FDA label 6bc7eb85-0a9a-3b56-e053-2991aa0a8215

5 WARNINGS AND PRECAUTIONS Risks with Neuraxial Administration: Local anesthetics should only be administered after insuring the immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. ( 5.1 ) ( 6 ) ( 10 ) Cardiovascular System Reactions: hypotension and bradycardia. ( 5.2 ) ( 6 ) ( 10 ) Central Nervous System Reactions: paresthesia, loss of sensitivity, motor weakness, paralysis, cauda equina syndrome and permanent neurological injury. ( 5.3 ) ( 6.2 ) ( 10 ) Allergic Reactions: in patients with a known hypersensitivity to the active substance or to other formulation ingredients. ( 5.4 ) ( 6.2 ) Chondrolysis : in intra-articular infusions in arthroscopic and other surgical procedures. ( 5.5 ) 5.1 Risks with Neuraxial Administration Local anesthetics should only be administered by clinicians who are well versed in diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Adverse Reaction (6) and Overdosage (10) ] . 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. The clinician should take the appropriate measures to avoid an intravascular injection [see Administration (2.2) ] . In addition, it is essential for the clinician to know how to recognize and treat undesirable effects, systemic toxicity and other complications. If signs of acute systemic toxicity or total spinal block are observed, the injection of the local anesthetic must be stopped immediately [see Overdosage (10) ]. 5.2 Cardiovascular System Reactions Hypotension and bradycardia are well known side effects of all local anesthetics [see Adverse Reaction (6) and Overdosage (10) ] . A serious, undesirable effect of spinal anesthesia is high or total spinal block, with consequent cardiovascular and respiratory depression. Cardiovascular depression is induced by an extended block of the sympathetic nervous system, which may induce severe hypotension and bradycardia to the point of cardiac arrest. Respiratory depression is induced by the block of the respiratory musculature and the diaphragm. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be accomplished after CLOROTEKAL injection. Patients over 65 years, particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of CLOROTEKAL. Blood pressure should, therefore, be carefully monitored after CLOROTEKAL injection. Hypotension may be controlled by vasoconstrictors in dosages depending on the severity of hypotension and response of treatment. 5.3 Central Nervous System Reactions Neurological damage may occur after spinal anesthesia, manifesting as paresthesia, loss of sensitivity, motor weakness, paralysis, cauda equina syndrome. Occasionally these symptoms persist and can be permanent. Carefully evaluate patients with underlying neuromuscular disorders and consider the risk-benefit ratio prior to treatment. Carefully and constantly monitor cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness after local anesthetic injection. Restlessness, headache, anxiety, incoherent speech problems, lightheadedness, paresthesia, numbness and tingling of the mouth and lips, hearing problems, tinnitus, dizziness, blurred vision, convulsions, loss of consciousness tremors, depression, or drowsiness may be early warning signs of central nervous system toxicity [see Adverse Reactions (6.2) and Overdosage (10) ] . 5.4 Risk of Hypersensitivity Reactions CLOROTEKAL is contraindicated in patients hypersensitive to drugs of the PABA ester group. Allergic type reactions may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylaxis type symptomatology (including severe hypotension). Cross sensitivity among members of the ester-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established [see Adverse Reactions (6.2) ] . 5.5 Risk of Chondrolysis in Patients Receiving Intraarticular Injections Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness, and loss of motion, can be variable, but may begin as early as the 2 nd month after surgery. Currently, there is no effective treatment for chondrolysis. Patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. 