Xylocaine Ointment 5 %

Drug Interactions

Local Anesthetics and Agents Structurally Related to Amide-type Local Anesthetics

β-blockers and Cimetidine

Drug-Food Interactions

Drug-Laboratory Test Interactions

Erythromycin and Itraconazole

Antiarrhythmic Drugs

Drug-Herb Interactions

Class I Antiarrhythmic Drugs

Drug-Lifestyle Interactions

Drug-Drug Interactions

Fluvoxamine

Class III Antiarrhythmic Drugs

Strong Inhibitors of CYP1A2 and CYP3A4

Overview

Information for the Patient

Xylocaine Ointment 5%

Special Handling Instructions

On initial opening, do not use if the protective membrane of the tube is punctured.

Dosage and Administration

Maximum Dosage

Children (Under 12 Years)

Special Populations

XYLOCAINE Ointment 5%

Recommended Dose and Dosage Adjustment

General

Administration

Dosing Considerations

Adults

Adverse Reactions

Skin Irritation

Central Nervous System

Allergic

Cardiovascular System

Indications and Clinical Use

XYLOCAINE Ointment 5% (lidocaine) is indicated for:

• Temporary relief of pain associated with minor burns and abrasions of the skin, e.g. sunburn, herpes zoster and labialis, pruritus, sore nipples, insect bites;

  
  

• Anesthesia of mucous membranes, e.g. various anal conditions such as hemorrhoids and fissures;

  
  

• The alleviation of pain during examination and instrumentation, e.g. proctoscopy, sigmoidoscopy, cystoscopy, endotracheal intubation.

  Overdosage

  Symptoms

  Central nervous system 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 central nervous system, 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.

  
  

  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 convulsions occur, the objective of the treatment is to maintain ventilation and oxygenation and support circulation. Oxygen must be given and ventilation assisted if necessary (mask and bag or tracheal intubation). Should convulsions not stop spontaneously after 15-20 seconds, an anticonvulsant should be given iv to facilitate adequate ventilation and oxygenation. Thiopental sodium 1-3 mg/kg iv is the first choice. Alternatively diazepam 0.1 mg/kg bw iv may be used, although its action will be slow. Prolonged convulsions may jeopardize the patient's ventilation and oxygenation. If so, injection of a muscle relaxant (e.g. succinylcholine 1 mg/kg bw) will facilitate ventilation, and oxygenation can be controlled. Early endotracheal intubation is required when succinylcholine is used to control motor seizure activity.

  
  

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

  
  

  Should circulatory arrest occur, immediate cardiopulmonary resuscitation should be instituted. Continual 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 (0.1-0.2 mg as intravenous or intracardial injections) should be given as soon as possible and repeated, if necessary.

  
  

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

  
  
  

  Dosage Forms, Composition and Packaging

  Each g of white to greyish-white ointment contains: lidocaine (base) 50 mg. Nonmedicinal ingredients: polyethylene glycol, propylene glycol and purified water. Aluminum tubes of 35 g.

  Warnings and Precautions

  Geriatrics

  Elderly patients may be more sensitive to systemic effects due to increased blood levels of lidocaine following repeated doses and may require dose reductions.

  Hepatic/Biliary/Pancreatic

  Because amide-type local anesthetics such as lidocaine are metabolized by the liver, these drugs, especially repeated 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.

  Renal

  Lidocaine is metabolized primarily by the liver to monoethylglycinexylidine (MEGX, which has some CNS activity), and then further to metabolites glycinexylidine (GX) and 2,6-xylidine (see Action and Clinical Pharmacology). Only a small fraction (2%) of lidocaine is excreted unchanged in the urine. The pharmacokinetics of lidocaine and its main metabolite were not altered significantly in hemodialysis patients (n=4) who received an intravenous dose of lidocaine. Therefore, renal impairment is not expected to significantly affect the pharmacokinetics of lidocaine when XYLOCAINE Ointment 5% is used for short treatment durations, according to dosage instructions (see Dosage and Administration). Caution is recommended when lidocaine is used in patients with severely impaired renal function because lidocaine metabolites may accumulate during long term treatment (see Dosage and Administration).

  Special Populations

  Debilitated patients, acutely ill patients, and patients with sepsis should be given reduced doses commensurate with their age, weight and physical condition because they may be more sensitive to systemic effects due to increased blood levels of lidocaine following repeated doses.

  
  

  Lidocaine should be used with caution in patients with epilepsy or impaired renal function.

  Carcinogenesis and Mutagenesis

  Genotoxicity tests with lidocaine showed no evidence of mutagenic potential. A metabolite of lidocaine, 2,6-xylidine, showed weak evidence of activity in some genotoxicity tests. A chronic oral toxicity study of the metabolite 2,6-xylidine (0, 14, 45, 135 mg/kg) administered in feed to rats showed that there was a significantly greater incidence of nasal cavity tumors in male and female animals that had daily oral exposure to the highest dose of 2,6-xylidine for 2 years. The lowest tumor-inducing dose tested in animals (135 mg/kg) corresponds to approximately 40 times the amount of 2,6-xylidine to which a 50 kg subject would be exposed following the application of 8 g of lidocaine ointment 5% for 24 hours on the mucosa, assuming the highest theoretical extent of absorption of 100% and 80% conversion to 2,6-xylidine. Based on a yearly exposure (once daily dosing with 2,6-xylidine in animals and 5 treatment sessions with 8 g lidocaine ointment 5% in humans), the safety margins would be approximately 3000 times when comparing the exposure in animals to man.

