LIDOCAINE HYDROCHLORIDE (lidocaine hydrochloride anhydrous) injection, solution

AQUEOUS SOLUTIONS FOR INFILTRATION

AND NERVE BLOCK

Ampul

Plastic Multiple-dose Fliptop Vial

Glass Teartop Vial

Rx only

DESCRIPTIONLidocaine Hydrochloride Injection, USP is a sterile, nonpyrogenic solution of lidocaine hydrochloride in water for injection for parenteral administration in various concentrations with characteristics as follows:

Multiple-dose vials contain 0.1% of methylparaben added as preservative. May contain sodium hydroxide and/or hydrochloric acid for pH adjustment. The pH is 6.5 (5.0 to 7.0). See HOW SUPPLIED section for various sizes and strengths.

Lidocaine is a local anesthetic of the amide type.

Lidocaine Hydrochloride, USP is chemically designated 2-(diethylamino)-N-(2,6-dimethylphenyl)-acetamide monohydrochloride monohydrate, a white powder freely soluble in water. The molecular weight is 288.82. It has the following structural formula:

The semi-rigid vial used for the plastic vials is fabricated from a specially formulated polyolefin. It is a copolymer of ethylene and propylene. The safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers. The container requires no vapor barrier to maintain the proper drug concentration.

CLINICAL PHARMACOLOGYMechanism of action: Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action.

Hemodynamics: Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded.

Pharmacokinetics and metabolism: Information derived from diverse formulations, concentrations and usages reveals that lidocaine is completely absorbed following parenteral administration, its rate of absorption depending, for example, upon various factors such as the site of administration and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration.

The plasma binding of lidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg of free base per mL, 60 to 80 percent of lidocaine is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein.

Lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion.

Lidocaine is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine. Approximately 90% of lidocaine administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2, 6-dimethylaniline.

The elimination half-life of lidocaine following an intravenous bolus injection is typically 1.5 to 2.0 hours. Because of the rapid rate at which lidocaine is metabolized, any condition that affects liver function may alter lidocaine kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites.

Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 mcg free base per mL. In the rhesus monkey arterial blood levels of 18-21 mcg/mL have been shown to be threshold for convulsive activity.

INDICATIONS AND USAGELidocaine Hydrochloride Injection, USP is indicated for production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks, when the accepted procedures for these techniques as described in standard textbooks are observed.

CONTRAINDICATIONSLidocaine is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type.

WARNINGSLIDOCAINE HYDROCHLORIDE INJECTION, FOR INFILTRATION AND NERVE BLOCK, SHOULD BE EMPLOYED ONLY BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES THAT MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED AND THEN ONLY AFTER ENSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY EQUIPMENT, AND THE PERSONNEL NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES (See also ADVERSE REACTIONS and PRECAUTIONS). DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

To avoid intravascular injection, aspiration should be performed before the local anesthetic solution is injected. The needle must be repositioned until no return of blood can be elicited by aspiration. Note, however, that the absence of blood in the syringe does not guarantee that intravascular injection has been avoided.

Local anesthetic solutions containing antimicrobial preservatives (e.g., methylparaben) should not be used for epidural or spinal anesthesia because the safety of these agents has not been established with regard to intrathecal injection, either intentional or accidental.

PRECAUTIONS General:The safety and effectiveness of lidocaine depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Standard textbooks should be consulted for specific techniques and precautions for various regional anesthetic procedures.

Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. (See WARNINGS and ADVERSE REACTIONS). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Syringe aspirations should also be performed before and during each supplemental injection when using indwelling catheter techniques. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and that the patient be monitored for central nervous system toxicity and cardiovascular toxicity, as well as for signs of unintended intrathecal administration before proceeding. When clinical conditions permit, consideration should be given to employing local anesthetic solutions that contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. Repeated doses of lidocaine may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients and children should be given reduced doses commensurate with their age and physical condition. Lidocaine should also be used with caution in patients with severe shock or heart block. Lumbar and caudal epidural anesthesia should be used with extreme caution in persons with the following conditions: existing neurological disease, spinal deformities, septicemia and severe hypertension.

Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully circumscribed quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Preparations containing a vasoconstrictor should be used with caution in patients during or following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions.

Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be accomplished after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of central nervous system toxicity.

