IHEEZO TM is indicated for ocular surface anesthesia.

{ "type": "p", "children": [], "text": "IHEEZO\n TM is indicated for ocular surface anesthesia.\n " }

The recommended dose of IHEEZO TM is 3 drops applied topically to the ocular surface in the area of the planned procedure. IHEEZO TM may be reapplied as needed to maintain anesthetic effect.

{ "type": "p", "children": [], "text": "The recommended dose of IHEEZO\n TM is 3 drops applied topically to the ocular surface in the area of the planned procedure. IHEEZO\n TM may be reapplied as needed to maintain anesthetic effect.\n " }

IHEEZO TM (chloroprocaine hydrochloride ophthalmic gel) 3% contains 24 mg of chloroprocaine hydrochloride per vial (800 mg of gel).

{ "type": "p", "children": [], "text": "IHEEZO\n TM (chloroprocaine hydrochloride ophthalmic gel) 3% contains 24 mg of chloroprocaine hydrochloride per vial (800 mg of gel).\n " }

IHEEZO TM is contraindicated in patients with a history of hypersensitivity to any component of this preparation.

{ "type": "p", "children": [], "text": "IHEEZO\n TM is contraindicated in patients with a history of hypersensitivity to any component of this preparation.\n " }

IHEEZO TM should not be injected or intraocularly administered.

Patients should not touch the eye for at least 10 to 20 minutes after using anesthetic as accidental injuries can occur due to insensitivity of the eye.

Prolonged use of a topical ocular anesthetic may produce permanent corneal opacification and ulceration with accompanying visual loss.

Do not touch the dropper tip to any surface as this may contaminate the gel.

IHEEZO TM is indicated for administration under the direct supervision of a healthcare provider. IHEEZO TM is not intended for patient self-administration.

Because clinical trials 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 trials of another drug and may not reflect the rates observed in practice.

The data described below reflect 201 patients undergoing various surgical ocular procedures in two placebo-controlled trials (Study 1 and Study 2). Patients in Study 1 were randomized to receive a single instillation of 3 drops of IHEEZO TM or placebo. Patients in Study 2 were randomized to receive a single or multiple instillations of 1, 3 or 3+3 drops of IHEEZO TM or placebo.

The most common adverse reactions in these studies, (incidence greater than or equal to 5%) following IHEEZO TM administration were mydriasis, conjunctival hyperemia and eye irritation.

Adverse Reactions Reported in Controlled Trials

Table 1. Adverse Reactions in 5% or more of IHEEZO TM Treated Patients in Studies 1 and 2

<div class="scrollingtable"><table border="0" width="100%"> <tbody class="Headless"> <tr class="First"> <td></td><td><span class="Bold">IHEEZO <span class="Sup">TM</span></span></td><td><span class="Bold">Placebo</span></td> </tr> <tr> <td><span class="Bold">Preferred Term</span></td><td> <p class="First"> <span class="Bold">N=151</span> </p> <p> <span class="Bold">n (%)</span> </p> </td><td> <p class="First"> <span class="Bold">N=50</span> </p> <p> <span class="Bold">n (%)</span> </p> </td> </tr> <tr> <td>Mydriasis</td><td>39 (26%)</td><td> <p class="First">1 (2%)</p> </td> </tr> <tr> <td>Conjunctival hyperemia</td><td>16 (11%)</td><td>6 (12%)</td> </tr> <tr class="Last"> <td>Eye irritation</td><td>9 (6%)</td><td>2 (4%)</td> </tr> </tbody> </table></div>

Risk Summary

There are no adequate and well-controlled studies of IHEEZO TM use in pregnant women to inform a drug associated risk. There are no animal reproduction studies for chloroprocaine.

Risk Summary

There are no data on the presence of chloroprocaine in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for IHEEZO TM and any potential adverse effects on the breastfed infant from IHEEZO TM.

The safety and effectiveness of IHEEZO TM have not been established in pediatric patients.

No overall differences in safety or effectiveness of IHEEZO TM have been observed between elderly and younger patients.

IHEEZO TM is a sterile, single-patient‑use ophthalmic gel preparation for topical ocular anesthesia containing chloroprocaine hydrochloride as the active pharmaceutical ingredient. Chloroprocaine hydrochloride is an ester anesthetic. It is a water-soluble white crystalline powder and its chemical name is 2-(Diethylamino)ethyl 4‑amino-2-chlorobenzoate monohydrochloride. The molecular weight is 307.22 and the molecular formula is C 13H 19ClN 2O 2·HCl. It is represented by the following structural formula:

{ "type": "p", "children": [], "text": "IHEEZO\n TM is a sterile, single-patient‑use ophthalmic gel preparation for topical ocular anesthesia containing chloroprocaine hydrochloride as the active pharmaceutical ingredient. Chloroprocaine hydrochloride is an ester anesthetic. It is a water-soluble white crystalline powder and its chemical name is 2-(Diethylamino)ethyl 4‑amino-2-chlorobenzoate monohydrochloride. The molecular weight is 307.22 and the molecular formula is C\n 13H\n 19ClN\n 2O\n 2·HCl. It is represented by the following structural formula:\n " }

IHEEZO TM contains:

{ "type": "p", "children": [], "text": "IHEEZO\n TM contains:\n " }

Active: 30 mg of chloroprocaine hydrochloride (equivalent to 26 mg of chloroprocaine) per gram of gel.

{ "type": "p", "children": [], "text": "Active: 30 mg of chloroprocaine hydrochloride (equivalent to 26 mg of chloroprocaine) per gram of gel. " }

Inactive ingredients: Hydroxyethyl Cellulose (HEC), and Water for Injection. The pH may be adjusted to 3.0 to 5.0 with Hydrochloric Acid. This product does not contain an antimicrobial preservative.

