PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of RHOFADE have not been established in pediatric patients below the age of 18 years.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The pharmacodynamics of RHOFADE has not been studied.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence 1%) are application site dermatitis, worsening inflammatory lesions of rosacea, application site pruritus, application site erythema, and application site pain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. total of 489 subjects with persistent facial erythema associated with rosacea were treated with RHOFADE once daily for weeks in controlled clinical trials. An additional 440 subjects with persistent facial erythema associated with rosacea were also treated with RHOFADE once daily for up to one year in long-term (open-label) clinical trial. Adverse reactions that occurred in at least 1% of subjects treated with RHOFADE through weeks of treatment are presented in Table below.Table 1: Adverse Reactions Reported by 1% of Subjects through Weeks of Treatment in Controlled Clinical Trials Adverse ReactionPooled Controlled Clinical TrialsRHOFADE Cream(N 489)Vehicle Cream(N 483)Application site dermatitis9 (2%)0Worsening inflammatory lesions of rosacea7 (1%)1 (<1%)Application site pruritus5 (1%)4 (1%)Application site erythema5 (1%)2 (<1%)Application site pain4 (1%)1 (<1%)In the long-term (open-label) clinical trial, the rates of adverse reactions over one-year treatment period were as follows: worsening inflammatory lesions of rosacea (3%), application site dermatitis (3%), application site pruritus (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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, 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 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Oxymetazoline is an alpha1A adrenoceptor agonist. Oxymetazoline acts as vasoconstrictor.. 12.2 Pharmacodynamics. The pharmacodynamics of RHOFADE has not been studied.. 12.3 Pharmacokinetics. AbsorptionThe pharmacokinetics of oxymetazoline was evaluated following topical administration of RHOFADE in 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 (Cmax) and area under the concentration-time curves from time to 24 hours (AUC0-24hr) were 60.5 +- 53.9 pg/mL and 895 +-798 pghr/mL, respectively. Following once daily applications for 28 days, the mean +- SD Cmax and AUC0-24hr were 66.4 +- 67.1 pg/mL and 1050 +- 992 pghr/mL, respectively. Following twice daily applications (twice the recommended frequency of application) for 28 days, the mean +- SD Cmax and AUC0-24hr were 68.8 +- 61.1 pg/mL and 1530 +- 922 pghr/mL, respectively.DistributionAn in vitro study demonstrated that oxymetazoline is 56.7% to 57.5% bound to human plasma proteins.MetabolismIn 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 120-minute incubation with human liver microsomes. ExcretionThe excretion of oxymetazoline following administration of RHOFADE has not been characterized in humans.Drug InteractionIn 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.

CLINICAL STUDIES SECTION.

6.1 Clinical Studies Experience. Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. total of 489 subjects with persistent facial erythema associated with rosacea were treated with RHOFADE once daily for weeks in controlled clinical trials. An additional 440 subjects with persistent facial erythema associated with rosacea were also treated with RHOFADE once daily for up to one year in long-term (open-label) clinical trial. Adverse reactions that occurred in at least 1% of subjects treated with RHOFADE through weeks of treatment are presented in Table below.Table 1: Adverse Reactions Reported by 1% of Subjects through Weeks of Treatment in Controlled Clinical Trials Adverse ReactionPooled Controlled Clinical TrialsRHOFADE Cream(N 489)Vehicle Cream(N 483)Application site dermatitis9 (2%)0Worsening inflammatory lesions of rosacea7 (1%)1 (<1%)Application site pruritus5 (1%)4 (1%)Application site erythema5 (1%)2 (<1%)Application site pain4 (1%)1 (<1%)In the long-term (open-label) clinical trial, the rates of adverse reactions over one-year treatment period were as follows: worsening inflammatory lesions of rosacea (3%), application site dermatitis (3%), application site pruritus (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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4). None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. RHOFADE (oxymetazoline hydrochloride) cream 1% contains oxymetazoline hydrochloride, an alpha1A adrenoceptor agonist. RHOFADE is white to off-white cream. It has chemical name of 3-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-6-(1,1-dimethylethyl)-2,4-dimethyl-phenol hydrochloride and molecular weight of 296.8. It is freely soluble in water and ethanol and has partition coefficient of 0.1 in 1-octanol/water. The molecular formula of oxymetazoline HCl is C16H25ClN2O and its structural formula is: Each gram of RHOFADE (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: sodium citrate dihydrate, citric acid anhydrous, disodium edetate dihydrate, butylated hydroxytoluene, anhydrous lanolin, medium chain triglycerides, diisopropyl adipate, oleyl alcohol, polyethylene glycol 300, PEG-6 stearate, glycol stearate, PEG-32 stearate, cetostearyl alcohol, ceteareth-6, stearyl alcohol, ceteareth-25, methylparaben, propylparaben, phenoxyethanol, and purified water.. The structural formula for RHOFADE (oxymetazoline hydrochloride) cream 1% contains oxymetazoline hydrochloride, an alpha1A adrenoceptor agonist. RHOFADE is white to off-white cream. It has chemical name of 3-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-6-(1,1-dimethylethyl)-2,4-dimethyl-phenol hydrochloride and molecular weight of 296.8. It is freely soluble in water and ethanol and has partition coefficient of 0.1 in 1-octanol/water. The molecular formula of oxymetazoline HCl is C16H25ClN2O.