Since amide-type local anesthetics are metabolized by the liver, lidocaine should be used with caution in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. Lidocaine should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for the management of malignant hyperthermia should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using).

Proper tourniquet technique, as described in publications and standard textbooks, is essential in the performance of intravenous regional anesthesia. Solutions containing epinephrine or other vasoconstrictors should not be used for this technique.

Lidocaine should be used with caution in persons with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine.

Use in the Head and Neck Area: Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression and/or respiratory arrest and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injections of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded. (See DOSAGE AND ADMINISTRATION).

Information for Patients:When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body following proper administration of epidural anesthesia.

Clinically Significant Drug Interactions:The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe prolonged hypertension.

Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.

Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.

Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytoxic drugs may cause severe persistent hypertension or cerebrovascular accidents.

Drug Laboratory Test Interactions:The intramuscular injection of lidocaine may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination without isoenzyme separation as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine.

Carcinogenesis, Mutagenesis, Impairment of Fertility:Studies of lidocaine in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted.

Pregnancy:Teratogenic Effects. Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine. There are, however, no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. General consideration should be given to this fact before administering lidocaine to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place.

Labor and Delivery:Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity (See CLINICAL PHARMACOLOGY—Pharmacokinetics). The potential for toxicity depends 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 central nervous system peripheral vascular tone and cardiac function.

Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable.

Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, spinal and epidural anesthesia have 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. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering paracervical block in prematurity, toxemia of pregnancy and fetal distress. Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication.

Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a 5-minute interval between sides.

Nursing Mothers:It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine is administered to a nursing woman.

Pediatric Use:Dosages in pediatric patients should be reduced, commensurate with age, body weight and physical condition. See DOSAGE AND ADMINISTRATION.

ADVERSE REACTIONSReactions to bupivacaine are characteristic of those associated with other amide-type local anesthetics.

The most commonly encountered acute adverse experiences which demand immediate countermeasures following the administration of spinal anesthesia are hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia. These may lead to cardiac arrest if untreated. In addition, dose-related convulsions and cardiovascular collapse may result from diminished tolerance, rapid absorption from the injection site or from unintentional intravascular injection of a local anesthetic solution. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance.

Respiratory System: Respiratory paralysis or underventilation may be noted as a result of upward extension of the level of spinal anesthesia and may lead to secondary hypoxic cardiac arrest if untreated. Preanesthetic medication, intraoperative analgesics and sedatives, as well as surgical manipulation, may contribute to underventilation. This will usually be noted within minutes of the injection of spinal anesthetic solution, but because of differing surgical maximal onset times, differing intercurrent drug usage and differing manipulation, it may occur at any time during surgery or the immediate recovery period.

Cardiovascular System: Hypotension due to loss of sympathetic tone is a commonly encountered extension of the clinical pharmacology of spinal anesthesia. This is more commonly observed in patients with shrunken blood volume, shrunken interstitial fluid volume, cephalad spread of the local anesthetic, and/or mechanical obstruction of venous return. Nausea and vomiting are frequently associated with hypotensive episodes following the administration of spinal anesthesia. High doses, or inadvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, bradycardia, heart block, ventricular arrhythmias, and, possibly, cardiac arrest. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE sections.)

Central Nervous System: Respiratory paralysis or underventilation secondary to cephalad spread of the level of spinal anesthesia (see Respiratory System) and hypotension for the same reason (see Cardiovascular System) are the two most commonly encountered central nervous system-related adverse observations which demand immediate countermeasures.

High doses or inadvertent intravascular injection may lead to high plasma levels and related central nervous system toxicity characterized by excitement and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest.

Neurologic: 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. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug.

Neurologic effects following spinal anesthesia may include loss of perineal sensation and sexual function, persistent anesthesia, paresthesia, weakness and paralysis of the lower extremities, and loss of sphincter control all of which may have 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.

Allergic: Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and, possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established.

Other: Nausea and vomiting may occur during spinal anesthesia.

OVERDOSAGEAcute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use or to underventilation (and perhaps apnea) secondary to upward extension of spinal anesthesia. Hypotension is commonly encountered during the conduct of spinal anesthesia due to relaxation of sympathetic tone, and sometimes, contributory mechanical obstruction of venous return.

Management of Local Anesthetic Emergencies: The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.

