Xylocaine (Lidocaine HCl)

XYLOCAINE® 4% STERILE SOLUTION

Astra

Lidocaine HCl

Local Anesthetic

Action And Clinical Pharmacology: Mechanism 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. Local anesthetics of the amide type are thought to act within sodium channels of the nerve membrane.

Onset of Action: The onset of action is rapid. For retrobulbar injection, 4 mL of Xylocaine 4% provides an average duration of action of 1 to 1 1/2 hours. This duration may be extended to ophthalmic surgery by the addition of epinephrine, the usual recommended dilution being 1:50 000 to 1:100 000.

Hemodynamics: Lidocaine, like other local anesthetics, may also have effects on excitable membranes in the brain and myocardium. If excessive amounts of drug reach systemic circulation rapidly, symptoms and signs of toxicity will appear, emanating from the central nervous and cardiovascular systems.

CNS toxicity (see Overdose: Symptoms and Treatment) usually precedes the cardiovascular effects since it occurs at lower plasma concentrations. Direct effects of local anesthetics on the heart include slow conduction, negative inotropism and eventually cardiac arrest.

Pharmacokinetics: Lidocaine is completely absorbed following parenteral administration. The rate of absorption depends on the dose, route of administration, and the vascularity of the injection site. The highest peak plasma levels are obtained following intercostal nerve block (approximately 1.5 g/mL/100 mg injected) while abdominal s.c. injections give the lowest (approximately 0.5 g/mL/100 mg injected). Epidural and major nerve blocks are intermediate.

Absorption is considerably slowed by the addition of epinephrine, although it also depends on the site of injection. Peak plasma concentrations are reduced by 50% following s.c. injection, by 30% following epidural injection and by 20% following intercostal block if epinephrine 5 g/mL is added.

The rate of absorption of local anesthetic agents, following topical application to wound surfaces and mucous membranes is high, and occurs most rapidly after intratracheal and bronchial administration. Lidocaine is also well absorbed from the gastrointestinal tract, although little intact drug may appear in the circulation because of biotransformation in the liver.

Lidocaine has a total plasma clearance of 0.95 L/min, a volume of distribution at steady state of 91 L, an elimination half-life of 1.6 h and an estimated hepatic extraction ratio of 0.65. The clearance of lidocaine is almost entirely due to liver metabolism, and depends both on liver blood flow and the activity of metabolizing enzymes.

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

Lidocaine readily crosses the placenta, and equilibrium in regard to free, unbound drug will be reached. Because the degree of plasma protein binding in the fetus is less than in the mother, the total plasma concentration will be greater in the mother, but the free concentrations will be the same.

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. Only 2% of lidocaine is excreted unchanged. Most of it is metabolized first to monoethylglycinexylidide (MEGX) and then to glycinexylidide (GX) and 2,6-xylidine. Up to 70% appears in the urine as 4-hydroxy-2,6-xylidine.

The elimination half-life of lidocaine following i.v. bolus injection is typically 1.5 to 2.0 hours. The elimination half-life in neonates (3.2 hours) is approximately twice that of adults. 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.

Acidosis increases the systemic toxicity of lidocaine while the use of CNS depressants may increase the levels of lidocaine required to produce overt CNS effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 g free base/mL.

Indications And Clinical Uses: For parenteral or topical use for the production of local anesthesia of the mucous membranes of the respiratory tract or the genitourinary tract. It may be injected transtracheally to anesthetize the larynx and trachea. It may be administered by retrobulbar injection to provide anesthesia for ophthalmic surgery.

Contra-Indications: In patients with a known history of hypersensitivity to local anesthetics of the amide type.

Manufacturers’ Warnings In Clinical States: Local anesthetics should only be employed 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 Effects 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.

It is essential that aspiration for blood be done prior to injecting any local anesthetics, both the original and all subsequent doses, to avoid intravascular injection. The needle must be repositioned until no return of blood can be elicited by aspiration. However, a negative aspiration does not ensure against an intravascular injection.

Lidocaine should be used with caution in patients with sepsis and/or traumatized mucosa at the area of application, since under such conditions there is the potential for rapid systemic absorption.

Precautions: The safety and effectiveness of Xylocaine 4% Sterile Solution 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 Overdose: Symptoms and Treatment). During major regional nerve blocks, the patient should have i.v. fluids running via an indwelling catheter to assure a functioning i.v. pathway. The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects.

Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection.

Repeated doses of Xylocaine may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Absorption from mucous membranes is variable but especially high from the bronchial tree. 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 epilepsy, impaired cardiac conduction, bradycardia, impaired hepatic or renal function and in severe shock.

Because amide-type local anesthetics such as lidocaine are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously 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 AV conduction produced by these drugs.