{ "type": "p", "children": [], "text": "Inactive ingredients: Hydroxyethyl Cellulose (HEC), and Water for Injection. The pH may be adjusted to 3.0 to 5.0 with Hydrochloric Acid. This product does not contain an antimicrobial preservative." }

12.1 Mechanism of Action

Chloroprocaine, like other local anesthetics, blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

The systemic exposure to chloroprocaine following topical ocular administration of IHEEZO TM has not been studied.

Elimination

Metabolism

Chloroprocaine is metabolized by plasma pseudocholinesterases and nonspecific esterases in ocular tissues. Chloroprocaine is rapidly metabolized in plasma by hydrolysis of the ester linkage by pseudocholinesterase. The hydrolysis of chloroprocaine results in the production of ß-diethylaminoethanol and 2-chloro-4-aminobenzoic acid, which inhibits the action of the sulfonamides.

Excretion

Chloroprocaine plasma half-life in vitro is approximately 25 seconds in adults and approximately 43 seconds in neonates. The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH.

Carcinogenesis

Long-term studies in animals to evaluate carcinogenic potential of chloroprocaine have not been conducted.

Mutagenesis

2-chloroprocaine and the main metabolite, ACBA, were negative in the in vitro bacterial reverse mutation test (Ames assay) and the in vitro chromosome aberrations assay.

Impairment of Fertility

Studies in animals to evaluate the impairment of fertility have not been conducted with chloroprocaine.

Study 1 (NCT04779606) and Study 2 (NCT04753710) were randomized, double-blinded placebo-controlled studies conducted to evaluate the efficacy, safety, and local tolerability of IHEEZO TM in 145 healthy volunteers.

In Study 1, 85 healthy male and female were randomized in a 4:1 ratio to receive a single ocular instillation of IHEEZO TM (N=68) or placebo (N=17). The double blinded treatment included a IHEEZO TM or a placebo dose of 3 drops instilled at 1 minute ± 15 seconds intervals in the right eye of each volunteer. The median age was 39 years (range 19 to 55 years); 59% female and 41% male.

In Study 2, 60 healthy male and female were randomized (40:20) to receive single or multiple ocular instillations of IHEEZO TM dose of 3 drops in the right eye. The median age was 25 years (range 18 to 59 years); 54% female ad 46% male.

The efficacy in Study 1 and 2 was determined by proportion of patients achieving full conjunctival anesthesia evaluated by conjunctival pinching, 5 minutes after administration.

Efficacy results of Study 1

The proportion of subjects with successful anesthesia was 90% in IHEEZO TM group and 12% in the placebo group (p<0.01). The median time for the IHEEZO TM group achieving anesthesia was 0.67 minutes. The median duration of anesthesia was 14.3 minutes.

Efficacy results of Study 2

The proportion of subjects with successful anesthesia was 95% in the IHEEZO TM group and 20% in the placebo group (p<0.01). The median time for the IHEEZO TM group achieving anesthesia was 0.67 minutes. The median duration of anesthesia was 19.3 minutes.

Study 3 (NCT04685538) was a randomized, prospective, multi-center, active-controlled, observer-masked study conducted to evaluate the efficacy and safety of IHEEZO TM (N=166) versus tetracaine ophthalmic solution 0.5% (N=172) in patients undergoing cataract surgery.

The primary endpoint was defined as the proportion of patients in each treatment group gaining successful anesthesia without any supplementation. On average, patients needed 1-1.5 minutes to obtain sufficient anesthesia to successfully perform the surgical procedure which lasted on average 22 minutes.

No patient treated with IHEEZO TM required supplemental treatment to complete the intended surgical procedure.

IHEEZO TM (chloroprocaine hydrochloride ophthalmic gel) 3% is supplied as a sterile, clear, colorless to light yellow gel in a single-patient‑use vial. Each single‑patient‑use vial contains 24 mg chloroprocaine in 800 mg of gel.

{ "type": "p", "children": [], "text": "IHEEZO\n TM (chloroprocaine hydrochloride ophthalmic gel) 3% is supplied as a sterile, clear, colorless to light yellow gel in a single-patient‑use vial. Each single‑patient‑use vial contains 24 mg chloroprocaine in 800 mg of gel.\n " }

Aluminum pouch containing 1 LDPE single-patient‑use vial of IHEEZO TM.

{ "type": "p", "children": [], "text": "Aluminum pouch containing 1 LDPE single-patient‑use vial of IHEEZO\n TM.\n " }

The outer surface of the vial is not sterile.

{ "type": "p", "children": [], "text": "The outer surface of the vial is not sterile." }

NDC 82667-300-01 Package of 1 unit of 1.25 mL single-patient‑use vial (800 mg filled)

{ "type": "p", "children": [], "text": "NDC 82667-300-01 Package of 1 unit of 1.25 mL single-patient‑use vial (800 mg filled)" }

NDC 82667-300-10 Package of 10 units of 1.25 mL single-patient‑use vials (800 mg filled)

{ "type": "p", "children": [], "text": "NDC 82667-300-10 Package of 10 units of 1.25 mL single-patient‑use vials (800 mg filled)" }

NDC 82667-300-00 Sample package of 1 unit of 1.25 mL single-patient-use vial (800 mg filled)

{ "type": "p", "children": [], "text": "NDC 82667-300-00 Sample package of 1 unit of 1.25 mL single-patient-use vial (800 mg filled)" }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Store at 15°C to 25°C (59°F to 77°F).

{ "type": "p", "children": [], "text": "Store at 15°C to 25°C (59°F to 77°F)." }

Discard after use.