The first step in the management of systemic toxic reactions, as well as underventilation 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. This may prevent convulsions if they have not already occurred.

If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus I.V. injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus I.V. dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force).

Hypotension due to sympathetic relaxation may be managed by giving intravenous fluids (such as Sodium Chloride Injection 0.9% or Lactated Ringer’s Injection), in an attempt to relieve mechanical obstruction of venous return, or by using vasopressors (such as ephedrine which increases the force of myocardial contractions) and, if indicated, by giving plasma expanders or whole blood.

Endotracheal intubation, employing 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.

Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest.

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. Underventilation 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, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary. Recovery has been reported after prolonged resuscitative efforts.

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 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.

The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 µg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg to 8 mg/kg and 38 mg/kg to 54 mg/kg, respectively.

DOSAGE AND ADMINISTRATIONThe dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, 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. The smallest dose and concentration required to produce the desired result should be administered. Dosages of Bupivacaine Spinal (Bupivacaine in Dextrose Injection, USP) should be reduced for elderly and debilitated patients and patients with cardiac and/or liver disease.

For specific techniques and procedures, refer to standard textbooks.

There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Bupivacaine Spinal is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

The extent and degree of spinal anesthesia depends upon several factors including dosage, specific gravity of the anesthetic solution, volume of solution used, force of injection, level of puncture, and position of the patient during and immediately after injection.

Seven and one-half mg (7.5 mg or 1.0 mL) Bupivacaine Spinal has generally proven satisfactory for spinal anesthesia for lower extremity and perineal procedures including TURP and vaginal hysterectomy. Twelve mg (12 mg or 1.6 mL) has been used for lower abdominal procedures such as abdominal hysterectomy, tubal ligation, and appendectomy. These doses are recommended as a guide for use in the average adult and may be reduced for elderly or debilitated patients. Because experience with Bupivacaine Spinal is limited in patients below the age of 18 years, dosage recommendations in this age group cannot be made.

Obstetrical Use: Doses as low as 6 mg bupivacaine hydrochloride have been used for vaginal delivery under spinal anesthesia. The dose range of 7.5 mg to 10.5 mg (1 mL to 1.4 mL) bupivacaine hydrochloride has been used for Cesarean section under spinal anesthesia.

In recommended doses, Bupivacaine Spinal produces complete motor and sensory block.

Unused portions of solutions should be discarded following initial use.

Bupivacaine Spinal should be inspected visually for discoloration and particulate matter prior to administration; solutions which are discolored or which contain particulate matter should not be administered.

Bupivacaine Spinal may be autoclaved once at 15 pounds pressure, 121°C (250°F) for 15 minutes. Do not administer any solution which is discolored or contains particulate matter.

HOW SUPPLIEDBupivacaine Spinal (Bupivacaine in Dextrose Injection, USP) is supplied in 2 mL ampuls (15 mg bupivacaine hydrochloride with 165 mg dextrose anhydrous) packaged in cartons of 10 (NDC No. 0409-3613-01).

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]

Revised: February, 2010

Printed in USA EN-2403

Hospira, Inc., Lake Forest, IL 60045 USA

1:1000 (1 mg/mL)

Ampul

Protect from light until ready to use.

Rx only

Epinephrine Injection, USP 1:1000 is a sterile, nonpyrogenic solution. Each mL contains epinephrine 1 mg; sodium chloride 9 mg; sodium metabisulfite 0.9 mg added. May contain hydrochloric acid for pH adjustment.

The solution contains no bacteriostat or antimicrobial agent. It is administered by the following routes: intravenous, intracardiac (left ventricular chamber), via endotracheal tube into the bronchial tree, subcutaneous or intramuscular.

Epinephrine, USP is a sympathomimetic (adrenergic) agent designated chemically as 4‑[1‑hydroxy-2 (methylamino) ethyl]-1,2 benzenediol, a white, microcrystalline powder. It has the following structural formula:

Sodium Chloride, USP is chemically designated NaCl, a white, crystalline compound freely soluble in water.

The actions of epinephrine resemble the effects of stimulation of adrenergic nerves. To a variable degree it acts on both alpha and beta receptor sites of sympathetic effector cells. Its most prominent actions are on the beta receptors of the heart, vascular and other smooth muscle. When given by rapid intravenous injection, it produces a rapid rise in blood pressure, mainly systolic, by (1) direct stimulation of cardiac muscle which increases the strength of ventricular contraction, (2) increasing the heart rate and (3) constriction of the arterioles in the skin, mucosa and splanchnic areas of the circulation.

