Chloroprocaine Hydrochloride Ophthalmic Gel

IHEEZO TM is indicated for ocular surface anesthesia. IHEEZO TM is an ester anesthetic indicated for ocular surface anesthesia. ( 1 )

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. The recommended dose of IHEEZO TM is 3 drops applied topically to the ocular surface in the area of the planned procedure. ( 2 ) IHEEZO TM may be reapplied as needed to maintain anesthetic effect. ( 2 )

IHEEZO TM (chloroprocaine hydrochloride ophthalmic gel) 3% contains 24 mg of chloroprocaine hydrochloride per vial (800 mg of gel). IHEEZO TM (chloroprocaine hydrochloride ophthalmic gel) 3% contains 24 mg of chloroprocaine hydrochloride per vial (800 mg). Clear, colorless to light yellow gel in single‑patient‑use vial. ( 3 )

IHEEZO TM is contraindicated in patients with a history of hypersensitivity to any component of this preparation. IHEEZO TM is contraindicated in patients with a history of hypersensitivity to any component of this preparation. ( 4 )

5 WARNINGS AND PRECAUTIONS Not for Injection or Intraocular Administration ( 5.1 ). Corneal Injury Due to Insensitivity ( 5.2 ). Corneal Opacification ( 5.3 ) For Administration by Healthcare Provider : IHEEZO TM is not intended for patient self-administration ( 5.5 ).

5.1 Not for Injection or Intraocular Administration IHEEZO TM should not be injected or intraocularly administered.

5.2 Corneal Injury Due to Insensitivity 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.

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

5.4 Risk of Contamination Do not touch the dropper tip to any surface as this may contaminate the gel.

5.5 For Administration by Healthcare Provider IHEEZO TM is indicated for administration under the direct supervision of a healthcare provider. IHEEZO TM is not intended for patient self-administration.

5.1 Not for Injection or Intraocular Administration IHEEZO TM should not be injected or intraocularly administered.

5.2 Corneal Injury Due to Insensitivity 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.

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

5.4 Risk of Contamination Do not touch the dropper tip to any surface as this may contaminate the gel.

5.5 For Administration by Healthcare Provider IHEEZO TM is indicated for administration under the direct supervision of a healthcare provider. IHEEZO TM is not intended for patient self-administration.

Most common adverse reaction is mydriasis (approximately 25%) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Harrow at 844.446.6979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience 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 IHEEZO TM Placebo Preferred Term N=151 n (%) N=50 n (%) Mydriasis 39 (26%) 1 (2%) Conjunctival hyperemia 16 (11%) 6 (12%) Eye irritation 9 (6%) 2 (4%)

6.1 Clinical Trials Experience 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 IHEEZO TM Placebo Preferred Term N=151 n (%) N=50 n (%) Mydriasis 39 (26%) 1 (2%) Conjunctival hyperemia 16 (11%) 6 (12%) Eye irritation 9 (6%) 2 (4%)

8.1 Pregnancy 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.

8.2 Lactation 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 .

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

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

8.1 Pregnancy 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.

8.2 Lactation 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 .

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

8.5 Geriatric Use 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 13 H 19 ClN 2 O 2 ·HCl. It is represented by the following structural formula: IHEEZO TM contains: 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. chemstru

12.1 Mechanism of Action 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.

12.3 Pharmacokinetics 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.

12.1 Mechanism of Action 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.

12.3 Pharmacokinetics 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.