{ "type": "p", "children": [], "text": "Discard after use." }

Eye Care Precaution

{ "type": "p", "children": [], "text": "\nEye Care Precaution\n" }

Do not touch the dropper tip to any surface as this may contaminate the gel.

{ "type": "p", "children": [], "text": "Do not touch the dropper tip to any surface as this may contaminate the gel." }

Advise patients that their eyes will be insensitive for up to 20 minutes due to the effect of the anesthetic, and that care should be taken to avoid accidental injuries.

{ "type": "p", "children": [], "text": "Advise patients that their eyes will be insensitive for up to 20 minutes due to the effect of the anesthetic, and that care should be taken to avoid accidental injuries." }

Manufactured by

{ "type": "p", "children": [], "text": "Manufactured by" }

Laboratoire Unither

{ "type": "p", "children": [], "text": "Laboratoire Unither" }

1 Rue de l’Arquerie

{ "type": "p", "children": [], "text": "1 Rue de l’Arquerie" }

50200 COUTANCES

{ "type": "p", "children": [], "text": "50200 COUTANCES" }

France

{ "type": "p", "children": [], "text": "France" }

Distributed by

{ "type": "p", "children": [], "text": "Distributed by" }

Harrow Eye, LLC

{ "type": "p", "children": [], "text": "Harrow Eye, LLC" }

102 Woodmont Blvd. Suite 610

{ "type": "p", "children": [], "text": "102 Woodmont Blvd. Suite 610" }

Nashville, TN 37205

{ "type": "p", "children": [], "text": "Nashville, TN 37205" }

USA

{ "type": "p", "children": [], "text": "USA" }

NDC 82667-300-01 Sterile Rx Only

{ "type": "p", "children": [], "text": "NDC 82667-300-01 Sterile Rx Only" }

Iheezo TM

{ "type": "p", "children": [], "text": "Iheezo\n TM\n" }

(chloroprocaine hydrochloride ophthalmic gel) 3%

{ "type": "p", "children": [], "text": "(chloroprocaine hydrochloride ophthalmic gel) 3%" }

For topical ophthalmic use

{ "type": "p", "children": [], "text": "For topical ophthalmic use" }

Contains no preservatives. 1 Vial 800 mg each HARROW ®

{ "type": "p", "children": [], "text": "Contains no preservatives. 1 Vial 800 mg each HARROW\n ®\n" }

NDC 82667-300-01

{ "type": "p", "children": [], "text": "NDC 82667-300-01" }

Iheezo TM

{ "type": "p", "children": [], "text": "Iheezo\n TM\n" }

(chloroprocaine hydrochloride ophthalmic gel) 3%

{ "type": "p", "children": [], "text": "(chloroprocaine hydrochloride ophthalmic gel) 3%" }

To be administered by physician only.

{ "type": "p", "children": [], "text": "To be administered by physician only." }

Single-Patient-Use Vial

{ "type": "p", "children": [], "text": "Single-Patient-Use Vial" }

Discard unused portion.

{ "type": "p", "children": [], "text": "Discard unused portion." }

For topical ophthalmic use.

{ "type": "p", "children": [], "text": "For topical ophthalmic use." }

Contains no preservatives.

{ "type": "p", "children": [], "text": "Contains no preservatives." }

Sterile (outer surface of the vial not sterile)

{ "type": "p", "children": [], "text": "Sterile (outer surface of the vial not sterile)" }

LOT: 1234

{ "type": "p", "children": [], "text": "LOT: 1234" }

EXP: YYYY-MM

{ "type": "p", "children": [], "text": "EXP: YYYY-MM" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Vial 800 mg

{ "type": "p", "children": [], "text": "Vial 800 mg" }

NDC 82667-300-00

{ "type": "p", "children": [], "text": "NDC 82667-300-00" }

Professional sample - Not for sale Sterile Rx Only

{ "type": "p", "children": [], "text": "Professional sample - Not for sale Sterile Rx Only" }

Iheezo TM

{ "type": "p", "children": [], "text": "Iheezo\n TM\n" }

(chloroprocaine hydrochloride ophthalmic gel) 3%

{ "type": "p", "children": [], "text": "(chloroprocaine hydrochloride ophthalmic gel) 3%" }

For topical ophthalmic use

{ "type": "p", "children": [], "text": "For topical ophthalmic use" }

Contains no preservatives. 1 Vial 800 mg each HARROW ®

{ "type": "p", "children": [], "text": "Contains no preservatives. 1 Vial 800 mg each HARROW\n ®\n" }

CLOROTEKAL® (chloroprocaine hydrochloride) is indicated for intrathecal injection for the production of subarachnoid block (spinal anesthesia) in adults undergoing surgical procedures. Indicated procedures include those suitable for CLOROTEKAL®'s short duration of action.

{ "type": "p", "children": [], "text": "CLOROTEKAL® (chloroprocaine hydrochloride) is indicated for intrathecal injection for the production of subarachnoid block (spinal anesthesia) in adults undergoing surgical procedures. Indicated procedures include those suitable for CLOROTEKAL®'s short duration of action." }

CLOROTEKAL® must only be administered by clinicians with the necessary knowledge and experience in the intrathecal anesthesia administration. The equipment, drugs, and personnel capable of dealing with an emergency, e.g. maintaining the patency of the airways and administering oxygen, must be immediately available, because in rare cases severe reactions, sometimes with a fatal outcome, have been reported after using local anesthetics, even in the absence of individual hypersensitivity in the patient's case history.

Not for epidural administration.

Monitor vital signs during dural puncture and provide oxygen via face mask or nasal cannula. Slowly inject the entire dose, while monitoring the patient's vital signs.

