Oxymetazoline Hydrochloride

Oxymetazoline hydrochloride cream is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults. Oxymetazoline hydrochloride cream is an alpha 1A adrenoceptor agonist indicated for the topical treatment of persistent facial erythema associated with rosacea in adults. ( 1 )

For topical use only. Oxymetazoline hydrochloride is not for oral, ophthalmic, or intravaginal use. Apply a pea-sized amount of oxymetazoline hydrochloride cream, once daily in a thin layer to cover the entire face (forehead, nose, each cheek, and chin) avoiding the eyes and lips. Wash hands immediately after applying oxymetazoline hydrochloride cream. Not for oral, ophthalmic, or intravaginal use. ( 2 ) Apply a pea-sized amount once daily in a thin layer to cover the entire face (forehead, nose, each cheek, and chin) avoiding the eyes and lips. ( 2 ) Wash hands after application. ( 2 )

Oxymetazoline hydrochloride cream, 1% is a white to off-white cream. Each gram of cream contains 10 mg (1%) oxymetazoline hydrochloride, equivalent to 8.8 mg (0.88%) of oxymetazoline free base. Cream, 1%. Each gram of cream contains 10 mg (1%) oxymetazoline hydrochloride, equivalent to 8.8 mg (0.88%) of oxymetazoline free base. ( 3 )

None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Alpha-adrenergic agonists as a class may impact blood pressure. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension or hypotension to seek medical care if their condition worsens. ( 5.1 ) Use with caution in patients with cerebral or coronary insufficiency, Raynaud's phenomenon, thromboangiitis obliterans, scleroderma, or Sjögren's syndrome and advise patients to seek medical care if signs and symptoms of potentiation of vascular insufficiency develop. ( 5.2 ) Advise patients to seek immediate medical care if signs and symptoms of acute narrow-angle glaucoma develop. ( 5.3 )

5.1 Potential Impacts on Cardiovascular Disease Alpha-adrenergic agonists may impact blood pressure. Oxymetazoline hydrochloride should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease, orthostatic hypotension, and uncontrolled hypertension or hypotension. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension to seek immediate medical care if their condition worsens.

5.2 Potentiation of Vascular Insufficiency Oxymetazoline hydrochloride should be used with caution in patients with cerebral or coronary insufficiency, Raynaud's phenomenon, thromboangiitis obliterans, scleroderma, or Sjögren's syndrome. Advise patients to seek immediate medical care if signs and symptoms of potentiation of vascular insufficiency develop.

5.3 Risk of Angle Closure Glaucoma Oxymetazoline hydrochloride may increase the risk of angle closure glaucoma in patients with narrow-angle glaucoma. Advise patients to seek immediate medical care if signs and symptoms of acute angle closure glaucoma develop.

7.1 Anti-hypertensives/Cardiac Glycosides Alpha-adrenergic agonists, as a class, may impact blood pressure. Caution in using drugs such as beta-blockers, anti-hypertensives and/or cardiac glycosides is advised. Caution should also be exercised in patients receiving alpha 1 adrenergic receptor antagonists such as in the treatment of cardiovascular disease, benign prostatic hypertrophy, or Raynaud's disease.

