Prescription Drugs

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. Hemodynamics Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. These changes may be attributable to a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. Pharmacokinetics And Metabolism Lidocaine is absorbed following topical administration to mucous membranes, its rate and extent of absorption being dependent 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 occurs most rapidly after intratracheal administration. Lidocaine is also well-absorbed from the gastrointestinal tract, but little intact drug appears in the circulation because of biotransformation in the liver. The plasma binding of lidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg of free base per mL, 60 to 80 percent of lidocaine is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion. Lidocaine is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine. Approximately 90% of lidocaine administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2, 6-dimethylaniline. The elimination half-life of lidocaine following an intravenous bolus injection is typically 1.5 to 2 hours. Because of the rapid rate at which lidocaine is metabolized, any condition that affects liver function may alter lidocaine kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 mcg free base per mL. In the rhesus monkey arterial blood levels of 18 to 21 mcg/mL have been shown to be threshold for convulsive activity.

XYLOCAINE® VISCOUS 2% (lidocaine hydrochloride) Solution DESCRIPTION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients Topical Liquid, 20 mg/mL Methyparaben, propylparaben For a complete listing see Dosage Forms, Composition and Packaging section.

INDICATIONS Xylocaine (lidocaine HCl) 2% Viscous Solution is indicated for the production of topical anesthesia of irritated or inflamed mucous membranes of the mouth and pharynx. It is also useful for reducing gagging during the taking of X-ray pictures and dental impressions. DOSAGE AND ADMINISTRATION Adult The maximum recommended single dose of Xylocaine (lidocaine HCl) 2% Viscous Solution for healthy adults should be such that the dose of lidocaine HCl does not exceed 4.5 mg/kg or 2 mg/lb body weight and does not in any case exceed a total of 300 mg. For symptomatic treatment of irritated or inflamed mucous membranes of the mouth and pharynx, the usual adult dose is one 15 mL tablespoonful undiluted. For use in the mouth, the solution should be swished around in the mouth and spit out. For use in the pharynx, the undiluted solution should be gargled and may be swallowed. This dose should not be administered at intervals of less than three hours, and not more than eight doses should be given in a 24-hour period. The dosage should be adjusted commensurate with the patient's age, weight and physical condition (see PRECAUTIONS). Pediatric Care must be taken to ensure correct dosage in all pediatric patients as there have been cases of overdose due to inappropriate dosing. It is difficult to recommend a maximum dose of any drug for children since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child's weight or age. For example: in a child of 5 years weighing 50 lbs., the dose of lidocaine hydrochloride should not exceed 75 to 100 mg (3.7 to 5 mL of Xylocaine 2% Viscous Solution). For infants and in children under 3 years of age, the solution should be accurately measured and no more than 1.2 mL be applied to the immediate area with a cotton-tipped applicator. Wait at least 3 hours before giving the next dose; a maximum of four doses may be given in a 12-hour period. Xylocaine 2% Viscous Solution should only be used if the underlying condition requires treatment with a volume of product that is less than or equal to 1.2 mL. HOW SUPPLIED Xylocaine 2% (lidocaine HCl) Viscous Solution is available as: Product No. NDC No. Size 807100 63323-807-00 100 mL polyethylene squeeze bottles. 807193 63323-807-93 450 mL polyethylene squeeze bottles. The solutions should be stored at controlled room temperature 15° to 30°C (59° to 86°F). Fresenius Kabi USA, LLC, Lake Zurich, IL 60047. Issued: September 2014

PATIENT INFORMATION Parents and caregivers should be cautioned about the following: For patients under 3 years of age, special care must be given to accurately measuring the prescribed dose and not administering the product more often than prescribed. To ensure accuracy, we recommend you use a measuring device to carefully measure the correct volume. The product should only be used for the prescribed indication. To reduce the risk of accidental ingestion, the product container should be tightly closed and the product should be stored well out of reach of all children immediately after each use. If the patient shows signs of systemic toxicity (e.g., lethargy, shallow breathing, seizure activity) emergency medical attention should be sought immediately and no additional product should be administered. Unused product should be discarded in a manner that prevents possible exposure to children and pets. All patients should be aware that when topical anesthetics are used in the mouth or throat, the production of topical anesthesia may impair swallowing and thus enhance the danger of aspiration. For this reason, food should not be ingested for 60 minutes following use of local anesthetic preparations in the mouth or throat area. This is particularly important in children because of their frequency of eating.

