{"adverse_reactions":["6 ADVERSE REACTIONS The most common adverse reaction was instillation site pain (incidence 24.5%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact American Genomics at 855-242-9559 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. In controlled trials, the most common adverse reaction with CYKLX was instillation site pain reported in 24.5% (70/286) of subjects, compared to 6.9% (14/203) of subjects in the placebo group."],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long term studies in animals have not been performed to evaluate carcinogenic potential. Mutagenesis Articaine hydrochloride did not show any potential to cause mutagenicity or genetic toxicity in five standard tests, including three in vitro tests (the nonmammalian Ames test, the mammalian Chinese hamster ovary chromosomal aberration test, and a mammalian gene mutation test with articaine HCl) and two in vivo mouse micronucleus tests (one with articaine and epinephrine 1:100,000 and one with articaine HCl alone). Impairment of Fertility Subcutaneous administration of articaine and epinephrine (1:100,000) produced no adverse effects on fertility in rats at doses up to 80 mg/kg/day (approximately 80 times the MRHOD based on body surface area)."],"clinical_pharmacology":["12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Articaine hydrochloride is an amide local anesthetic. Local anesthetics block the generation and 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 the affected nerve fibers. 12.3 Pharmacokinetics Following ocular administration of CYKLX (2 drops), the geometric mean (geometric CV%) maximum plasma concentration (C max ) is 5.4 ng/mL and total systemic exposure (AUC) is 5.1 ng*hr/mL. Absorption Articaine median (min, max) time to maximum plasma concentration (T max ) is 0.25 hour (0.25 – 1.03 hour) Distribution Approximately 60 to 80% of articaine HCl is bound to human serum albumin and γ-globulins at 37°C in vitro. Elimination Articaine estimated elimination half-life is 1.5 hours with an apparent clearance of 872 L/hr. Metabolism Articaine HCl is metabolized by plasma carboxyesterase to its primary metabolite, articainic acid, which is inactive. In vitro studies show that the human liver microsome P450 isoenzyme system metabolizes approximately 5% to 10% of available articaine with nearly quantitative conversion to articainic acid. Excretion Articaine is excreted primarily through urine with 53-57% of the administered dose eliminated in the first 24 hours following submucosal administration. Articainic acid is the primary metabolite in urine. A minor metabolite, articainic acid glucuronide, is also excreted in urine."],"clinical_studies":["14 CLINICAL STUDIES The efficacy of CYKLX was evaluated in two randomized, placebo-controlled, double masked, parallel-arm studies in 240 healthy subjects. A total of 120 subjects were randomized to CYKLX (2 drops 30 seconds apart) and 120 subjects were randomized to vehicle. More than two-thirds of subjects treated with CYKLX achieved ocular anesthesia at 5 minutes. The treatment effect (difference from placebo) was 65% in both studies (P<0.01)."],"contraindications":["4 CONTRAINDICATIONS CYKLX is contraindicated in patients with known hypersensitivity to any component of this preparation. CYKLX is contraindicated in patients with a hypersensitivity to any component of this preparation. ( 4 )"],"description":["11 DESCRIPTION CYKLX (articaine ophthalmic solution) 8% contains articaine, an amide local anesthetic. CYKLX is an aseptically prepared, sterile, clear and colorless solution for topical ophthalmic use with a pH range of 4.5- 5.0. The chemical name of articaine hydrochloride is methyl 4-methyl-3-[2-(propylamino)propionamido]-2-thiophenecarboxylate, monohydrochloride and the molecular formula is C 13 H 20 N 2 O 3 S∙HCl. The molecular weight of articaine hydrochloride is 320.84 g/mol, or 283.374 g/mol as articaine (free base). Articaine hydrochloride is represented by the following structural formula: Each mL of CYKLX contains 80 mg of articaine (equivalent to 90.2 mg articaine hydrochloride) as the active ingredient. Inactive ingredients: boric acid, edetate disodium dihydrate, glacial acetic acid, mannitol, sodium acetate trihydrate, water for injection. CYKLX does not contain an antimicrobial preservative. Chemical Structure"],"dosage_and_administration":["2 DOSAGE AND ADMINISTRATION The recommended dose of CYKLX is 2 drops applied 30 seconds apart to the ocular surface. The recommended dose of CYKLX is 2 drops applied 30 seconds apart to the ocular surface. ( 2 )"],"dosage_forms_and_strengths":["3 DOSAGE FORMS AND STRENGTHS Ophthalmic Solution: clear and colorless solution containing 8% articaine in single-dose vial. Ophthalmic Solution: 8% articaine in single-dose vial. ( 3 )"],"effective_time":"20260707","geriatric_use":["8.5 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger adult subjects."],"how_supplied":["16 HOW SUPPLIED/STORAGE AND HANDLING CYKLX 8%, is supplied as an aseptically prepared, sterile, clear and colorless solution for topical ophthalmic use contained in a low-density polyethylene, single-dose vial with a 0.4 mL fill. 5 single-dose vials are packaged into a foil pouch, with 10 foil pouches in a carton. NDC 87047-7852-01: Carton of 10 foil pouches, 50 single-dose vials. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F), not to exceed the expiration date printed on the carton and pouch. Store unopened single-dose vials in pouch until ready for use. Discard opened vial after use."],"id":"56125dc9-3deb-fd7d-e063-6394a90a1f5d","indications_and_usage":["1 INDICATIONS AND USAGE CYKLX is indicated for ocular surface anesthesia prior to ocular procedures and/or intraocular injections in adults and pediatric patients. CYKLX is an amide local anesthetic indicated for ocular surface anesthesia prior to ocular procedures and/or intraocular injections in adults and pediatric patients. ( 1 )"],"information_for_patients":["17 PATIENT COUNSELING INFORMATION Eye Care Precaution Do not touch the dropper tip to the eye, eyelids, or to any other surface as this may contaminate the product. Advise patients to avoid touching the eye for at least 10 to 20 minutes after using CYKLX as accidental injuries can occur due to insensitivity of the eye."],"mechanism_of_action":["12.1 Mechanism of Action Articaine hydrochloride is an amide local anesthetic. Local anesthetics block the generation and 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 the affected nerve fibers."],"nonclinical_toxicology":["13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long term studies in animals have not been performed to evaluate carcinogenic potential. Mutagenesis Articaine hydrochloride did not show any potential to cause mutagenicity or genetic toxicity in five standard tests, including three in vitro tests (the nonmammalian Ames test, the mammalian Chinese hamster ovary chromosomal aberration test, and a mammalian gene mutation test with articaine HCl) and two in vivo mouse micronucleus tests (one with articaine and epinephrine 1:100,000 and one with articaine HCl alone). Impairment of Fertility Subcutaneous administration of articaine and epinephrine (1:100,000) produced no adverse effects on fertility in rats at doses up to 80 mg/kg/day (approximately 80 times the MRHOD based on body surface area)."],"openfda":{},"overdosage":["10 OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution."],"package_label_principal_display_panel":["Manufactured by: Woodstock Sterile Solutions 2210 Lake Shore Drive Woodstock, IL 60098 Principal display panel"],"pediatric_use":["8.4 Pediatric Use The safety and effectiveness of CYKLX for ocular surface anesthesia prior to ocular procedures and/or intraocular injections have been established in pediatric patients. Use of CYKLX for this indication is supported by evidence from adequate and well-controlled studies in adults with additional safety data from a single active-controlled study in pediatric patients aged birth to 11 years old [see Clinical Studies (14) ] . A similar safety profile was observed between pediatric and adult patients."],"pharmacokinetics":["12.3 Pharmacokinetics Following ocular administration of CYKLX (2 drops), the geometric mean (geometric CV%) maximum plasma concentration (C max ) is 5.4 ng/mL and total systemic exposure (AUC) is 5.1 ng*hr/mL. Absorption Articaine median (min, max) time to maximum plasma concentration (T max ) is 0.25 hour (0.25 – 1.03 hour) Distribution Approximately 60 to 80% of articaine HCl is bound to human serum albumin and γ-globulins at 37°C in vitro. Elimination Articaine estimated elimination half-life is 1.5 hours with an apparent clearance of 872 L/hr. Metabolism Articaine HCl is metabolized by plasma carboxyesterase to its primary metabolite, articainic acid, which is inactive. In vitro studies show that the human liver microsome P450 isoenzyme system metabolizes approximately 5% to 10% of available articaine with nearly quantitative conversion to articainic acid. Excretion Articaine is excreted primarily through urine with 53-57% of the administered dose eliminated in the first 24 hours following submucosal administration. Articainic acid is the primary metabolite in urine. A minor metabolite, articainic acid glucuronide, is also excreted in urine."],"pregnancy":["8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women with CYKLX to inform a drug associated risk. In animal reproduction studies, subcutaneous administration of articaine hydrochloride and epinephrine (1:100,000) to rabbits throughout organogenesis resulted in maternal toxicity, embryofetal death and increased fetal skeletal variations at doses approximately 160 times the maximum recommended human ophthalmic dose (MRHOD) of CYKLX (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data Human Data No adequate and well-controlled trials of CYKLX have been conducted in pregnant women. Animal Data In embryo-fetal toxicity studies, subcutaneous administration of articaine hydrochloride and epinephrine (1:100,000) to pregnant rabbits throughout organogenesis produced maternal toxicity, including seizures, at doses of 80 mg/kg/day (approximately 160-fold higher than the bilateral maximum recommended human ophthalmic dose [MRHOD] of 9.6 mg, based on body surface area). Embryofetal death and skeletal