7.2 Monoamine Oxidase Inhibitors Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

Most common adverse reactions (incidence ≥ 1%) are application site dermatitis, worsening inflammatory lesions of rosacea, application site pruritis, application site erythema, and application site pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience Because clinical trials are conducted under 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. A total of 489 subjects with persistent facial erythema associated with rosacea were treated with oxymetazoline hydrochloride once daily for 4 weeks in 3 controlled clinical trials. An additional 440 subjects with persistent facial erythema associated with rosacea were also treated with oxymetazoline hydrochloride once daily for up to one year in a long-term (open-label) clinical trial. Adverse reactions that occurred in at least 1% of subjects treated with oxymetazoline hydrochloride through 4 weeks of treatment are presented in Table 1 below. Table 1: Adverse Reactions Reported by ≥ 1% of Subjects through 4 Weeks of Treatment in Controlled Clinical Trials Adverse Reaction Pooled Controlled Clinical Trials Oxymetazoline Hydrochloride Cream (N = 489) Vehicle Cream (N = 483) Application site dermatitis 9 (2%) 0 Worsening inflammatory lesions of rosacea 7 (1%) 1 (<1%) Application site pruritus 5 (1%) 4 (1%) Application site erythema 5 (1%) 2 (<1%) Application site pain 4 (1%) 1 (<1%) In the long-term (open-label) clinical trial, the rates of adverse reactions over a one-year treatment period were as follows: worsening inflammatory lesions of rosacea (3%), application site dermatitis (3%), application site pruritis (2%), application site pain (2%), and application site erythema (2%). Subjects with persistent erythema along with inflammatory lesions were allowed to use additional therapy for the inflammatory lesions of rosacea.

Oxymetazoline hydrochloride is not for oral use. If oral ingestion occurs, seek medical advice. Monitor patient closely and administer appropriate supportive measures as necessary. Accidental ingestion of topical solutions (nasal sprays) containing imidazoline derivatives (e.g., oxymetazoline) in children has resulted in serious adverse events requiring hospitalization, including nausea, vomiting, lethargy, tachycardia, decreased respiration, bradycardia, hypotension, hypertension, sedation, somnolence, mydriasis, stupor, hypothermia, drooling, and coma. Keep oxymetazoline hydrochloride out of reach of children.

Risk Summary There are no available data on oxymetazoline hydrochloride use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. A literature article describing intranasal decongestant use in pregnant women identified a potential association between second-trimester exposure to oxymetazoline (with no decongestant exposure in the first trimester) and renal collecting system anomalies [see Data ] . In animal reproduction studies, there were no adverse developmental effects observed after oral administration of oxymetazoline hydrochloride in pregnant rats and rabbits at systemic exposures up to 3 times and 73 times, respectively, the exposure associated with the maximum recommended human dose (MRHD) [see Data ] . The estimated background risks of major birth defects and miscarriage for the indicated population are 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 Fetal/Neonatal Adverse Reactions Following repeated use of oxymetazoline hydrochloride solution nasal spray for the treatment of nasal congestion at a dose 5 times higher than recommended, one case of fetal distress was reported in a 41-week pregnant patient. The fetal distress resolved hours later, prior to the delivery of the healthy infant. The anticipated exposures for the case are 8- to 18-fold higher than plasma exposures after topical administration of oxymetazoline hydrochloride. Data Human Data No adequate and well-controlled trials of oxymetazoline hydrochloride have been conducted in pregnant women. Across all clinical trials of oxymetazoline hydrochloride, two pregnancies were reported. One pregnancy resulted in the delivery of a healthy child. One pregnancy resulted in a spontaneous abortion, which was considered to be unrelated to the trial medication. A literature article summarizing the results of exploratory analyses of intranasal decongestant use during pregnancy identified a potential association between second-trimester exposure to oxymetazoline hydrochloride solution (with no decongestant exposure in the first trimester) and renal collecting system anomalies. Animal Data Effects on embryo-fetal development were evaluated in rats and rabbits following oral administration of oxymetazoline hydrochloride during the period of organogenesis. Oxymetazoline hydrochloride did not cause adverse effects to the fetus at oral doses up to 0.2 mg/kg/day in pregnant rats during the period of organogenesis (3 times the MRHD on an AUC comparison basis). Oxymetazoline hydrochloride did not cause adverse effects to the fetus at oral doses up to 1 mg/kg/day in pregnant rabbits during the period of organogenesis (73 times the MRHD on an AUC comparison basis). Maternal toxicity, such as decreased maternal body weight, was produced at the high dose of 1 mg/kg/day in pregnant rabbits and was associated with findings of delayed skeletal ossification. In a rat perinatal and postnatal development study, oxymetazoline hydrochloride was orally administered to pregnant rats once daily from gestation day 6 through lactation day 20. Maternal toxicity was produced at the high dose of 0.2 mg/kg/day (3 times the MRHD on an AUC comparison basis) in pregnant rats and was associated with an increase in pup mortality and reduced pup body weights. Delayed sexual maturation was noted at 0.1 and 0.2 mg/kg/day (2 times the MRHD and 3 times the MRHD on an AUC comparison basis, respectively). Oxymetazoline hydrochloride did not have any adverse effects on fetal development at a dose of 0.05 mg/kg/day (one-half of the MRHD on an AUC comparison basis).

