25°C and 1.03 at 37°C. BUPIVACAINE SPINAL does not contain any preservatives. Chemical formula for Bupivacaine Hydrochloride Chemical formula for Dextrose

10 OVERDOSAGE Clinical Presentation Acute emergencies from BUPIVACAINE SPINAL are generally related to hypoventilation (and perhaps apnea) secondary to upward extension of spinal anesthesia or high plasma levels encountered during therapeutic use [see Warnings and Precautions (5.3) , Adverse Reactions (6) ] . Hypotension is commonly encountered during the conduct of spinal anesthesia due to loss of sympathetic tone, and sometimes, contributory mechanical obstruction of venous return due to the gravid uterus exerting pressure on the great vessels [see Warnings and Precautions (5.2) , Adverse Reactions (6) ] . If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Hypoventilation or apnea due to a high or total spinal 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 a high or total spinal, 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 benzodiazepine will counteract the CNS stimulation related to BUPIVACAINE SPINAL. 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. Hypotension due to sympathetic relaxation may be managed by giving intravenous fluids (such as isotonic saline or lactated Ringer’s solution), in an attempt to relieve mechanical obstruction of venous return, or by using vasopressor agents (such as ephedrine which increases myocardial contractility) and, if indicated, by giving plasma expanders or blood products.

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.] BUPIVACAINE SPINAL solution may be autoclaved once at 15 pound pressure, 121°C (250°F) for 15 minutes. This product is clear and colorless. Do not use the solution if it is discolored or contains particulate matter. Single-dose ampules of 2 mL BUPIVACAINE SPINAL (bupivacaine hydrochloride in dextrose injection) (15 mg bupivacaine hydrochloride with 165 mg dextrose) are supplied as follows: Unit of Sale Concentration NDC 0409-3613-01 Carton of 10 Single-dose ampules 15 mg/2 mL (7.5 mg/mL) Discard the unused portion.