EPINEPHRINE: 15,112 Adverse Event Reports & Safety Profile

AUVI-Q (epinephrine injection, USP) 0.3 mg, 0.15 mg and 0.1 mg is an auto-injector and a combination product containing drug and device components. AUVI-Q includes audible (electronic voice instructions, beeps) and visible (LED lights) cues for use. The needle automatically retracts after the injection is complete. Each AUVI-Q 0.3 mg delivers a single dose of 0.3 mg epinephrine from epinephrine injection, USP (0.3 mL) in a sterile solution. Each AUVI-Q 0.15 mg delivers a single dose of 0.15 mg epinephrine from epinephrine injection, USP (0.15 mL) in a sterile solution. Each AUVI-Q 0.1 mg delivers a single dose of 0.1 mg epinephrine from epinephrine injection, USP (0.1 mL) in a sterile solution . AUVI-Q 0.3 mg, AUVI-Q 0.15 mg and AUVI-Q 0.1 mg each contain 0.76 mL epinephrine solution. 0.3 mL, 0.15 mL and 0.1 mL epinephrine solution is dispensed for AUVI-Q 0.3 mg, AUVI-Q 0.15 mg and AUVI-Q 0.1 mg, respectively, when activated. The remaining solution is not available for future use and should be discarded.

Each

0.3 mL in AUVI-Q 0.3 mg contains 0.3 mg epinephrine, 2.3 mg sodium chloride, 0.5 mg sodium bisulfite, hydrochloric acid to adjust pH, and water for injection. The pH range is 2.2–5.0.

Each

0.15 mL in AUVI-Q 0.15 mg contains 0.15 mg epinephrine, 1.2 mg sodium chloride, 0.2 mg sodium bisulfite, hydrochloric acid to adjust pH, and water for injection. The pH range is 2.2–5.0.

Each

0.1 mL in AUVI-Q 0.1 mg contains 0.1 mg epinephrine, 0.78 mg sodium chloride, 0.15 mg sodium bisulfite, hydrochloric acid to adjust pH, and water for injection. The pH range is 2.2–5.0. Epinephrine is a sympathomimetic catecholamine. Chemically, epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl]benzyl alcohol with the following structure: Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin. AUVI-Q is not made with natural rubber latex. AUVI-Q instructional and safety systems should be thoroughly reviewed with patients and caregivers prior to use [ see PATIENT COUNSELING INFORMATION ( 17.1 ) ].

Chemical

Structure

AND USAGE Epinephrine Injection, 0.3 mg and Epinephrine Injection, 0.15 mg are indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitoes), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis.

Epinephrine

Injection, 0.3 mg and Epinephrine Injection, 0.15 mg are intended for immediate administration in patients who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Anaphylactic reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema.

Epinephrine

Injection, 0.3 mg and Epinephrine Injection, 0.15 mg are intended for immediate administration as emergency supportive therapy only and are not a substitute for immediate medical care.

Epinephrine

Injection, 0.3 mg and Epinephrine Injection, 0.15 mg contain epinephrine, are non-selective alpha and beta-adrenergic receptor agonist indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis. ( 1 )

AND ADMINISTRATION See Full Prescribing Information for recommended dosages and administration information for adult and pediatric patients ( 2 )

2.1 Important Dosage and Administration Information

• Lidocaine Hydrochloride and Epinephrine Injection is not recommended for intrathecal use.
• Avoid use of Lidocaine Hydrochloride and Epinephrine solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [see Warnings and Precautions (5.3) ] .
• 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.

Lidocaine

Hydrochloride and Epinephrine Injections are clear, colorless to slightly yellow solutions. Do not administer solutions which are discolored or contain particulate matter.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions which are discolored (e.g., pinkish or darker than slightly yellow) or which contain particulate matter or precipitate should not be administered.
• Mixing or the prior or intercurrent use of any other local anesthetic with Lidocaine Hydrochloride and Epinephrine Injection is not recommended because of insufficient data on the clinical use of such mixtures.