  Neurologic

  
  
  

  General

  Excessive dosage, or short intervals between doses, can result in high plasma levels of lidocaine or its metabolites and serious adverse effects. Absorption from wound surfaces and the mucous membranes is variable but is especially high from the bronchial tree. Such applications may therefore result in rapidly rising or excessive plasma concentrations, with an increased risk for toxic symptoms, such as convulsions. Patients should be instructed to strictly adhere to the recommended dosage. This is especially important in children where doses vary with weight. The management of serious adverse reactions may require the use of resuscitative equipment, oxygen and other resuscitative drugs (see Overdosage).

  
  

  The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Tolerance to elevated blood levels varies with the status of the patient.

  
  

  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.

  
  

  XYLOCAINE Ointment 5% (lidocaine) should be used with caution in children under the age of 2 as there is insufficient data to support the safety and efficacy of this product in this patient population at this time.

  
  

  In patients under general anesthesia who are paralyzed, higher plasma concentrations may occur than in spontaneously breathing patients. Unparalyzed patients are more likely to swallow a large proportion of the dose, which then undergoes considerable first-pass hepatic metabolism following absorption from the gut.

  
  

  Avoid contact with eyes.

  
  

  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.

  
  

  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. See also Information for the Patient.

  
  

  XYLOCAINE Ointment 5% is ineffective when applied to intact skin.

  Sensitivity/Resistance

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

  Locomotion and Coordination

  Topical lidocaine formulations generally result in low plasma concentrations because of a low degree of systemic absorption. However, depending on the dose, local anesthetics may have a very mild effect on mental function and coordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

  Epilepsy

  The risk of central nervous system side effects when using lidocaine in patients with epilepsy is very low, provided that the dose recommendations are followed (see Dosage and Administration).

  Pediatrics

  Children should be given reduced doses commensurate with their age, weight and physical condition because they may be more sensitive to systemic effects due to increased blood levels of lidocaine following repeated doses (see Dosage and Administration).

  
  

  XYLOCAINE Ointment 5% should be used with caution in children under the age of 2 as there is insufficient data to support the safety and efficacy of this product in this patient population at this time.

  Labour and Delivery

  Should XYLOCAINE Ointment 5% be used concomitantly with other products containing lidocaine during labour and delivery, the total dose contributed by all formulations must be kept in mind.

  Pregnant Women

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

  
  

  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.

  Nursing Women

  Lidocaine and its metabolites are excreted in the breast milk. At therapeutic doses the quantities of lidocaine and its metabolites in breast milk are small and generally are not expected to be a risk for the infant.

  Cardiovascular

  Lidocaine should be used with caution in patients with bradycardia or impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by amide-type local anesthetics.

  
  

  Lidocaine should be used with caution in patients in severe shock.

  
  
  

  Storage and Stability

  Store at 15-30°C. Protect from freezing.

  Action and Clinical Pharmacology

  Distribution

  Lidocaine has a total plasma clearance of 0.95 L/min and a volume of distribution at steady state of 91 L.

  
  

  Following insertion of an endotracheal tube lubricated with a mean of 1.26 g (range 0.49-2.45) XYLOCAINE Ointment 5% in patients 18 to 80 years old, the mean peak venous plasma concentration of lidocaine was 0.45 (range 0.2-0.9) µg/mL and was usually observed within 15 min. A dose increase of 1 g ointment resulted in an average increase of 0.22 µg/mL.

  
  

  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.

  
  

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

  Pharmacokinetics

  
  
  

  Special Populations and Conditions

  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 µg free base per mL.

  Absorption

  The rate and extent of absorption depends upon concentration and total dose administered, the specific site of application and duration of exposure. In general, 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.

  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 the sodium channels of the nerve membrane.

  Excretion

  Lidocaine has 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 elimination half-life of lidocaine following an intravenous bolus injection is typically 1.5 to 2.0 hours. The elimination half-life in neonates (3.2 h) 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.

  Onset of Action

  Anesthesia usually occurs within 3-5 minutes when applied to mucous membrane. The duration of analgesia for burn wound pain is about 4 hours. The application of gauze over the cream may prolong duration of analgesia in burn wounds. XYLOCAINE Ointment 5% (lidocaine) is ineffective when applied to intact skin.

  Metabolism

  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.

  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.

  
  

  Central nervous system toxicity (see Overdosage) 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.

  
  
  

  Contraindications

  XYLOCAINE Ointment 5% (lidocaine) is contraindicated in:

  
  

  • patients with a known history of hypersensitivity to local anesthetics of the amide type or to other components of the ointment (see Dosage Forms, Composition and Packaging).