In general, the following points should be taken into consideration:

The extent and degree of spinal anesthesia depend upon several factors including dosage, specific gravity of the anesthetic solution, volume of solution used, force of injection, level of puncture, and position of the patient during and immediately after injection.

To obtain an effective block to the T 10 level with one single administration in an adult of average height and weight (approximately 70 kg), the recommended dose is 50 mg.

Doses above 50 mg have not been adequately tested for efficacy and safety.

CLOROTEKAL® is supplied as a single-dose sterile, clear, colorless solution in a Type I (USP) glass ampule that provides 50 mg of chloroprocaine hydrochloride in 5 mL aqueous solution (concentration: 10 mg/mL) equivalent to 44.05 mg/5 mL (8.81 mg/mL) chloroprocaine.

{ "type": "p", "children": [], "text": "CLOROTEKAL® is supplied as a single-dose sterile, clear, colorless solution in a Type I (USP) glass ampule that provides 50 mg of chloroprocaine hydrochloride in 5 mL aqueous solution (concentration: 10 mg/mL) equivalent to 44.05 mg/5 mL (8.81 mg/mL) chloroprocaine." }

{ "type": "ul", "children": [ "CLOROTEKAL® is contraindicated in patients with a known hypersensitivity to the active substance, medicinal products of the PABA (para-aminobenzoic acid) ester group, other ester-type local anesthetics or to any of the excipients [see Risk of Hypersensitivity Reactions (5.4)] \n", "General and specific contraindications to spinal anesthesia regardless of the local anesthetic used, should be taken into account (e.g., decompensated cardiac insufficiency, hypovolemic shock, coagulopathy)", "Intravenous regional anesthesia (the anesthetic agent is introduced into the limb and allowed to set in while tourniquets retain the agent within the desired area)", "Serious problems with cardiac conduction", "Local infection at the site of proposed lumbar puncture", "Septicemia" ], "text": "" }

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)].

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.

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)].

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)].

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.

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:

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.

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.

<div class="scrollingtable"><table> <caption> <span>Table 1: Treatment-Emergent Adverse Events (TEAEs) in Controlled Trials (Phase 2 and Phase 3 Trials)</span> </caption> <col/> <col/> <col/> <thead> <tr class="First Last"> <th valign="top">System Organ Class <br/>Preferred Term </th><th align="center" valign="top">Chloroprocaine 10 mg/mL <br/>(50 mg) <br/>N = 81 <br/>n (%) </th><th align="center" valign="top">Bupivacaine 0.5% <br/>(10 mg) <br/>N=64 <br/>n (%) </th> </tr> </thead> <tfoot> <tr class="First Last"> <td colspan="3" valign="top">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. <br/>TEAE = Treatment-Emergent Adverse Event (both related and non-related). </td> </tr> </tfoot> <tbody> <tr class="First"> <td valign="top">Subjects with Any TEAE</td><td align="center" valign="top"> 17 (21.0)</td><td align="center" valign="top"> 3 (4.7)</td> </tr> <tr> <td valign="top">Injury, Poisoning and Procedural Complications</td><td align="center" valign="top"> 13 (16.0)</td><td align="center" valign="top"> 0 (0.0)</td> </tr> <tr> <td valign="top">Procedural Pain</td><td align="center" valign="top"> 13 (16.0)</td><td align="center" valign="top"> 0 (0.0)</td> </tr> <tr> <td valign="top">General Disorders and Administration Site Conditions</td><td align="center" valign="top"> 3 (3.7)</td><td align="center" valign="top"> 2 (3.1)</td> </tr> <tr> <td valign="top">Injection Site Pain</td><td align="center" valign="top"> 3 (3.7)</td><td align="center" valign="top"> 2 (3.1)</td> </tr> <tr> <td valign="top">Vascular Disorders</td><td align="center" valign="top"> 4 (4.9)</td><td align="center" valign="top"> 1 (1.6)</td> </tr> <tr class="Last"> <td valign="top">Hypotension</td><td align="center" valign="top"> 4 (4.9)</td><td align="center" valign="top"> 1 (1.6)</td> </tr> </tbody> </table></div>

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).

<div class="scrollingtable"><table> <caption> <span>Table 2: Post-Marketing Reports of Adverse Drug Reactions</span> </caption> <col/> <col/> <thead> <tr class="First Last"> <th align="center" class="Botrule Lrule Rrule Toprule">System Organ Class</th><th align="center" class="Botrule Lrule Rrule Toprule">Adverse Reactions</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Immune System Disorders</span></td><td class="Botrule Lrule Rrule Toprule" valign="top">Hypersensivity (including urticaria, pruritus, erythema multiforme, angioedema with possible airway obstruction), anaphylaxis</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Injury, Poisoning and Procedural Complications</span></td><td class="Botrule Lrule Rrule Toprule" valign="top">Urinary retention postoperative, delayed recovery from anesthesia, anesthetic complication</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">General Disorders and Administration Site Conditions</span></td><td class="Botrule Lrule Rrule Toprule" valign="top">Feeling hot, malaise</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Musculoskeletal and Connective Tissue Disorders</span></td><td class="Botrule Lrule Rrule Toprule" valign="top">Back pain, groin pain, pain in extremity</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Nervous System Disorders</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">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> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Eye Disorders </span></td><td class="Botrule Lrule Rrule Toprule" valign="top">Diplopia, photophobia</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Cardiac Disorders</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Bradycardia, tachycardia, arrhythmia, myocardial depression, cardiac arrest</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Psychiatric Disorders</span></td><td class="Botrule Lrule Rrule Toprule" valign="top">Anxiety</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Vascular Disorders</span></td><td class="Botrule Lrule Rrule Toprule" valign="top">Hypertension, hypotension</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Respiratory, Thoracic and Mediastinal Disorders</span></td><td class="Botrule Lrule Rrule Toprule" valign="top">Respiratory depression, dyspnea, respiratory arrest</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Gastrointestinal Disorders</span></td><td class="Botrule Lrule Rrule Toprule" valign="top">Nausea, vomiting</td> </tr> </tbody> </table></div>

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.