Administration

Precautions

• Lidocaine Hydrochloride and Epinephrine 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 Lidocaine Hydrochloride and Epinephrine 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 (5.1) , 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 Lidocaine Hydrochloride and Epinephrine Injection [see Warnings and Precautions (5.1) , Drug Interactions (7.1) , Overdosage (10) ] .
• Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting Lidocaine Hydrochloride and Epinephrine Injection, both 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 (5.7) ] .
• Avoid rapid injection of a large volume of Lidocaine Hydrochloride and Epinephrine 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 Lidocaine Hydrochloride and Epinephrine 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.
• Use Lidocaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis [see Warnings and Precautions (5.10) ] .

2.2 Recommended Concentrations and Dosages of Lidocaine Hydrochloride and Epinephrine Injection/Lidocaine Hydrochloride Injection (without Epinephrine) in Adults The dosage of Lidocaine Hydrochloride and Epinephrine Injection 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. Administer the smallest dosage and concentration required to produce the desired result. The types of block and recommended Lidocaine Hydrochloride Injection (without epinephrine) concentrations are shown in Table 1. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. Consider administration of solutions containing epinephrine when large volumes are required.

Table

1: Recommended Dosages in Adults Procedure Lidocaine Hydrochloride Injection (without epinephrine) Conc (%) Vol (mL)

Total

Dose (mg)

Infiltration Percutaneous

0.5 or 1 1 to 60 5 to 300 Intravenous regional 0.5 10 to 60 50 to 300 Dose should not exceed 4 mg/kg.

Peripheral Nerve

Blocks, e.g., Brachial 1.5 15 to 20 225 to 300 Dental 2 1 to 5 20 to 100 Intercostal 1 3 30 Paravertebral 1 3 to 5 30 to 50 Pudendal (each side) 1 10 100 Paracervical Obstetrical analgesia (each side) 1 10 100 Sympathetic Nerve Blocks, e.g., Cervical (stellate ganglion) 1 5 50 Lumbar 1 5 to 10 50 to 100 Central Neural Blocks Epidural Dose determined by number of dermatomes to be anesthetized (2 to 3 mL/dermatome).

Thoracic

1 20 to 30 200 to 300 Lumbar Analgesia 1 25 to 30 250 to 300 Anesthesia 1.5 15 to 20 225 to 300 2 10 to 15 200 to 300 Caudal Obstetrical analgesia 1 20 to 30 200 to 300 Surgical anesthesia 1.5 15 to 20 225 to 300 The above suggested concentrations and volumes serve only as a guide. Other volumes and concentrations may be used provided the total maximum recommended dose is not exceeded [see Dosage and Administration (2.5) ] . These recommended doses serve only as a guide to the amount of local anesthetic required for most indicated procedures. The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient. In all cases, the lowest concentration and smallest dose that will produce the desired result should be given. The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site.

2.3 Use in Epidural Anesthesia During the administration of epidural anesthesia, it is recommended that a test dose of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the initial and all supplemental doses, because a catheter in the epidural space can migrate into a blood vessel or through the dura <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . During epidural administration, administer Lidocaine Hydrochloride and Epinephrine Injection, 1.5% (15 mg/mL) and 2% (20 mg/mL) solutions in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Administer injections slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Perform syringe aspirations before and during each supplemental injection in continuous (intermittent) catheter techniques. Repeat doses of lidocaine should be preceded by a test dose containing epinephrine if not clinically contraindicated. Use only the single-dose vials for caudal or epidural anesthesia; avoid use of the multiple-dose vials for these procedures, which contain a preservative <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.4 ), Warnings and Precautions (5.7) ]</span> .

2.4 Test Dose for Epidural Blocks In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter. Three mL of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit. This test dose may serve as a warning of unintended intravascular or intrathecal injection. Closely monitor for early clinical signs of toxicity following each test dose <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> . Allot adequate time for onset of spinal block to detect possible intrathecal injection. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal, or cardiovascular effects from the epinephrine <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) , Overdosage (10) ]</span> .

