2.1 Important Dosage and Administration Information

• Lidocaine hydrochloride injection is not recommended for intrathecal use.
• Avoid use of lidocaine hydrochloride injection solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [ see Warnings and Precautions (5.3)].
• Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit. Lidocaine hydrochloride injection is a clear, colorless 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 injection is not recommended because of insufficient data on the clinical use of such mixtures.

Administration Precautions

• Lidocaine hydrochloride 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 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 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 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 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 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 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 [ seeWarnings and Precautions (5.10)].

2.2 Recommended Concentrations and Dosages of lidocaine hydrochloride injection in Adults

The dosage of lidocaine hydrochloride 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 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

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.

2.6 Maximum Recommended Dosage

Adults

For normal healthy adults, 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.

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 [ see Pregnancy (8.1)].

Pediatric Patients

A maximum dose of lidocaine hydrochloride 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).

5.1 Dose-Related Toxicity

The safety and effectiveness of lidocaine hydrochloride 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's state of consciousness should be performed after injection of lidocaine hydrochloride 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 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 injection solution and administer fractional (incremental) doses when feasible.

Injection of repeated doses of lidocaine hydrochloride 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 [ see Drug Interactions (7.5)]. 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 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 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 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

5.5 Risk of Adverse Reactions Due to Drug Interactions with lidocaine hydrochloride injection

Risk of Severe, Persistent Hypertension Due to Drug Interactions Between lidocaine hydrochloride injection and Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

Administration of lidocaine hydrochloride 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's hemodynamic status is essential [ see Drug Interactions (7.2)].

Risk of Severe, Persistent Hypertension or Cerebrovascular Accidents Due to Drug Interactions Between lidocaine hydrochloride injection and Ergot-Type Oxytocic Drugs

Concurrent administration of lidocaine hydrochloride injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of lidocaine hydrochloride injection concomitantly with ergot-type oxytocic drugs [ see Drug Interactions (7.3)].

Risk of Hypertension and Bradycardia Due to Drug Interactions Between lidocaine hydrochloride injection and Nonselective Beta-Adrenergic Antagonists

Administration of lidocaine hydrochloride 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's blood pressure and heart rate is essential [ see Drug Interactions (7.4)]

5.6 Allergic-Type Reactions to Sulfite in Lidocaine Hydrochloride Injection and Anaphylactic Reactions

Lidocaine hydrochloride injection without epinephrine does not contain sodium metabisulfite.

Anaphylactic reactions may occur following administration of lidocaine hydrochloride [ see Adverse Reactions (6)]. 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 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 nerve blocks near the vertebral column has resulted in underventilation or apnea ("Total or High Spinal"). A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia [ see Adverse Reactions (6)].

Aspirate for blood or cerebrospinal fluid (where applicable) before injecting lidocaine hydrochloride 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.

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 injection, especially with repeat doses [ see Use in Specific Populations (8.6)].

5.9 Risk of Use in Patients with Impaired Cardiovascular Function

Lidocaine hydrochloride injection 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.

5.12 Risk of Adverse Reactions with Use in the Head and Neck Area

Small doses of local anesthetics (e.g., lidocaine hydrochloride 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 intraarterial 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 injection blocks. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [ see Dosage and Administration (2.2)].

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 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 [ see Warnings and Precautions (5.14)]. 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.

5.16 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.

7.1 Local Anesthetics

The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with lidocaine hydrochloride injection cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [ see Warnings and Precautions (5.1)].

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

The administration of lidocaine hydrochloride 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 situation when concurrent therapy is necessary, careful monitoring of the patient’s hemodynamic status is essential [ see Warnings and Precautions (5.5)].

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 injection concomitantly with ergot-type oxytocic drugs [ see Warnings and Precautions (5.5)].

7.4 Nonselective Beta-Adrenergic Antagonists

Administration of lidocaine hydrochloride 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's blood pressure and heart rate is essential [ see Warnings and Precautions (5.5)].