Safety and effectiveness of oxymetazoline hydrochloride have not been established in pediatric patients below the age of 18 years.

One hundred and ninety-three subjects aged 65 years and older received treatment with oxymetazoline hydrochloride (n = 135) or vehicle (n = 58) in clinical trials. No overall differences in safety or effectiveness were observed between subjects ≥ 65 years of age and younger subjects, based on available data. Clinical studies of oxymetazoline hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Oxymetazoline hydrochloride cream, 1% contains oxymetazoline hydrochloride, an alpha 1A adrenoceptor agonist. Oxymetazoline hydrochloride is a white to off-white cream. It has a chemical name of 3-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-6-(1,1-dimethylethyl)-2,4-dimethyl-phenol hydrochloride and a molecular weight of 296.8. It is freely soluble in water and ethanol and has a partition coefficient of 0.1 in 1-octanol/water. The molecular formula of oxymetazoline HCl is C 16 H 25 CIN 2 O and its structural formula is: Each gram of oxymetazoline hydrochloride cream contains 10 mg (1%) oxymetazoline hydrochloride, equivalent to 8.8 mg (0.88%) of oxymetazoline free base. The cream contains the following inactive ingredients: butylated hydroxytoluene, ceteareth-6 (and) stearyl alcohol, ceteareth-25, cetostearyl alcohol, citric acid anhydrous, di-isopropyl adipate, edetate disodium, lanolin, medium chain triglycerides, methylparaben, oleyl alcohol super refined, phenoxyethanol, polyethylene glycol 300, polysorbate 60, propylparaben, purified water, sodium citrate dihydrate, and sorbitan monostearate. Chemical Structure

12.1 Mechanism of Action Oxymetazoline is an alpha 1A adrenoceptor agonist. Oxymetazoline acts as a vasoconstrictor.

12.2 Pharmacodynamics The pharmacodynamics of oxymetazoline hydrochloride has not been studied.

12.3 Pharmacokinetics Absorption The pharmacokinetics of oxymetazoline was evaluated following topical administration of oxymetazoline hydrochloride in a thin layer to cover the entire face in adult subjects with erythema associated with rosacea. The median weight of cream for each dose administration was 0.3 g. Plasma oxymetazoline concentrations were measurable in most of the subjects. Following the first dose application, the mean ± standard deviation (SD) peak concentrations (C max ) and area under the concentration-time curves from time 0 to 24 hours (AUC 0-24hr ) were 60.5 ± 53.9 pg/mL and 895 ±798 pg*hr/mL, respectively. Following once daily applications for 28 days, the mean ± SD C max and AUC 0-24hr were 66.4 ± 67.1 pg/mL and 1050 ± 992 pg*hr/mL, respectively. Following twice daily applications (twice the recommended frequency of application) for 28 days, the mean ± SD C max and AUC 0-24hr were 68.8 ± 61.1 pg/mL and 1530 ± 922 pg*hr/mL, respectively. Distribution An in vitro study demonstrated that oxymetazoline is 56.7% to 57.5% bound to human plasma proteins. Metabolism In vitro studies using human liver microsomes showed that oxymetazoline was minimally metabolized, generating mono-oxygenated and dehydrogenated products of oxymetazoline. The percentage of parent drug oxymetazoline remaining was 95.9% after a 120-minute incubation with human liver microsomes. Excretion The excretion of oxymetazoline following administration of oxymetazoline hydrochloride has not been characterized in humans. Drug Interaction In vitro studies using human liver microsomes demonstrated that oxymetazoline up to the tested concentration of 100 nM had no inhibition on the activities of the cytochrome P450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5. Treatment of cultured human hepatocytes with up to 100 nM oxymetazoline did not induce CYP1A2, CYP2B6, or CYP3A4.