2.5 Maximum Recommended Dosage Adults For normal healthy adults, the individual maximum recommended dose of Lidocaine Hydrochloride and Epinephrine Injection should not exceed 7 mg/kg of body weight, and in general it is recommended that the maximum total dose not exceed 500 mg. When used without epinephrine, the maximum individual dose should not exceed 4.5 mg/kg of body weight, and in general it is recommended that the maximum total dose does not exceed 300 mg. For continuous epidural or caudal anesthesia, the maximum recommended dosage should not be administered at intervals of less than 90 minutes. When continuous lumbar or caudal epidural anesthesia is used for non-obstetrical procedures, a higher total dose may be administered if required to produce adequate anesthesia. The maximum recommended dose per 90 minute period of lidocaine hydrochloride for paracervical block in obstetrical patients and non-obstetrical patients is 200 mg total. One half of the total dose is usually administered to each side. Inject slowly, five minutes between sides <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> .

Pediatric

Patients A maximum dose of Lidocaine Hydrochloride and Epinephrine Injection for children varies based on age and weight. For children over 3 years of age with a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight. For example, in a child of 5 years weighing approximately 23 kg, the dose of lidocaine hydrochloride should not exceed approximately 75 mg to 100 mg (3.3 mg/kg to 4.4 mg/kg). The use of dilute solutions (i.e., 0.25% to 0.5%) and total dosages not to exceed 3 mg/kg are recommended for induction of intravenous regional anesthesia in children. The lowest effective concentration and lowest effective dose should be used. Dilution of available concentrations with 0.9% sodium chloride injection may be required to obtain the required final concentration.

Lidocaine Hydrochloride and Epinephrine Injections are contraindicated in patients with a known hypersensitivity to lidocaine or to any local anesthetics of the amide-type or to other components of Lidocaine Hydrochloride and Epinephrine Injections. Known hypersensitivity to any local anesthetic agent of the amide-type or to other components of Lidocaine Hydrochloride and Epinephrine Injection. ( 4 )

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Systemic

Adverse experiences following the administration of lidocaine HCl are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or inadvertent intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported: Central Nervous System CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine HCl is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption.

Cardiovascular System

Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest.

Allergic

Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to the methylparaben used as a preservative in the multiple dose vials. Allergic reactions, including anaphylactic reactions, may occur as a result of sensitivity to lidocaine, but are infrequent. If allergic reactions do occur, they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. There have been no reports of cross sensitivity between lidocaine hydrochloride and procainamide or between lidocaine hydrochloride and quinidine.

Neurologic

The incidences of adverse 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. In a prospective review of 10,440 patients who received lidocaine HCl for spinal anesthesia, the incidences of adverse reactions were reported to be about 3 percent each for positional headaches, hypotension and backache; 2 percent for shivering; and less than 1 percent each for peripheral nerve symptoms, nausea, respiratory inadequacy and double vision. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the local anesthetic. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter may occur. Subsequent adverse effects may depend partially on the amount of drug administered subdurally. These may include spinal block of varying magnitude (including total spinal block), hypotension secondary to spinal block, loss of bladder and bowel control, and loss of perineal sensation and sexual function. Persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances when caudal or lumbar epidural block has been attempted. Backache and headache have also been noted following use of these anesthetic procedures. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration.

Hematologic

Methemoglobinemia.

Systemic

Adverse experiences following the administration of lidocaine HCl are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or inadvertent intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported:

Central Nervous System CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine HCl is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption.

Cardiovascular System

Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest.

Allergic

Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to the methylparaben used as a preservative in the multiple dose vials. Allergic reactions, including anaphylactic reactions, may occur as a result of sensitivity to lidocaine, but are infrequent. If allergic reactions do occur, they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. There have been no reports of cross sensitivity between lidocaine hydrochloride and procainamide or between lidocaine hydrochloride and quinidine.

