BUPIVACAINE SPINAL

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

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 )

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 and hypertension. • Technical problems (persistent paresthesias, persistent bloody tap). • Arthritis or spinal deformity. • Extremes of age. • Psychosis, dementia, or other illnesses resulting in poor patient cooperation. 2.2 Recommended Dosages of BUPIVACAINE SPINAL 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 extent and degree of spinal anesthesia depend upon several factors including dosage, baricity of the anesthetic solution, volume of solution, force of injection, level of puncture, and position of the patient during and immediately after injection. In recommended doses, BUPIVACAINE SPINAL produces complete motor and sensory block. The following table summarizes general dosage guidelines for adult patients for the procedures described: PROCEDURES DOSAGE GUIDELINES Vaginal Delivery Starting dose, 6 mg (0.8 mL) Lower Extremity and Perineal Procedures, such as: • transurethral resection of the prostate (TURP) • vaginal hysterectomy 7.5 mg (1 mL) Lower Abdominal Procedures, such as: • abdominal hysterectomy • tubal ligation • appendectomy 12 mg (1.6 mL) Cesarean Section 7.5 mg to 10.5 mg (1 mL to 1.4 mL)

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 )

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, drowsiness, unconsciousness, and respiratory arrest. 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. 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. Neurologic effects following spinal anesthesia have included loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness and paralysis of the lower extremities, and loss of sphincter control with slow, incomplete, or no recovery; hypotension, high or total spinal block; urinary retention; headache; backache; septic meningitis, meningismus; arachnoiditis; slowing of labor; increased incidence of forceps delivery; shivering; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid; and fecal and urinary incontinence. Immune System Disorders : Allergic-type reactions have occurred as a result of sensitivity to bupivacaine. 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. Most common adverse reactions are hypotension due to loss of sympathetic tone, and diaphragmatic paralysis or hypoventilation due to cephalad spread and high motor block. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1‑800‑438‑1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• 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