When given by slow intravenous injection epinephrine usually produces only a moderate rise in systolic and a fall in diastolic pressure. Although some increase in pulse pressure occurs, there is usually no great elevation in mean blood pressure. Accordingly, the compensatory reflex mechanisms that come into play with a pronounced increase in blood pressure do not antagonize the direct cardiac actions of epinephrine as much as with catecholamines that have a predominant action on alpha receptors.

Total peripheral resistance decreases by action of epinephrine on beta receptors of the skeletal muscle vasculature and blood flow is thereby enhanced. Usually this vasodilator effect of the drug on the circulation predominates so that the modest rise in systolic pressure which follows slow injection or absorption is mainly the result of direct cardiac stimulation and increase in cardiac output. In some instances peripheral resistance is not altered or may even rise owing to a greater ratio of alpha to beta activity in different vascular areas.

Epinephrine relaxes the smooth muscles of the bronchi and iris and is a physiologic antagonist of histamine. The drug also produces an increase in blood sugar and glycogenolysis in the liver.

Intravenous injection produces an immediate and intensified response. Following intravenous injection epinephrine disappears rapidly from the blood stream.

Epinephrine is rapidly inactivated in the body and is degraded by enzymes in the liver and other tissues. The large portion of injection doses is excreted in the urine as inactivated compounds. The remainder is excreted in the urine as unchanged or conjugated compounds.

Epinephrine is used to relieve respiratory distress due to bronchospasm, to provide rapid relief of hypersensitivity reactions to drugs and other allergens, and to prolong the action of anesthetics. Its cardiac effects may be of use in restoring cardiac rhythm in cardiac arrest due to various causes, but it is not used in cardiac failure or in hemorrhagic, traumatic, or cardiogenic shock. Epinephrine is used as a hemostatic agent. It is also used in treating mucosal congestion of hay fever, rhinitis, and acute sinusitis; to relieve bronchial asthmatic paroxysms; in syncope due to complete heart block or carotid sinus hypersensitivity; for symptomatic relief of serum sickness, urticaria, angioneurotic edema; for resuscitation in cardiac arrest following anesthetic accidents; in simple (open angle) glaucoma; for relaxation of uterine musculature and to inhibit uterine contractions. Epinephrine Injection can be utilized to prolong the action of anesthetics used in local and regional anesthesia.

Epinephrine is contraindicated in patients with known hypersensitivity to sympathomimetic amines, in patients with angle closure glaucoma, and patients in shock (nonanaphylactic). It should not be used in patients anesthetized with agents such as cyclopropane or halothane as these may sensitize the heart to the arrhythmic action of sympathomimetic drugs. Addition of epinephrine to local anesthetics for injection of certain areas (e.g., fingers, toes, ears, etc.) is contraindicated because of danger that vasoconstriction may result in sloughing of tissue.

Except as diluted for admixture with local anesthetics to reduce absorption and prolong action, epinephrine should not ordinarily be used in those cases where vasopressor drugs may be contraindicated, e.g., in thyrotoxicosis, diabetes, in obstetrics when maternal blood pressure is in excess of 130/80 and in hypertension and other cardiovascular disorders.

Inadvertently induced high arterial blood pressure may result in angina pectoris, aortic rupture or cerebral hemorrhage.

Epinephrine may induce potentially serious cardiac arrhythmias in patients not suffering from heart disease and in patients with organic heart disease or who are receiving drugs that sensitize the myocardium.

Parenterally administered epinephrine initially may produce constriction of renal blood vessels and decrease urine formation.

Epinephrine Injection, USP is subject to oxidation and should be protected against exposure to light and stored in light-resistant containers.

Epinephrine is the preferred treatment for serious allergic or other emergency situations even though this product contains sodium metabisulfite, a sulfite that may in other products cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations.

Do not use the Injection if its color is pinkish or darker than slightly yellow or if it contains a precipitate.

Do not administer unless solution is clear and container is intact. Discard unused portion.

Although epinephrine can produce ventricular fibrillation, its actions in restoring electrical activity in asystole and in enhancing defibrillation of the fibrillating ventricle are well documented. The drug, however, should be used with caution in patients with ventricular fibrillation.