Neurologic

The incidences of adverse 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. In a prospective review of 10,440 patients who received lidocaine HCl for spinal anesthesia, the incidences of adverse reactions were reported to be about 3 percent each for positional headaches, hypotension and backache; 2 percent for shivering; and less than 1 percent each for peripheral nerve symptoms, nausea, respiratory inadequacy and double vision. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the local anesthetic. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter may occur. Subsequent adverse effects may depend partially on the amount of drug administered subdurally. These may include spinal block of varying magnitude (including total spinal block), hypotension secondary to spinal block, loss of bladder and bowel control, and loss of perineal sensation and sexual function. Persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances when caudal or lumbar epidural block has been attempted. Backache and headache have also been noted following use of these anesthetic procedures. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration.

Hematologic

Methemoglobinemia.

AND PRECAUTIONS

• Dose-Related Toxicity : Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after injection of Lidocaine Hydrochloride and Epinephrine. ( 5.1 )
• Methemoglobinemia : Cases of methemoglobinemia have been reported in association with local anesthetics use. See full prescribing information for more details on managing these risks. ( 5.2 )
• Chondrolysis with Intra-Articular Infusion : Avoid intra-articular infusions as there have been post-marketing reports of chondrolysis in patients receiving such infusion. ( 5.4 )
• Allergic-Type Reactions to Sulfites in Lidocaine Hydrochloride and Epinephrine Injection and Anaphylactic Reactions : Lidocaine Hydrochloride and Epinephrine Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. ( 5.6 )
• Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection : Unintended intravascular or intrathecal injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progression ultimately to respiratory arrest. Aspirate for blood or cerebrospinal fluid (where applicable) prior to each dose and consider using a test dose of Lidocaine Hydrochloride and Epinephrine. ( 5.7 )

5.1 Dose-Related Toxicity The safety and effectiveness of Lidocaine Hydrochloride and Epinephrine Injection depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient&apos;s state of consciousness should be performed after injection of Lidocaine Hydrochloride and Epinephrine Injection solutions. Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. 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. 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. Use the lowest dosage of Lidocaine Hydrochloride and Epinephrine Injection that results in effective anesthesia to avoid high plasma levels and serious adverse effects. Avoid rapid injection of a large volume of Lidocaine Hydrochloride and Epinephrine Injection solution and administer fractional (incremental) doses when feasible. Injection of repeated doses of Lidocaine Hydrochloride and Epinephrine Injection may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status.

5.2 Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition <span class="opacity-50 text-xs">[see Drug Interactions (7.5)]</span>. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death.

Discontinue Lidocaine

Hydrochloride and Epinephrine Injection and any other oxidizing agents. Depending on the severity of the symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

5.3 Antimicrobial Preservatives in Multiple-Dose Vials Avoid use of Lidocaine Hydrochloride and Epinephrine Injection solutions containing antimicrobial preservatives (i.e., those supplied in multiple-dose vials) for epidural or caudal anesthesia because safety has not been established with such use.

5.4 Chondrolysis with Intra-Articular Infusion 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 2 nd 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.

5.5 Risk of Adverse Reactions Due to Drug Interactions with Lidocaine Hydrochloride and Epinephrine Injection Risk of Severe, Persistent Hypertension Due to Drug Interactions Between Lidocaine Hydrochloride and Epinephrine Injection and Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Administration of Lidocaine Hydrochloride and Epinephrine Injection in patients receiving monoamine oxidase inhibitors (MAOI), or tricyclic antidepressants may result in severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient&apos;s hemodynamic status is essential <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Risk of Severe, Persistent Hypertension or Cerebrovascular Accidents Due to Drug Interactions Between Lidocaine Hydrochloride and Epinephrine Injection and Ergot-Type Oxytocic Drugs Concurrent administration of Lidocaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of Lidocaine Hydrochloride and Epinephrine Injection concomitantly with ergot-type oxytocic drugs <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> . Risk of Hypertension and Bradycardia Due to Drug Interactions Between Lidocaine Hydrochloride and Epinephrine Injection and Nonselective Beta-Adrenergic Antagonists Administration of Lidocaine Hydrochloride and Epinephrine Injection in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient&apos;s blood pressure and heart rate is essential <span class="opacity-50 text-xs">[see Drug Interactions (7.4) ]</span> .