5.6 Conditions Requiring Special Attention Some patients require special attention in order to reduce the risk of serious undesirable effects, even when locoregional anesthesia constitutes the optimum choice for the surgical intervention: Patients with total or partial heart block, since local anesthetics can suppress myocardial conduction Patients with high grade cardiac decompensation Patients with advanced liver or kidney damage [see Use in Specific Populations (8.6) ] Elderly patients and patients in poor general condition [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] Patients with genetic deficiency of plasma cholinesterase [ see Adverse Reactions (6) and Clinical Pharmacology (12.3) ] Patients taking anticoagulants or with congenital or acquired bleeding disorder Patients with severe anemia Because ester-type local anesthetics are hydrolyzed by plasma cholinesterase produced by the liver, use CLOROTEKAL cautiously in patients with advanced hepatic disease [see Use in Specific Populations (8.6) ]. Local anesthetics should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Cardiovascular System Reactions [see Warnings and Precautions (5.2) ] Central Nervous System Reactions [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] Adverse reactions reported with an incidence greater than or equal to 2 % following CLOROTEKAL administration are procedural pain, injection site pain and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer's U.S. phone number which should be a toll-free number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. During clinical investigations, a total of 111 patients undergoing various surgical procedures received CLOROTEKAL. Patients were administered a dose ranging from 30 to 50 mg of CLOROTEKAL. Taking into consideration data for 50 mg dose only, the most common adverse reaction in these studies, (incidence greater than or equal to 10%) following CLOROTEKAL administration was procedural pain. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following CLOROTEKAL administration were injection site pain and hypotension. The less common/rare adverse reactions (incidence less than 2%) following CLOROTEKAL administration were anesthetic complication, nausea, headache and hyperglycemia. Adverse Reactions Reported in Controlled Trials All Treatment Emergent Adverse Reactions in clinical studies comparing CLOROTEKAL (dose 50 mg) to Bupivacaine 0.5% (10 mg) are shown in Table 1. Table 1: Treatment-Emergent Adverse Events (TEAEs) in Controlled Trials (Phase 2 and Phase 3 Trials) System Organ Class Preferred Term Chloroprocaine 10 mg/mL (50 mg) N = 81 n (%) Bupivacaine 0.5% (10 mg) N=64 n (%) Note: Subjects are summarized according to the product they actually received. The denominator for calculating the proportions is the number of subjects in each treatment group and overall. TEAE = Treatment-Emergent Adverse Event (both related and non-related). Subjects with Any TEAE 17 (21.0) 3 (4.7) Injury, Poisoning and Procedural Complications 13 (16.0) 0 (0.0) Procedural Pain 13 (16.0) 0 (0.0) General Disorders and Administration Site Conditions 3 (3.7) 2 (3.1) Injection Site Pain 3 (3.7) 2 (3.1) Vascular Disorders 4 (4.9) 1 (1.6) Hypotension 4 (4.9) 1 (1.6) 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval of use of CLOROTEKAL outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure ( Table 2 ). Table 2: Post-Marketing Reports of Adverse Drug Reactions System Organ Class Adverse Reactions Immune System Disorders Hypersensivity (including urticaria, pruritus, erythema multiforme, angioedema with possible airway obstruction), anaphylaxis Injury, Poisoning and Procedural Complications Urinary retention postoperative, delayed recovery from anesthesia, anesthetic complication General Disorders and Administration Site Conditions Feeling hot, malaise Musculoskeletal and Connective Tissue Disorders Back pain, groin pain, pain in extremity Nervous System Disorders Restlessness, paresthesia, dizziness, tremor, seizure, oral paresthesia, oral hypoesthesia, hearing disability, visual disorders, blurred vision, tinnitus, speech disorders, loss of consciousness, peripheral neuropathy, somnolence, unintentional total spinal block, urinary and anal incontinence, perineal disorder and sexual dysfunction, arachnoiditis, akathisia, presyncope, burning sensation, spinal cord injury, cauda equina syndrome, hypoesthesia, dysesthesia, motor dysfunction, myoclonus, phantom pain, headache Eye Disorders Diplopia, photophobia Cardiac Disorders Bradycardia, tachycardia, arrhythmia, myocardial depression, cardiac arrest Psychiatric Disorders Anxiety Vascular Disorders Hypertension, hypotension Respiratory, Thoracic and Mediastinal Disorders Respiratory depression, dyspnea, respiratory arrest Gastrointestinal Disorders Nausea, vomiting