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 REACTIONS and WARNINGS AND PRECAUTIONS). It should be kept in mind that clinically relevant pharmacodynamic drug interactions (i.e., toxic effects) may occur with lidocaine and other local anesthetics or structurally related drugs, and Class I and Class III antiarrhythmic drugs due to additive effects (see DRUG INTERACTIONS). 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, hyperkalaemia, hypocalcaemia and hypoxia increase and extend 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 0.1mg/kg bw iv may be used, although its action will be slow. Prolonged convulsions may jeopardise the patient's ventilation and oxygenation. If so, injection of a muscle relaxant (e.g. succinylcholine 1mg/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 repeated, if necessary, after 2 - 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 - 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. CONTRAINDICATIONS XYLOCAINE Viscous 2% (lidocaine hydrochloride) is contraindicated in: patients with a known history of hypersensitivity to local anesthetics of the amide type or to other components of the solution (see DOSAGE FORMS, COMPOSITION AND PACKAGING). patients with a known hypersensitivity to methylparaben and/or propylparaben (preservatives used in XYLOCAINE Viscous (lidocaine hydrochloride solution) 2%), or to their metabolite para amino benzoic acid (PABA). Formulations of lidocaine containing parabens should also be avoided in patients with a history of allergic reactions to ester local anesthetics, which are metabolized to PABA.

SIDE EFFECTS 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 excessive dosage or rapid absorption, 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 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 the local anesthetic agent or to the methylparaben and/or propylparaben used in this formulation. Allergic reactions as a result of sensitivity to lidocaine are extremely rare and, if they occur, should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS General EXCESSIVE DOSAGE, OR SHORT INTERVALS BETWEEN DOSES, CAN RESULT IN HIGH PLASMA LEVELS OF LIDOCAINE OR ITS METABOLITES AND SERIOUS ADVERSE EFFECTS. Following too high or repeated doses of viscous lidocaine in children under the age of three, serious side effects have been reported. Absorption from the wound surfaces and 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. XYLOCAINE VISCOUS 2% (lidocaine hydrochloride) IS FOR TOPICAL USE ONLY AND MUST NOT BE USED FOR 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. XYLOCAINE Viscous (lidocaine hydrochloride solution) 2% 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 Part III: Consumer Information. XYLOCAINE Viscous (lidocaine hydrochloride solution) 2% is ineffective when applied to intact skin. Lidocaine has been shown to be porphyrinogenic in animal models. XYLOCAINE Topical 4% should only be prescribed to patients with acute porphyria on strong or urgent indications, when they can be closely monitored. Appropriate precautions should be taken for all porphyric patients. 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. Neurologic 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). 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. 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-dimethylaniline (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 haemodialysis 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 Viscous (lidocaine hydrochloride solution) 2% 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). Hepatic 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. Sensitivity Lidocaine should be used with caution in persons with known drug sensitivities. XYLOCAINE Viscous (lidocaine hydrochloride solution) 2% is contraindicated in patients with known hypersensitivities to local anesthetics of the amide type, to other components in the formulation, methylparaben and/or propylparaben (preservatives) and their metabolite para amino benzoic acid (PABA). The use of paraben-containing lidocaine preparations should also be avoided in patients who are allergic to ester local anesthetics (see CONTRAINDICATIONS). 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. 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. Labour and Delivery: Should XYLOCAINE Viscous (lidocaine hydrochloride solution) 2% be used concomitantly with other products containing lidocaine during labour and delivery, the total dose contributed by all formulations must be kept in mind. 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. 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 Viscous (lidocaine hydrochloride solution) 2% 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. 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. Carcinogenesis and Mutagenesis Genotoxicity tests with lidocaine showed no evidence of mutagenic potential. A metabolite of lidocaine, 2,6-dimethylaniline, showed weak evidence of activity in some genotoxicity tests. A chronic oral toxicity study of the metabolite 2,6-dimethylaniline (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-dimethylaniline for 2 years. The lowest tumor-inducing dose tested in animals (135 mg/kg) corresponds to approximately 50 times the amount of 2,6-dimethylaniline to which a 50 kg subject would be exposed following the application of 20 g of lidocaine viscous 2% for 24 hours on the mucosa, assuming the highest theoretical extent of absorption of 100% and 80% conversion to 2,6-dimethylaniline. Based on a yearly exposure (once daily dosing with 2,6-dimethylaniline in animals and 5 treatment sessions with 20 g lidocaine viscous 2% in humans), the safety margins would be approximately 3400 times when comparing the exposure in animals to man.