5.6 Allergic-Type Reactions to Sulfites in Lidocaine Hydrochloride and Epinephrine Injection and Anaphylactic Reactions Lidocaine Hydrochloride and Epinephrine Injection solutions contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. Anaphylactic reactions may occur following administration of lidocaine hydrochloride <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . Lidocaine hydrochloride 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 hydrochloride.

5.7 Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection Unintended intravascular or intrathecal injection of Lidocaine Hydrochloride and Epinephrine Injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Unintentional intrathecal injection during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column has resulted in underventilation or apnea (&quot;Total or High Spinal&quot;). A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . Aspirate for blood or cerebrospinal fluid (where applicable) before injecting Lidocaine Hydrochloride and Epinephrine Injection, both 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. Use of Test Dose with Epidural Anesthesia To serve as a warning of unintended intravascular or intrathecal injection, 3 mL of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) may be used as a test dose prior to administration of the full dose in caudal and lumbar epidural blocks <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Three mL of Lidocaine Hydrochloride and Epinephrine Injection (1.5% lidocaine with 1:200,000 epinephrine) without antimicrobial preservative contains 45 mg lidocaine and 15 mcg epinephrine. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. Signs/symptoms of unintended intravascular or intrathecal injection of the test dose of Lidocaine Hydrochloride and Epinephrine Injection and monitoring recommendations are described below.

• Unintended intravascular injection: Likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for increases. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure.
• Unintended intrathecal injection: Evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects [see Overdosage (10) ] .

5.8 Risk of Toxicity in Patients with Hepatic Impairment Because amide local anesthetics such as lidocaine are metabolized by the liver, consider reduced dosing and increased monitoring for lidocaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with lidocaine hydrochloride, especially with repeat doses <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span> .

5.9 Risk of Use in Patients with Impaired Cardiovascular Function Lidocaine should also be given in reduced doses 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. Monitor patients closely for blood pressure, heart rate, and ECG changes.

5.10 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood Supply Use Lidocaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply, such as digits, nose, external ear, or penis. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.

5.11 Risk of Cardiac Arrhythmias with Concomitant Use of Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Lidocaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics <span class="opacity-50 text-xs">[see Drug Interactions (7.6) ]</span> . In deciding whether to concurrently use Lidocaine Hydrochloride and Epinephrine Injection with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account.

5.12 Risk of Adverse Reactions with Use in the Head and Neck Area Small doses of local anesthetics (e.g., Lidocaine Hydrochloride and Epinephrine Injection) 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. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Monitor circulation and respiration and constantly observe patients receiving Lidocaine Hydrochloride and Epinephrine Injection blocks. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

5.13 Familial Malignant Hyperthermia 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).

5.14 Risk of Respiratory Arrest with Use in Ophthalmic Surgery Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block (e.g., with Lidocaine Hydrochloride and Epinephrine Injection), as with all other regional procedures, resuscitative equipment and drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be immediately available. As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses.

5.15 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa in Dental Applications Because of the long duration of anesthesia, when Lidocaine Hydrochloride and Epinephrine Injection [0.5% (5 mg/mL) of lidocaine] is used for dental injections, warn patients about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns <span class="opacity-50 text-xs">[see Patient Counseling Information (17) ]</span> .

5.16 Drug/Laboratory Test Interactions The intramuscular injection of lidocaine hydrochloride 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 hydrochloride.