<table width="75%"> <caption>Table 1: Treatment-Emergent Adverse Events (TEAEs) in Controlled Trials (Phase 2 and Phase 3 Trials)</caption> <col width="46%" align="left" valign="top"/> <col width="27%" align="center" valign="top"/> <col width="27%" align="center" valign="top"/> <thead> <tr> <th>System Organ Class Preferred Term </th> <th>Chloroprocaine 10 mg/mL (50 mg) N = 81 n (%) </th> <th>Bupivacaine 0.5% (10 mg) N=64 n (%) </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3">Note: Subjects are summarized according to the product they actually received. The denominator for calculating the proportions is the number of subjects in each treatment group and overall. TEAE = Treatment-Emergent Adverse Event (both related and non-related). </td> </tr> </tfoot> <tbody> <tr> <td>Subjects with Any TEAE</td> <td>17 (21.0)</td> <td>3 (4.7)</td> </tr> <tr> <td>Injury, Poisoning and Procedural Complications</td> <td>13 (16.0)</td> <td>0 (0.0)</td> </tr> <tr> <td> Procedural Pain</td> <td>13 (16.0)</td> <td>0 (0.0)</td> </tr> <tr> <td>General Disorders and Administration Site Conditions</td> <td>3 (3.7)</td> <td>2 (3.1)</td> </tr> <tr> <td> Injection Site Pain</td> <td>3 (3.7)</td> <td>2 (3.1)</td> </tr> <tr> <td>Vascular Disorders</td> <td>4 (4.9)</td> <td>1 (1.6)</td> </tr> <tr> <td> Hypotension</td> <td>4 (4.9)</td> <td>1 (1.6)</td> </tr> </tbody> </table>

<table width="75%"> <caption>Table 2: Post-Marketing Reports of Adverse Drug Reactions</caption> <col width="50%" align="left" valign="top"/> <col width="50%" align="left" valign="top"/> <thead> <tr> <th align="center" styleCode="Lrule Rrule" valign="middle">System Organ Class</th> <th align="center" styleCode="Rrule" valign="middle">Adverse Reactions</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule" valign="middle"> <content styleCode="italics">Immune System Disorders</content> </td> <td styleCode="Rrule">Hypersensivity (including urticaria, pruritus, erythema multiforme, angioedema with possible airway obstruction), anaphylaxis</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="italics">Injury, Poisoning and Procedural Complications</content> </td> <td styleCode="Rrule">Urinary retention postoperative, delayed recovery from anesthesia, anesthetic complication</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="italics">General Disorders and Administration Site Conditions</content> </td> <td styleCode="Rrule">Feeling hot, malaise</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="italics">Musculoskeletal and Connective Tissue Disorders</content> </td> <td styleCode="Rrule">Back pain, groin pain, pain in extremity</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="italics">Nervous System Disorders</content> </td> <td styleCode="Rrule">Restlessness, paresthesia, dizziness, tremor, seizure, oral paresthesia, oral hypoesthesia, hearing disability, visual disorders, blurred vision, tinnitus, speech disorders, loss of consciousness, peripheral neuropathy, somnolence, unintentional total spinal block, urinary and anal incontinence, perineal disorder and sexual dysfunction, arachnoiditis, akathisia, presyncope, burning sensation, spinal cord injury, cauda equina syndrome, hypoesthesia, dysesthesia, motor dysfunction, myoclonus, phantom pain, headache</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="italics">Eye Disorders </content> </td> <td styleCode="Rrule">Diplopia, photophobia</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="italics">Cardiac Disorders</content> </td> <td styleCode="Rrule">Bradycardia, tachycardia, arrhythmia, myocardial depression, cardiac arrest</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="italics">Psychiatric Disorders</content> </td> <td styleCode="Rrule">Anxiety</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="italics">Vascular Disorders</content> </td> <td styleCode="Rrule">Hypertension, hypotension</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="italics">Respiratory, Thoracic and Mediastinal Disorders</content> </td> <td styleCode="Rrule">Respiratory depression, dyspnea, respiratory arrest</td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="italics">Gastrointestinal Disorders</content> </td> <td styleCode="Rrule">Nausea, vomiting</td> </tr> </tbody> </table>