Solutions containing epinephrine should be used with caution in patients whose medical history and physical evaluation suggest the existence of untreated hypertension, poorly controlled thyrotoxicosis, diabetes, ischemic heart disease, heart block, cerebral vascular insufficiency and peripheral vascular disorder. These solutions should also be used cautiously in areas of the body supplied by end arteries, such as digits, or otherwise having a compromised blood supply (see also Drug Interactions).

Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression or drowsiness may be early warning signs of CNS toxicity.

Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. It has been shown that the use of amide local anesthetics in malignant hyperthermia patients is safe. However, there is no guarantee that neural blockade will prevent the development of malignant hyperthermia during surgery. It is also difficult to predict the need for supplemental general anesthesia. Therefore, a standard protocol for the management of malignant hyperthermia should be available.

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 caused by inadvertent injection to an artery. These reactions may be similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Inadvertent injections into an artery can cause cerebral symptoms even at low doses. Confusion, convulsions, respiratory depression and/or respiratory arrest, and cardiovascular stimulation or depression leading to cardiac arrest have been reported. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed.

Retrobulbar injections may very occasionally reach the cranial subarachnoid space causing temporary blindness, cardiovascular collapse, apnea, convulsions, etc.. These reactions, which may be due to intra-arterial injection or direct injection into the CNS via the sheaths of the optic nerve, must be diagnosed and treated promptly.

When local anesthetic solutions are employed for retrobulbar block, lack of corneal sensation should not be relied upon to determine whether or not the patient is ready for surgery, since corneal sensation usually precedes clinically acceptable external ocular muscle akinesia.

Drug Interactions: Lidocaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects are additive.

Lidocaine with epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur and cerebrovascular and cardiac accidents are possible. Likewise, lidocaine with epinephrine or another vasoconstrictor should be used with extreme caution in patients receiving MAO inhibitors or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.

If sedatives are employed to reduce patient apprehension, they should be used in reduced doses, since local anesthetic agents, like sedatives, are CNS depressants which in combination may have an additive effect.

Solutions containing epinephrine should be used with caution in patients undergoing general anesthesia with inhalation agents such as halothane, due to the risk of serious cardiac arrhythmias.

Drug/Laboratory Test Interactions : The i.m. 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 i.m. injection of lidocaine.

Information for the Patient: When topical anesthetics are used in the mouth, the patient should be aware that the production of topical anesthesia may impair swallowing and thus enhance the danger of aspiration. Numbness of the tongue or buccal mucosa may enhance the danger of unintentional biting trauma. Food or chewing gum should not be taken while the mouth or throat area is anesthetized.

Pregnancy : It is reasonable to assume that a large number of pregnant women and women of child-bearing age have been given lidocaine. No specific disturbances to the reproductive process have so far been reported, e.g., no increased incidence of malformations. However, care should be given during early pregnancy when maximum organogenesis takes place.

There are no adequate and well-controlled studies in pregnant women on the effect of lidocaine on the developing fetus.

Labor and Delivery: Lidocaine is not contraindicated in labor and delivery. Should Xylocaine 4% Sterile Solution be used concomitantly with other products containing lidocaine, the total dose contributed by all formulations must be kept in mind.

Lactation : Lidocaine is excreted in the breast milk, but in such small quantities that there is generally no risk of affecting the infant at therapeutic dose levels.

Adverse Reactions: Adverse experiences following the administration of lidocaine 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 overdosage, 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:

CNS: CNS manifestations are excitatory and/or depressant and may be characterized by circumoral paresthesia, lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, hyperacusis, tinnitus, blurred 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 is usually an early sign of a high lidocaine plasma level and may occur as a consequence of rapid absorption.

Cardiovascular: 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, in the most severe instances, anaphylactic shock. Allergic reactions of the amide type are rare and may occur as a result of sensitivity either to the local anesthetic agent or to other components in the formulation.

Neurologic: The incidence of adverse reactions may be related to the total dose of local anesthetic administered but is also dependent upon the particular drug used, the route of administration and the physical status of the patient. Neuropathy and spinal cord dysfunction (e.g., anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome), have been associated with regional anesthesia. Neurological effects may be related to local anesthetic techniques, with or without a contribution from the drug.

Symptoms And Treatment Of Overdose: Acute systemic toxicity from local anesthetics is generally related to high plasma levels encountered during therapeutic use of local anesthetics and originates mainly in the central nervous and the cardiovascular systems (see Adverse Effects, Warnings, and Precautions).Symptoms: With accidental intravascular injections, the toxic effect will be obvious within 1 to 3 minutes, while with overdosage, peak plasma concentrations may not be reached for 20 to 30 minutes depending on the site of injection, with signs of toxicity thus being delayed.

CNS toxicity is a graded response, with symptoms and signs of escalating severity. The first symptoms are circumoral paresthesia, numbness of the tongue, lightheadedness, hyperacusis and tinnitus. Visual disturbance and muscular tremors are more serious and precede the onset of generalized convulsions. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly following convulsions due to the increased muscular activity, together with the interference with normal respiration. In severe cases apnea may occur. Acidosis increases the toxic effects of local anesthetics.