PRECAUTIONS General The safety and effectiveness of lidocaine HCl 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 HCl 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 HCl 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 Hydrochloride and Epinephrine Injection 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

Hydrochloride and Epinephrine Injection 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 HCl 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 HCl. 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 injection 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. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

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 oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

Drug/Laboratory

Test Interactions The intramuscular injection of lidocaine HCl 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 HCl. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: 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, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, paraaminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of lidocaine HCl in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted.

Pregnancy Teratogenic

Effects: 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 HCl. 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 HCl 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 and Metabolism ). 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 a 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 HCl is administered to a nursing woman.

Pediatric Use

Dosages in children should be reduced, commensurate with age, body weight and physical condition (see DOSAGE AND ADMINISTRATION ).

General

The safety and effectiveness of lidocaine HCl 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 HCl 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 HCl 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 Hydrochloride and Epinephrine Injection 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

Hydrochloride and Epinephrine Injection 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 HCl 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 HCl.

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 injection 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. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

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 oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

Drug/Laboratory

Test Interactions The intramuscular injection of lidocaine HCl 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 HCl. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: 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, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, paraaminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

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

Pregnancy Teratogenic

Effects: 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 HCl. 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 HCl 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 and Metabolism ). 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 a 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 HCl is administered to a nursing woman.

Pediatric Use

Dosages in children should be reduced, commensurate with age, body weight and physical condition (see DOSAGE AND ADMINISTRATION ).

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 )
• Monoamine Oxidase Inhibitors and Tricyclic Antidepressants : Administration of Lidocaine Hydrochloride and Epinephrine Injection to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension Concurrent use of these agents should generally be avoided. ( 5.5 , 7.2 )
• Ergot-type Oxytocic drugs : Concurrent administration of Lidocaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. ( 5.5 , 7.3 )
• Nonselective Beta-Adrenergic Antagonists : Administration of Lidocaine Hydrochloride and Epinephrine Injection in patients receiving nonselective beta-adrenergic antagonist may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. ( 5.5 , 7.4 )
• 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 )
• Potent Inhalation Anesthetics : Serious dose-related cardiac arrhythmias may occur if preparations containing epinephrine are used in patients during or following the administration of potent inhalation anesthetics. ( 5.11 , 7.6 )

7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with Lidocaine Hydrochloride and Epinephrine Injection cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants The administration of Lidocaine Hydrochloride and Epinephrine Injection to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient’s hemodynamic status is essential <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> .

7.3 Ergot-Type Oxytocic Drugs Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of Lidocaine Hydrochloride and Epinephrine Injection concomitantly with ergot-type oxytocic drugs <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> .

7.4 Nonselective Beta-Adrenergic Antagonists Administration of Lidocaine Hydrochloride and Epinephrine Injection in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient&apos;s blood pressure and heart rate is essential <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> .

7.5 Drugs Associated with Methemoglobinemia Patients that are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following oxidizing agents: Class Examples Nitrates/Nitrites nitroglycerin, nitroprusside, nitric oxide, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, rasburicase, ifosfamide, hydroxyurea Antibiotics dapsone, sulfonamides, nitrofurantoin, para- aminosalicylic acid Antimalarials chloroquine, primaquine Anticonvulsants phenytoin, sodium valproate, phenobarbital Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing epinephrine (e.g., Lidocaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics <span class="opacity-50 text-xs">[see Warnings and Precautions (5.11) ]</span> .

7.7 Phenothiazines and Butyrophenones Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of Lidocaine Hydrochloride with Epinephrine and these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.

ACTIVE INGREDIENTS - equal amounts of: Syzygium 4X, Hydrastis 6X, Adrenalinum 9X, Pancreatinum 9X, Pituitarum Posterium 9X, Bovista 12X, Insulin 12X, Lycopersicum 12X, Phosphoricum Ac 12X, Phosphorus 12X, Tarentula Hispana 12X, Terebinthina 12X, Uranium Nitricum 12X

OTHER INGREDIENTS Deionized water, glycerin, sodium bisulphate, sodium metabisulfate, dehydroxanthan gum, chlorobutanol, sodium chloride