{ "type": "p", "children": [], "text": "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." }

The para-aminobenzoic acid metabolite of chloroprocaine inhibits the action of sulfonamides. Therefore, avoid use in any condition in which a sulfonamide drug is being employed [see Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "The para-aminobenzoic acid metabolite of chloroprocaine inhibits the action of sulfonamides. Therefore, avoid use in any condition in which a sulfonamide drug is being employed [see Clinical Pharmacology (12.3)]. " }

No studies have been performed on interactions between chloroprocaine and class III antiarrhythmics (e.g., amiodarone). Carefully monitor these patients for cardiovascular effects.

{ "type": "p", "children": [], "text": "No studies have been performed on interactions between chloroprocaine and class III antiarrhythmics (e.g., amiodarone). Carefully monitor these patients for cardiovascular effects." }

The combination of various local anesthetics may result in additive effects affecting the cardiovascular system and the central nervous system. Monitor these patients for signs and symptoms of local anesthetic toxicity.

{ "type": "p", "children": [], "text": "The combination of various local anesthetics may result in additive effects affecting the cardiovascular system and the central nervous system. Monitor these patients for signs and symptoms of local anesthetic toxicity." }

Risk Summary

The limited available data with chloroprocaine use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. There are no animal reproduction studies for chloroprocaine. There are risks to the mother and the fetus associated with use of chloroprocaine during labor and delivery (see Clinical Considerations).

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

Clinical Considerations

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.

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.

Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable.

Risk Summary

There are no data on the presence of chloroprocaine in human milk, the effects on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CLOROTEKAL® and any potential adverse effects on the breastfed infant from CLOROTEKAL® or from the underlying maternal condition.

Safety and effectiveness in pediatric patient have not been established.

Patients over 65 years, particularly those with hypertension, may be at increased risk of developing hypotension while undergoing spinal anesthesia with CLOROTEKAL®.

Clinical studies of CLOROTEKAL® did not include sufficient numbers of subjects 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general an elderly patient will have greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions (5) and Clinical Pharmacology (12.3)].

Since ester-type local anesthetics are hydrolyzed by plasma cholinesterase produced by the liver, the risk of toxic reactions might be greater in patients with advanced hepatic disease [see Clinical Pharmacology (12.3)].

This drug and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions might be greater in patients with impaired renal function [see Clinical Pharmacology (12.3)].

Management of Local Anesthetic Emergencies: 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 injection. At the first sign of change, administration of CLOROTEKAL® must be stopped and oxygen should be administered [see Warning and Precautions (5.1)].

The first step in the management of convulsions, as well as underventilation or apnea, consists of immediate attention to the maintenance of a patient airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate or a benzodiazepine may be administered intravenously; the clinician should be familiar, prior to the use of anesthetics, with appropriate anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Recovery has been reported after prolonged resuscitative efforts. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patient's airway or if prolonged ventilatory support (assisted or controlled) is indicated.

CLOROTEKAL® is a sterile non pyrogenic local anesthetic.

{ "type": "p", "children": [], "text": "CLOROTEKAL® is a sterile non pyrogenic local anesthetic." }

The active ingredient in CLOROTEKAL® is chloroprocaine hydrochloride (benzoic acid, 4-amino-2-chloro-2-(diethylamino) ethyl ester, monohydrochloride), an ester local anesthetic, which is represented by the following structural formula:

{ "type": "p", "children": [], "text": "The active ingredient in CLOROTEKAL® is chloroprocaine hydrochloride (benzoic acid, 4-amino-2-chloro-2-(diethylamino) ethyl ester, monohydrochloride), an ester local anesthetic, which is represented by the following structural formula:" }

1 mL of solution for injection contains 10 mg of chloroprocaine hydrochloride, equivalent to 44.05 mg/5 mL (8.81 mg/mL) chloroprocaine. It also contains the following inactive ingredients: hydrochloric acid 1N (for pH adjustment), sodium chloride, water for injection. The pH of the solution is between 3.0 and 4.0. The osmolality of the solution is 270 – 300 mOsm/kg.

{ "type": "p", "children": [], "text": "1 mL of solution for injection contains 10 mg of chloroprocaine hydrochloride, equivalent to 44.05 mg/5 mL (8.81 mg/mL) chloroprocaine. It also contains the following inactive ingredients: hydrochloric acid 1N (for pH adjustment), sodium chloride, water for injection. The pH of the solution is between 3.0 and 4.0. The osmolality of the solution is 270 – 300 mOsm/kg." }

Chloroprocaine, like other local anesthetics, blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, with toxic blood concentrations myocardial contractility may be depressed and peripheral vasodilation may occur, leading to decreased cardiac output and arterial blood pressure.

Following systemic absorption, toxic blood concentrations of local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation may be manifested as restlessness, tremors and shivering, which may progress to convulsions. Depression and coma may occur, possibly progressing ultimately to respiratory arrest.

However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior stage of central nervous system stimulation.

The rate of systemic absorption of local anesthetic drugs is dependent upon the total dose concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic injection.

The onset of action with chloroprocaine is rapid (usually 6 to 12 minutes), and the duration of anesthesia, depending upon the amount used and the route of administration.

Local anesthetics appear to cross the placenta by passive diffusion. However, the rate and degree of diffusion varies considerably among the different drugs as governed by: (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility.

Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, since only the free, unbound drug is available for placental transfer. Thus, drugs with the highest protein binding capacity may have the lowest fetal/maternal ratios. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.

Distribution

Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of administration, and the age of the patient.

Chloroprocaine plasma half-life in vitro is about 25 seconds, whereas the apparent half-life in vivo was found to be 3.1±1.6 min (range 1.5 to 6.4 min) in maternal plasma after intrapartum epidural anesthesia.

Metabolism

Chloroprocaine is rapidly metabolized in plasma by hydrolysis of the ester linkage by pseudocholinesterase. The hydrolysis of chloroprocaine results in the production of ß-diethylaminoethanol and 2-chloro-4-aminobenzoic acid, which inhibits the action of the sulfonamides [see Drug Interactions (7)].

Excretion

The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH.

Pharmacokinetic after intrathecal administration

Plasma concentrations of chloroprocaine and 2-chloro-4-aminobenzoic acid (ACBA) after intrathecal administration of 50 mg dose of CLOROTEKAL® are reported in Table 3.

<div class="scrollingtable"><table> <caption> <span>Table 3 - PK Variables: Plasma Concentrations (ng/mL) of chloroprocaine and ACBA</span> </caption> <col/> <col/> <col/> <thead> <tr class="First"> <th class="Lrule Rrule Toprule" valign="top">Analyte</th><th align="center" class="Lrule Rrule Toprule" valign="top">chloroprocaine</th><th align="center" class="Lrule Rrule Toprule" valign="top">ACBA</th> </tr> <tr> <th class="Lrule Rrule Toprule" valign="top">Dose group</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">50 mg</th><th align="center" class="Lrule Rrule Toprule" valign="top">50 mg</th> </tr> <tr class="Last"> <th class="Lrule Rrule" valign="top"></th><th>N=15</th><th align="center" class="Lrule Rrule Toprule" valign="top">N=15</th> </tr> </thead> <tfoot> <tr class="First Last"> <td colspan="3" valign="top"> <span class="Italics">Mean ± SD is shown; BLQL: below the quantification limit (4.0 ng/mL)</span></td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Lrule Rrule Toprule" valign="top"> <span class="Bold">Pre-dose (0)</span></td><td align="center" class="Lrule Rrule Toprule" valign="top"> BLQL</td><td align="center" class="Lrule Rrule Toprule" valign="top"> BLQL</td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <span class="Bold">5 min post-dose</span></td><td align="center" class="Lrule Rrule Toprule" valign="top"> BLQL</td><td align="center" class="Lrule Rrule Toprule" valign="top"> 24.9±20.3</td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <span class="Bold">10 min post-dose</span></td><td align="center" class="Lrule Rrule Toprule" valign="top"> BLQL</td><td align="center" class="Lrule Rrule Toprule" valign="top"> 75.8±67.6</td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <span class="Bold">30 min post-dose</span></td><td align="center" class="Lrule Rrule Toprule" valign="top"> BLQL</td><td align="center" class="Lrule Rrule Toprule" valign="top"> 97.6±61.7</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule" valign="top"> <span class="Bold">60 min post-dose</span></td><td align="center" class="Lrule Rrule Toprule" valign="top"> BLQL</td><td align="center" class="Lrule Rrule Toprule" valign="top"> 78.4±48.4</td> </tr> </tbody> </table></div>

Specific Populations

Renal Impairment

Chloroprocaine is known to be substantially excreted by the kidney [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Carcinogenesis

Long-term studies in animals to evaluate carcinogenic potential of chloroprocaine have not been conducted.

Mutagenesis

2-chloroprocaine and the main metabolite, ACBA, were negative in the in vitro bacterial reverse mutation test (Ames assay) and the in vitro chromosome aberrations assay.

Impairment of Fertility

Studies in animals to evaluate the impairment of fertility have not been conducted with chloroprocaine.

A Phase 2 single-center, prospective, randomized, observer-blind study evaluated the efficacy and the tolerability of chloroprocaine 30, 40, and 50 mg after spinal injection in 45 patients (27 males and 18 females) undergoing short duration (< 40 minutes) lower limb surgery. The mean age was 41 years (range 19 to 63).

Efficacy was determined by proportion of patients who were able to complete the surgical procedure without the need for supplementary intravenous analgesic or sedation drugs.

Efficacy results

Neither rescue anesthesia nor rescue analgesia was required for subjects randomized to chloroprocaine 50 mg. Three subjects in the 30 mg dose group and three subjects in the 40 mg dose group required intraoperative rescue medications. Duration data such as time from injection to surgery end, etc., for the chloroprocaine 50 mg-administered subjects follow:

<div class="scrollingtable"><table> <caption> <span>Table 4 – Duration Data for Chloroprocaine 50 mg Subjects in Minutes (N = 15)</span> </caption> <col/> <col/> <col/> <col/> <col/> <thead> <tr class="First Last"> <th class="Botrule Lrule Rrule Toprule" valign="top"></th><th>Mean</th><th class="Botrule Lrule Rrule Toprule" valign="top">Median</th><th class="Botrule Lrule Rrule Toprule" valign="top">Minimum</th><th class="Botrule Lrule Rrule Toprule" valign="top">Maximum</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Time from injection to surgery start</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 22</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 20</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 11</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 42</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Time from injection to surgery end</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 41</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 40</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 24</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 60</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Time from injection to resolution of motor block</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 100</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 104</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 56</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 146</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Time from surgery start to surgery finish</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 20</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 20</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 5</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 40</td> </tr> </tbody> </table></div>

The maximum surgical duration in the 50 mg dose group was 40 minutes and 93% (14 of 15) of the 50 mg dose group had surgical procedures ≤ 30 minutes.