Recovery is due to redistribution and metabolism of the local anesthetic drug. Recovery may be rapid unless large amounts of the drug have been administered.

Cardiovascular effects may be seen in cases with high systemic concentrations. Severe hypotension, bradycardia, arrhythmia and cardiovascular collapse may be the result in such cases.

Cardiovascular toxic effects are generally preceded by signs of toxicity in the CNS, unless the patient is receiving a general anesthetic or is heavily sedated with drugs such as a benzodiazepine or barbiturate.

Treatment: 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 administration. At the first sign of change, oxygen should be administered. If signs of acute systemic toxicity appear, administration of the local anesthetic should be immediately stopped.

The first step in the management of systemic toxic reactions consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and 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 convulsions. An anticonvulsant should be given i.v. if the convulsions do not stop spontaneously in 15 to 20 seconds. Thiopental 100 to 150 mg i.v. will abort the convulsions rapidly. Alternatively, diazepam 5 to 10 mg i.v. may be used, although its action is slower. Succinylcholine will stop the muscle convulsions rapidly, but will require tracheal intubation and controlled ventilation, and should only be used by those familiar with these procedures.

If cardiovascular depression is evident (hypotension, bradycardia), ephedrine 5 to 10 mg i.v. should be given and may be repeated, if necessary, after 2 to 3 minutes.

Should circulatory arrest occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance, since hypoxia and acidosis will increase the systemic toxicity of local anesthetics. Epinephrine (0.1 to 0.2 mg as i.v. or intracardial injections) should be given as soon as possible and repeated, if necessary.

Children should be given doses commensurate with their age and weight.

Dosage And Administration: When Xylocaine 4% Sterile Solution is used concomitantly with other products containing lidocaine, the total dose contributed by all formulations must be kept in mind.

The dosage varies and depends upon the area to be anesthetized, vascularity of the tissues, individual tolerance and the technique of anesthesia. The lowest dosage needed to provide effective anesthesia should be administered. The degree of absorption is variable but especially high from the bronchial tree. Dosages should be reduced for children and for elderly and debilitated patients. For specific techniques and procedures, refer to standard textbooks.

The dosages below are for normal, healthy adults.

Retrobulbar Injection: The suggested dose for a 70 kg person is 3 to 5 mL (120 to 200 mg lidocaine HCl), i.e., 1.7 to 3 mg/kg body weight. A portion of this is injected retrobulbarly and the rest may be used to block the facial nerve.

Transtracheal Injection: For local anesthesia by the transtracheal route, 2 to 3 mL (80 to 120 mg lidocaine HCl) should be injected through a large enough needle so that the injection can be made rapidly. By injecting during inspiration, some of the drug will be carried into the bronchi and the resulting cough will distribute the rest of the drug over the vocal cords and the epiglottis.

Occasionally it may be necessary to spray the pharynx with lidocaine to achieve complete analgesia e.g., using an atomizer or nebulizer. For the combination of the injection and spray, it should rarely be necessary to utilize more than 5 mL (200 mg lidocaine HCl), i.e., 3 mg/kg body weight.

Topical Application: For laryngoscopy, bronchoscopy and endotracheal intubation, the pharynx may be sprayed with 1 to 5 mL (40 to 200 mg lidocaine HCl), i.e., 0.6 to 3 mg/kg body weight.

Maximum Dosage: Adults: No more than 7.5 mL (300 mg lidocaine HCl) should be used at any one time.

Children: It is difficult to recommend a maximum dose of any drug for children since this varies as a function of age and weight. In any case, the maximum amount of lidocaine administered should not exceed 4.5 mg/kg of body weight.

Sterilization, Storage and Technical Procedures: Adequate precautions should be taken to avoid prolonged contact between local anesthetic solutions containing epinephrine (low pH) and metal surfaces (e.g., needles or metal parts of syringes), since dissolved metal ions, particularly copper ions, may cause severe local irritation (swelling, edema) at the site of injection and accelerate the degradation of epinephrine.

The solubility of lidocaine is limited at pH >6.5. This must be taken into consideration when alkaline solutions, i.e., carbonates, are added since precipitation might occur. In the case of epinephrine-containing solutions, mixing with alkaline solutions may cause rapid degradation of epinephrine.

Xylocaine 4% Sterile Solution may be autoclaved for 15 to 20 minutes at 121°C.

Availability And Storage: Each mL of sterile solution contains: lidocaine HCl USP 40 mg. Nonmedicinal ingredients: sodium hydroxide and/or hydrochloric acid to adjust pH (5.0 to 7.0). Preservative-free. Single use vials of 5 mL. Discard unused portion. Store at controlled room temperature 15 to 30°C.

XYLOCAINE® 4% STERILE SOLUTION Astra Lidocaine HCl Local Anesthetic

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