malformations were observed at the same dose Articaine hydrochloride and epinephrine were not maternally toxic and did not produce adverse embryofetal effects in rats and rabbits at oral doses up to 40 mg/kg/day (approximately 40- and 80-fold higher than the MRHOD, respectively). In a pre-/ postnatal developmental study in rats, subcutaneous administration of articaine hydrochloride throughout gestation and lactation resulted in severe maternal toxicity, increased the number of stillbirths and adversely affected passive avoidance, a measure of learning, in pups at a dose of 80 mg/kg (approximately 80 times the MRHOD based on body surface area). A dose of 40 mg/kg (approximately 40 times the MRHOD based on body surface area) did not produce these effects."],"set_id":"60e89ad4-8b65-4049-82ba-f34d4836eac0","spl_product_data_elements":["CYKLX articaine hydrochloride BORIC ACID EDETATE DISODIUM ACETIC ACID MANNITOL SODIUM ACETATE ARTICAINE HYDROCHLORIDE ARTICAINE"],"storage_and_handling":["Storage and Handling: Store at 20°C to 25°C (68°F to 77°F), not to exceed the expiration date printed on the carton and pouch. Store unopened single-dose vials in pouch until ready for use. Discard opened vial after use."],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women with CYKLX to inform a drug associated risk. In animal reproduction studies, subcutaneous administration of articaine hydrochloride and epinephrine (1:100,000) to rabbits throughout organogenesis resulted in maternal toxicity, embryofetal death and increased fetal skeletal variations at doses approximately 160 times the maximum recommended human ophthalmic dose (MRHOD) of CYKLX (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data Human Data No adequate and well-controlled trials of CYKLX have been conducted in pregnant women. Animal Data In embryo-fetal toxicity studies, subcutaneous administration of articaine hydrochloride and epinephrine (1:100,000) to pregnant rabbits throughout organogenesis produced maternal toxicity, including seizures, at doses of 80 mg/kg/day (approximately 160-fold higher than the bilateral maximum recommended human ophthalmic dose [MRHOD] of 9.6 mg, based on body surface area). Embryofetal death and skeletal malformations were observed at the same dose Articaine hydrochloride and epinephrine were not maternally toxic and did not produce adverse embryofetal effects in rats and rabbits at oral doses up to 40 mg/kg/day (approximately 40- and 80-fold higher than the MRHOD, respectively). In a pre-/ postnatal developmental study in rats, subcutaneous administration of articaine hydrochloride throughout gestation and lactation resulted in severe maternal toxicity, increased the number of stillbirths and adversely affected passive avoidance, a measure of learning, in pups at a dose of 80 mg/kg (approximately 80 times the MRHOD based on body surface area). A dose of 40 mg/kg (approximately 40 times the MRHOD based on body surface area) did not produce these effects. 8.2 Lactation Risk Summary There is no information regarding the presence of CYKLX or its metabolites in human or animal milk, the effects on the breastfed infant, or the effects on milk production to inform risk of CYKLX to an infant during lactation. 8.4 Pediatric Use The safety and effectiveness of CYKLX for ocular surface anesthesia prior to ocular procedures and/or intraocular injections have been established in pediatric patients. Use of CYKLX for this indication is supported by evidence from adequate and well-controlled studies in adults with additional safety data from a single active-controlled study in pediatric patients aged birth to 11 years old [see Clinical Studies (14) ] . A similar safety profile was observed between pediatric and adult patients. 8.5 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger adult subjects."],"version":"5","warnings_and_cautions":["5 WARNINGS AND PRECAUTIONS CYKLX is not for injection or intraocular administration ( 5.1 ) 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 ( 5.2 ) Corneal Opacification : Prolonged use of topical ocular anesthetics may produce permanent corneal opacification and ulceration with accompanying visual loss. ( 5.3 ) Do not touch the dropper tip to the eye, eyelids, or any other surface as this may contaminate the solution ( 5.4 ) For Administration by Healthcare Provider : CYKLX is not intended for patient self-administration ( 5.5 ) 5.1 For Topical Ophthalmic Use CYKLX is not for injection or intraocular administration. 5.2 Corneal Injury Due to Insensitivity Patients should not touch the eye for at least 10 to 20 minutes after using CYKLX as accidental injuries can occur due to insensitivity of the eye. 5.3 Corneal Opacification Prolonged use of topical ocular anesthetics may produce permanent corneal opacification and ulceration with accompanying visual loss. 5.4 Risk of Contamination Do not touch the dropper tip to the eye, eyelids, or any other surface as this may contaminate the solution. 5.5 For Administration by Healthcare Provider CYKLX is indicated for administration under the direct supervision of a healthcare provider. CYKLX is not intended for patient self-administration."]}