Oxymetazoline is an alpha 1A adrenoceptor agonist. Oxymetazoline acts as a vasoconstrictor.

The pharmacodynamics of oxymetazoline hydrochloride has not been studied.

Absorption The pharmacokinetics of oxymetazoline was evaluated following topical administration of oxymetazoline hydrochloride in a thin layer to cover the entire face in adult subjects with erythema associated with rosacea. The median weight of cream for each dose administration was 0.3 g. Plasma oxymetazoline concentrations were measurable in most of the subjects. Following the first dose application, the mean ± standard deviation (SD) peak concentrations (C max ) and area under the concentration-time curves from time 0 to 24 hours (AUC 0-24hr ) were 60.5 ± 53.9 pg/mL and 895 ±798 pg*hr/mL, respectively. Following once daily applications for 28 days, the mean ± SD C max and AUC 0-24hr were 66.4 ± 67.1 pg/mL and 1050 ± 992 pg*hr/mL, respectively. Following twice daily applications (twice the recommended frequency of application) for 28 days, the mean ± SD C max and AUC 0-24hr were 68.8 ± 61.1 pg/mL and 1530 ± 922 pg*hr/mL, respectively. Distribution An in vitro study demonstrated that oxymetazoline is 56.7% to 57.5% bound to human plasma proteins. Metabolism In vitro studies using human liver microsomes showed that oxymetazoline was minimally metabolized, generating mono-oxygenated and dehydrogenated products of oxymetazoline. The percentage of parent drug oxymetazoline remaining was 95.9% after a 120-minute incubation with human liver microsomes. Excretion The excretion of oxymetazoline following administration of oxymetazoline hydrochloride has not been characterized in humans. Drug Interaction In vitro studies using human liver microsomes demonstrated that oxymetazoline up to the tested concentration of 100 nM had no inhibition on the activities of the cytochrome P450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5. Treatment of cultured human hepatocytes with up to 100 nM oxymetazoline did not induce CYP1A2, CYP2B6, or CYP3A4.

, Mutagenesis, Impairment of Fertility Oxymetazoline hydrochloride was not associated with an increased incidence of neoplastic or proliferative changes in transgenic mice given oral doses of 0.5, 1.0, or 2.5 mg/kg/day oxymetazoline hydrochloride for 6 months. Oxymetazoline hydrochloride revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and human lymphocyte chromosomal aberration assay) and one in vivo gentoxicity test (mouse micronucleus assay). Effects on fertility and early embryonic development were evaluated in rats following oral administration of 0.05, 0.1, or 0.2 mg/kg/day oxymetazoline hydrochloride prior to and during mating and through early pregnancy. Decreased number of corpora lutea and increased post-implantation losses were noted at 0.2 mg/kg/day oxymetazoline hydrochloride (3 times the MRHD on an AUC comparison basis). However, no treatment related effects on fertility or mating parameters were noted at 0.2 mg/kg/day oxymetazoline hydrochloride (3 times the MRHD on an AUC comparison basis).

17 PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use) . Important Administration Instructions Advise patients of the following: Oxymetazoline hydrochloride cream is for topical use only. Do not to apply oxymetazoline hydrochloride cream to irritated skin or open wounds. Avoid contact with the eyes and lips. Wash hands immediately after application. Keep oxymetazoline hydrochloride cream out of reach of children. Manufactured by: Sun Pharma Canada Inc., Brampton, Ontario, Canada L6T 1C1 Distributed by: Sun Pharmaceutical Industries, Inc., Cranbury, NJ 08512 Revised: December 2025 5217318 1225-01 57

Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].