Epinephrine should be used cautiously in patients with hyperthyroidism, hypertension and cardiac arrhythmias. All vasopressors should be used cautiously in patients taking monoamine oxidase (MAO) inhibitors.

Epinephrine should not be administered concomitantly with other sympathomimetic drugs (such as isoproterenol) because of possible additive effects and increased toxicity. Combined effects may induce serious cardiac arrhythmias. They may be administered alternately when the preceding effect of other such drugs has subsided.

Administration of epinephrine to patients receiving cyclopropane or halogenated hydrocarbon general anesthetics such as halothane which sensitize the myocardium, may induce cardiac arrhythmia. (See CONTRAINDICATIONS.) When encountered, such arrhythmias may respond to administration of a beta-adrenergic blocking drug. Epinephrine also should be used cautiously with other drugs (e.g., digitalis glycosides) that sensitize the myocardium to the actions of sympathomimetic agents.

Diuretic agents may decrease vascular response to pressor drugs such as epinephrine. Epinephrine may antagonize the neuron blockade produced by guanethidine resulting in decreased antihypertensive effect and requiring increased dosage of the latter.

Pregnancy Category C. Animal reproduction studies have not been conducted with epinephrine. It is also not known whether epinephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Epinephrine should be given to a pregnant woman only if clearly needed.

Labor and Delivery. Parenteral administration of epinephrine if used to support blood pressure during low or other spinal anesthesia for delivery can cause acceleration of fetal heart rate and should not be used in obstetrics when maternal blood pressure exceeds 130/80. (See CONTRAINDICATIONS.)

Transient and minor side effects of anxiety, headache, fear and palpitations occur only with systemic therapeutic doses, especially in hyperthyroid individuals. Adverse effects such as cardiac arrhythmias and excessive rise in blood pressure may occur with systemic therapeutic doses or with inadvertent overdosage. Other adverse reactions include cerebral hemorrhage, hemiplegia, subarachnoid hemorrhage, anginal pain in patients with angina pectoris, anxiety, restlessness, headache, tremor, weakness, dizziness, pallor and respiratory difficulty. Such reactions are unlikely when epinephrine is diluted to 1:200,000 for injection with local anesthetic agents.

Erroneous administration of large doses of epinephrine may lead to precordial distress, vomiting, headache, dyspnea, as well as unusually elevated blood pressure. (See WARNINGS.) Toxic effects of overdosage can be counteracted by injection of an alpha-adrenergic blocker and a beta-adrenergic blocker. In the event of a sharp rise in blood pressure, rapid-acting vasodilators such as the nitrites, or alpha-adrenergic blocking agents can be given to counteract the marked pressor effect of large doses of epinephrine.

Subcutaneously or intramuscularly – 0.2 to 1 mL (mg). Start with a small dose and increase if required.

Note: The subcutaneous is the preferred route of administration. If given intramuscularly, injection into the buttocks should be avoided.

Hypersensitivity Reactions

For bronchial asthma and certain allergic manifestations, e.g., angioedema, urticaria, serum sickness, anaphylactic shock, use epinephrine subcutaneously. The adult intravenous dose for hypersensitivity reactions or to relieve bronchospasm usually ranges from 0.1 to 0.25 mg injected slowly. Neonates may be given a dose of 0.01 mg per kg of body weight; for the infant 0.05 mg is an adequate initial dose and this may be repeated at 20 to 30 minute intervals in the management of asthma attacks.

Cardiac Resuscitation

A dose of 0.5 mL (0.5 mg) diluted to 10 mL with sodium chloride injection can be administered intravenously or intracardially to restore myocardial contractility.

Intracardiac injection should only be administered by personnel well trained in the technique, if there has not been sufficient time to establish an intravenous route.

External cardiac massage should follow intracardial administration to permit the drug to enter coronary circulation. The drug should be used secondarily to unsuccessful attempts with physical or electromechanical methods.

Ophthalmologic Use

Ophthalmologic use (for producing conjunctival decongestion, to control hemorrhage, produce mydriasis and reduce intraocular pressure) – use a concentration of 1:10,000 (0.1 mg/mL) to 1:1000 (1 mg/mL).