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:

8.1 Pregnancy

Risk Summary

Available published data and decades of clinical use with lidocaine hydrochloride injection in pregnant women have not identified any drug associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone and cardiac function ( see Clinical Considerations).

In a published animal reproduction study, pregnant rats administered lidocaine by continuous subcutaneous infusion at a dose approximately 9.6 times the maximum recommended human dose (MRHD) of 500 mg in lidocaine hydrochloride injection during the period of organogenesis resulted in lower fetal body weights [ see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15%to 20%, respectively.

Clinical Considerations

Maternal adverse reactions

Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient’s legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable.

Labor or 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 (12.3)]. The incidence and degree of toxicity depend 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. However, dosage recommendations for spinal anesthesia are much lower than dosage recommendations for other major blocks.

Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has 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.

Data

Animal Data

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 hydrochloride.

In a published study, lidocaine administered to pregnant rats by continuous subcutaneous infusion during the period of organogenesis at 100, 250, and 500 mg/kg/day, did not produce any structural abnormalities, but did result in lower fetal weights at 500 mg/kg/day dose (approximately 9.6 times the maximum recommended human dose [MRHD] of 500 mg lidocaine on a mg/m2 basis) in the absence of maternal toxicity.

8.2 Lactation

Risk Summary

Published data report the presence of lidocaine and its metabolites in human milk in low amounts, along with poor oral bioavailability. There are no data on the effect of lidocaine on the breastfed infant or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lidocaine hydrochloride injection and any potential adverse effects on the breastfed child from lidocaine hydrochloride injection or from the underlying maternal condition.

8.4 Pediatric Use

Dosages in children should be reduced, commensurate with age, body weight and physical condition [ see Dosage and Administration (2.6)].

8.5 Geriatric Use

Elderly patients should be given reduced doses commensurate with their age and physical condition. [ see Dosage and Administration (2.6)].

8.6 Hepatic Impairment

Amide-type local anesthetics such as lidocaine are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with hepatic impairment treated with lidocaine hydrochloride injection, especially with repeat doses [ see Warnings and Precautions (5.8)]

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine hydrochloride required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6 mcg free base per mL.

12.3 Pharmacokinetics

Systemic plasma levels of lidocaine following lidocaine hydrochloride injection do not correlate with local efficacy.

Absorption

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

Distribution

The plasma binding of lidocaine hydrochloride 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 hydrochloride is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine hydrochloride crosses the blood-brain and placental barriers, presumably by passive diffusion.

Elimination

The elimination half-life of lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2 hours.

Metabolism

Lidocaine hydrochloride is metabolized rapidly by the liver, and 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 hydrochloride.

Excretion

Approximately 90% of lidocaine hydrochloride administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged by the kidneys. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline.

Specific Populations

Patients with Hepatic Impairment
Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine HCl kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction.

Patients with Renal Impairment

Renal dysfunction does not affect lidocaine hydrochloride kinetics but may increase the accumulation of metabolites.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Studies of lidocaine hydrochloride in animals to evaluate the carcinogenic potential have not been conducted.

Mutagenesis

Studies of lidocaine hydrochloride in animals to evaluate the mutagenic potential have not been conducted.

Impairment of Fertility

In a published study, female Sprague-Dawley rats were treated subcutaneously with lidocaine via osmotic pumps starting two weeks prior to mating, and reproductive effects were assessed. Rats dosed up to the high dose of 500 mg/kg/day (approximately 45 times the MRDD on a mg/m2 basis) showed no effects on copulatory rate, pregnancy rate, numbers of corpora lutea, or implantations.

17.1 Allergic Type Reactions

Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials [ seeContraindications (4), Warnings and Precautions (5.6), Adverse Reactions (6)].

17.3 Methemoglobinemia

Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to stop use and 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 [ see Warnings and Precautions (5.2)].

Manufactured by:
Anthea Pharma Private Limited
Hyderabad, 502307, India