A Phase 3, multicenter, prospective, randomized, observer-blind study evaluated the safety and the efficacy of 50 mg of chloroprocaine 10 mg/mL in intrathecal anesthesia versus 10 mg of bupivacaine 0.5%, in 130 patients (69 males and 61 females) undergoing short duration (< 40 minutes) low abdominal surgery (gynecological or urological) and lower limb surgery that required T10 metameric level of sensory block and identical anesthesia procedures.

The mean age was 45 years (range 18 to 78) in the chloroprocaine group and 51 years (range 20 to 79) in the bupivacaine group. Each patient received a single dose of anesthetic (50 mg of chloroprocaine or 10 mg of bupivacaine) according to the randomization plan. Sixty-six subjects were randomized to the chloroprocaine group. Sixty-four subjects were randomized to the bupivacaine group.

Efficacy was determined by proportion of patients who were able to complete the surgical procedure without the need for rescue intravenous analgesic or sedation drugs.

Efficacy results

Six of 66 subjects (9%) in the chloroprocaine group required rescue compared to 6 of 64 (9%) in the bupivacaine group. Duration data such as time from injection to surgery end, etc., for the chloroprocaine-administered subjects follow:

<div class="scrollingtable"><table> <caption> <span>Table 5 – Duration Data in Minutes (N = 66)</span> </caption> <col/> <col/> <col/> <col/> <col/> <thead> <tr class="First Last"> <th class="Botrule Lrule Rrule Toprule" valign="top"></th><th>Mean</th><th class="Botrule Lrule Rrule Toprule" valign="top">Median</th><th class="Botrule Lrule Rrule Toprule" valign="top">Minimum</th><th class="Botrule Lrule Rrule Toprule" valign="top">Maximum</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Time from injection to surgery start</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 16</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 15</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 3</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 42</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Time from injection to surgery end</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 39</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 34</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 9</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 90</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> Time from injection to resolution of motor block</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 101</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 100</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 40</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 194</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> Time from surgery start to surgery finish</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 23</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 20</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 3</td><td class="Botrule Lrule Rrule Toprule" valign="top"> 78</td> </tr> </tbody> </table></div>

Only two subjects had surgical procedures lasting over 60 minutes, and both required intraoperative rescue medications.

Handling

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Inform patients in advance that chloroprocaine-containing products can cause temporary loss of sensation or motor activity, usually in the lower half of the body, following proper administration of spinal anesthesia.

{ "type": "p", "children": [], "text": "Inform patients in advance that chloroprocaine-containing products can cause temporary loss of sensation or motor activity, usually in the lower half of the body, following proper administration of spinal anesthesia. " }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Clorotekal® is a registered trademark of Sintetica S.A.

{ "type": "p", "children": [], "text": "Clorotekal® is a registered trademark of Sintetica S.A." }

Manufactured by:Sintetica S.A.Switzerland

{ "type": "p", "children": [], "text": "Manufactured by:Sintetica S.A.Switzerland" }

Manufactured for: B. Braun Medical Inc. Bethlehem, PA 18018-3524 USA1-800-227-2862

{ "type": "p", "children": [], "text": "Manufactured for:\nB. Braun Medical Inc.\nBethlehem, PA 18018-3524 USA1-800-227-2862" }

Made in Switzerland

{ "type": "p", "children": [], "text": "Made in Switzerland" }

LD-578-1

{ "type": "p", "children": [], "text": "LD-578-1" }

NDC 0264-7055-05REF D7055

{ "type": "p", "children": [], "text": "NDC 0264-7055-05REF D7055" }

Clorotekal®

{ "type": "p", "children": [], "text": "\nClorotekal®\n" }

(Chloroprocaine HCl Injection, USP)

{ "type": "p", "children": [], "text": "(Chloroprocaine HCl Injection, USP) " }

50 mg/5 mL (10 mg/mL)

{ "type": "p", "children": [], "text": "\n50 mg/5 mL\n(10 mg/mL) " }

LD-579-1

{ "type": "p", "children": [], "text": "LD-579-1" }

Rx OnlyInjectionFor Intrathecal Use Only 1 mL contains 10 mg Chloroprocaine HCI, equal to 8.81 mg Chloroprocaine base, Sodium Chloride, Hydrochloric Acid 1N, Water for Injection. 5 mL Single Dose Ampule. Discard Unused Portion. See package insert for dosage information

{ "type": "p", "children": [], "text": "\nRx OnlyInjectionFor Intrathecal Use Only\n1 mL contains 10 mg Chloroprocaine HCI, equal to 8.81 mg Chloroprocaine base, Sodium Chloride, Hydrochloric Acid 1N, Water for Injection. 5 mL Single Dose Ampule. Discard Unused Portion. See package insert for dosage information" }

68699 01

{ "type": "p", "children": [], "text": "68699 01" }

LOT

{ "type": "p", "children": [], "text": "LOT" }

EXP

{ "type": "p", "children": [], "text": "EXP" }

1%

{ "type": "p", "children": [], "text": "\n1%\n" }

NDC 0264-7055-10REF D7055

{ "type": "p", "children": [], "text": "NDC 0264-7055-10REF D7055" }

Clorotekal®

{ "type": "p", "children": [], "text": "\nClorotekal®\n" }

(Chloroprocaine HCl Injection, USP)

{ "type": "p", "children": [], "text": "(Chloroprocaine HCl Injection, USP)" }

50 mg/5 mL (10 mg/mL)

{ "type": "p", "children": [], "text": "\n50 mg/5 mL\n(10 mg/mL) " }

Injection For Intrathecal Use Only

{ "type": "p", "children": [], "text": "\nInjection For Intrathecal Use Only \n" }

Usual Dose: See Package Insert for Dosage Information

{ "type": "p", "children": [], "text": "Usual Dose: See Package Insert for Dosage Information " }

Each mL contains: 10 mg Chloroprocaine HCl, equivalent to 8.81 mg Chloroprocaine base, Sodium Chloride, Hydrochloric Acid 1N, Water for Injection.