Regional Anesthesia

A final concentration of 1:200,000 of epinephrine injection is recommended for infiltration injection, nerve block, caudal or other epidural blocks. From 0.3 to 0.4 mg of epinephrine (0.3 to 0.4 mL of 1:1000 solution) may be mixed with spinal anesthetic agents.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. (See PRECAUTIONS.)

Epinephrine Injection, USP 1:1000 (1 mg/mL) is supplied in a 1 mL ampul single-dose container (NDC 0409-7241-61).

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

Revised: October, 2008

Printed in USA EN-1927

Hospira, Inc., Lake Forest, IL 60045 USA

Drug Facts

Iodine povacrylex (0.7% available iodine)

Isopropyl alcohol, 74% w/w

Antiseptic

patient preoperative skin preparation:

for preparation of the skin prior to surgeryhelps reduce bacteria that potentially can cause skin infection

For external use only. Flammable, keep away from fire or flame.

To reduce the risk of fire, PREP CAREFULLY:

solution contains alcohol and gives off flammable vaporsdo not drape or use ignition source (e.g., cautery, laser) until solution is completely dry (minimum of 3 minutes on hairless skin; up to 1 hour in hair).avoid getting solution into hairy areas. Wet hair is flammable. Hair may take up to 1 hour to dry.do not allow solution to poolremove solution-stained material from prep area

Do not use

on patients with known allergies to iodine or any other ingredients in this producton open wounds, on mucous membranes, or as a general skin cleanserin infants less than 2 months old due to the risk of excessive skin irritation and transient hypothyroidism

When using this product

keep out of eyes, ears, and mouth. May cause serious injury if permitted to enter and remain. If contact occurs, flush with cold water right away and contact a doctor.to avoid skin injury, care should be taken when removing drapes, tapes, etc…applied over filmuse with caution in women who are breast-feeding due to the potential for transient hypothyroidism in the nursing newborn

Stop use and ask a doctor if irritation, sensitization or allergic reaction occurs. These may be signs of a serious condition. On rare occasions, use of this product has been associated with skin blistering.

Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away.

at the end of the prep, discard any portion of the solution which is not required to cover the prep area. It is not necessary to use the entire amount available.

Getting Patient Ready for Solution:

use in well-ventilated areado not microwave or heat the solution applicatorapply to clean, completely dry, residue-free, intact skinwhen hair removal is necessary, use a surgical clipper on the morning of the surgery. If a wet shave is used, thoroughly remove all soap residues.

Activating the Applicator:

grasp product by wrapping hand and fingers around the labeled portion of the applicator. Place thumb on the lever.with sponge face parallel to the floor, snap lever. Allow all fluid to flow into sponge.

When Applying Solution:

DO NOT SCRUB. Paint a single, uniform application and do not reprep area.do not allow solution to pool. Use sponge applicator to absorb excess solution and continue to apply a uniform coating. If solution accidentally gets outside of prep area, remove excess with gauze.tuck prep towels as needed under both sides of the neck to absorb excess solution. Remove towels before draping.avoid getting solution into hairy areas. Wet hair is flammable. Hair may take up to 1 hour to dry.when prepping skin folds, toes, or fingers, use a sterile-gloved hand to hold skin apart until completely dry. Otherwise, skin may adhere to itself.

After Applying Solution:

to reduce the risk of fire, wait until solution is completely dry (minimum of 3 minutes on hairless skin; up to 1 hour in hair). Solution will turn from a shiny to a dull appearance on skin alerting the user that the solution is completely dry and no longer flammable.

While Waiting for Solution to Completely Dry:

do not drape or use ignition source (e.g., cautery, laser)check for pooled solution. Use sterile gauze to soak up pooled solution. Do not blot because it may remove solution from skin.remove solution-stained materials. Replace if necessary.

After Solution is Completely Dry:

to reduce the risk of fire, begin draping and/or using cautery only after solution is completely dry and all solution-stained materials are removedif incise drapes are used, apply directly to dry prep. On completion of surgical procedure, removal of incise drape will remove film.apply dressing following standard practices

store between 20-25ºC (68-77ºF)avoid excessive heat above 40ºC (104ºF)solution is not water soluble and may stain. Therefore, avoid contact with reusable items (basins, instruments).

ethyl alcohol, water

call 1-800-228-3957 (Monday to Friday 7AM – 6PM CST). www.3M.com.

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