{ "type": "p", "children": [], "text": "Each mL contains: 10 mg Chloroprocaine HCl, equivalent to 8.81 mg Chloroprocaine base, Sodium Chloride, Hydrochloric Acid 1N, Water for Injection. " }

1%

{ "type": "p", "children": [], "text": "\n1%\n" }

Rx Only 10 Single Dose Ampules x 5 mL Discard Unused Portion

{ "type": "p", "children": [], "text": "\nRx Only\n10 Single Dose Ampules x 5 mL Discard Unused Portion " }

GTIN (01)LOT (10)EXPIRYSERIAL (21)

{ "type": "p", "children": [], "text": "GTIN (01)LOT (10)EXPIRYSERIAL (21)" }

Do not refrigerate or freeze. Store at 20°C to 25°C (68°F to 77°F)[See USP Controlled Room Temperature]. Retain in carton until time of use. Protect from light. Read the package Insert Labeling before use. Keep out of the reach and sight of children. Use immediately after first opening, for single use only. Any unused solution should be discarded.

{ "type": "p", "children": [], "text": "Do not refrigerate or freeze. Store at 20°C to 25°C (68°F to 77°F)[See USP Controlled Room Temperature]. Retain in carton until time of use. Protect from light. Read the package Insert Labeling before use. Keep out of the reach and sight of children. Use immediately after first opening, for single use only. Any unused solution should be discarded." }

Manufactured for: B. Braun Medical Inc.Bethlehem, PA 18018-3524 USA1-800-227-2862Made in Switzerland.

{ "type": "p", "children": [], "text": "\nManufactured for:\nB. Braun Medical Inc.Bethlehem, PA 18018-3524 USA1-800-227-2862Made in Switzerland." }

Manufactured by: Sintetica S.A. Switzerland

{ "type": "p", "children": [], "text": "\nManufactured by:\nSintetica S.A. Switzerland" }

Clorotekal is a registered trademark of Sintetica S.A.

{ "type": "p", "children": [], "text": "Clorotekal is a registered trademark of Sintetica S.A." }

66699 03LD-580-3-A

{ "type": "p", "children": [], "text": "66699 03LD-580-3-A" }

{ "type": "", "children": [], "text": "" }

NDC 0264-7055-10REF D7055

{ "type": "p", "children": [], "text": "NDC 0264-7055-10REF D7055" }

Clorotekal®

{ "type": "p", "children": [], "text": "\nClorotekal®\n" }

(Chloroprocaine HCl Injection, USP)

{ "type": "p", "children": [], "text": "(Chloroprocaine HCl Injection, USP)" }

50 mg/5 mL (10 mg/mL)

{ "type": "p", "children": [], "text": "\n50 mg/5 mL\n(10 mg/mL) " }

Injection For Intrathecal Use Only

{ "type": "p", "children": [], "text": "\nInjection For Intrathecal Use Only \n" }

Usual Dose: See Package Insert for Dosage Information

{ "type": "p", "children": [], "text": "Usual Dose: See Package Insert for Dosage Information " }

Each mL contains: 10 mg Chloroprocaine HCl, equivalent to 8.81 mg Chloroprocaine base, Sodium Chloride, Hydrochloric Acid 1N, Water for Injection.

{ "type": "p", "children": [], "text": "Each mL contains: 10 mg Chloroprocaine HCl, equivalent to 8.81 mg Chloroprocaine base, Sodium Chloride, Hydrochloric Acid 1N, Water for Injection. " }

1%

{ "type": "p", "children": [], "text": "\n1%\n" }

Rx Only 10 Single Dose Ampules x 5 mL Discard Unused Portion

{ "type": "p", "children": [], "text": "\nRx Only\n10 Single Dose Ampules x 5 mL Discard Unused Portion " }

GTIN (01)LOT (10)EXPIRYSERIAL (21)

{ "type": "p", "children": [], "text": "GTIN (01)LOT (10)EXPIRYSERIAL (21)" }

Do not refrigerate or freeze. Store at 20°C to 25°C (68°F to 77°F)[See USP Controlled Room Temperature]. Retain in carton until time of use. Protect from light. Read the package Insert Labeling before use. Keep out of the reach and sight of children. Use immediately after first opening, for single use only. Any unused solution should be discarded.

{ "type": "p", "children": [], "text": "Do not refrigerate or freeze. Store at 20°C to 25°C (68°F to 77°F)[See USP Controlled Room Temperature]. Retain in carton until time of use. Protect from light. Read the package Insert Labeling before use. Keep out of the reach and sight of children. Use immediately after first opening, for single use only. Any unused solution should be discarded." }

Manufactured for: B. Braun Medical Inc.Bethlehem, PA 18018-3524 USA1-800-227-2862Made in Switzerland.

{ "type": "p", "children": [], "text": "\nManufactured for:\nB. Braun Medical Inc.Bethlehem, PA 18018-3524 USA1-800-227-2862Made in Switzerland." }

Manufactured by: Sintetica S.A. Switzerland

{ "type": "p", "children": [], "text": "\nManufactured by:\nSintetica S.A. Switzerland" }

Clorotekal is a registered trademark of Sintetica S.A.

{ "type": "p", "children": [], "text": "Clorotekal is a registered trademark of Sintetica S.A." }

66699 03LD-580-3-B

{ "type": "p", "children": [], "text": "66699 03LD-580-3-B" }

{ "type": "", "children": [], "text": "" }