OVERDOSAGE SECTION.

10 OVERDOSAGE. RHOFADE 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 RHOFADE out of reach of children.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For topical use only. RHOFADE is not for oral, ophthalmic, or intravaginal use.Prime the RHOFADE pump before using for the first time. To do so, with the pump in the upright position, repeatedly depress the actuator until cream is dispensed and then pump three times. Discard the cream from priming actuations. It is only necessary to prime the pump before the first dose. RHOFADE tubes do not require priming.Apply pea-sized amount of RHOFADE cream, once daily in thin layer to cover the entire face (forehead, nose, each cheek, and chin) avoiding the eyes and lips. Wash hands immediately after applying RHOFADE cream. Not for oral, ophthalmic, or intravaginal use. (2) Prime pump bottle before initial use and discard product from first three pumps. (2) Apply pea-sized amount once daily in thin layer to cover the entire face (forehead, nose, each cheek, and chin) avoiding the eyes and lips. (2) Wash hands after application. (2). Not for oral, ophthalmic, or intravaginal use. (2) Prime pump bottle before initial use and discard product from first three pumps. (2) Apply pea-sized amount once daily in thin layer to cover the entire face (forehead, nose, each cheek, and chin) avoiding the eyes and lips. (2) Wash hands after application. (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. RHOFADE (oxymetazoline hydrochloride) cream, 1% is 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).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Anti-hypertensives/ Cardiac Glycosides Alpha-adrenergic agonists, as 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 alpha1 adrenergic receptor antagonists such as in the treatment of cardiovascular disease, benign prostatic hypertrophy, or Raynauds disease.. 7.2 Monoamine Oxidase Inhibitors Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

GERIATRIC USE SECTION.

8.5 Geriatric Use. One hundred and ninety-three subjects aged 65 years and older received treatment with RHOFADE (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 RHOFADE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. RHOFADE (oxymetazoline hydrochloride) cream, 1%, is white to off-white cream. The product is available in laminated tube and an airless pump polypropylene bottle in the following packaging configurations, each with child-resistant closure:NDC 0023-5300-30 30 gram tubeNDC 0023-5300-60 60 gram tubeNDC 0023-5300-35 30 gram pump NDC 0023-5300-65 60 gram pump Storage: Store at 20C-25C (68F-77F); excursions permitted to 15C-30oC (59F-86oF) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. RHOFADE(TM) cream is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.. RHOFADE(TM) is an alpha1A adrenoceptor agonist indicated for the topical treatment of persistent facial erythema associated with rosacea in adults. (1).

INFORMATION FOR PATIENTS SECTION.

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 InstructionsAdvise patients of the following:RHOFADE is for topical use only. RHOFADE pumps require priming before initial use and discard product from the first three pumps. Do not to apply RHOFADE to irritated skin or open wounds. Avoid contact with the eyes and lips. Wash hands immediately after application. Keep RHOFADE out of reach of children.Distributed by: Allergan USA, Inc.Madison, NJ 07940 (C) 2018 Allergan. All rights reserved.All trademarks are the property of their respective owners.Patented. See www.allergan.com/patentsv1.0USPI5300PATIENT INFORMATIONRHOFADE(TM) (roe fayd)(oxymetazoline hydrochloride) creamImportant: RHOFADE cream is for skin (topical) use on the face only. Do not use RHOFADE cream in your eyes, mouth, or vagina.Keep RHOFADE cream out of the reach of children. Get medical help right away if you, child, or anyone else swallows RHOFADE cream.What is RHOFADE creamRHOFADE cream is prescription medicine used on the skin (topical) to treat facial redness due to rosacea that does not go away (persistent) in adults. It is not known if RHOFADE cream is safe and effective in children under 18 years of age.Before you use RHOFADE cream, tell your healthcare provider about all of your medical conditions, including if you:have heart, blood vessel, or blood pressure problems. Call your healthcare provider or get medical help if these conditions worsen. have problems with blood circulation or have had stroke have Sjogrens Syndrome have scleroderma have Raynauds phenomenon have thromboangiitis obliterans have narrow-angle glaucoma. Call your healthcare provider or get medical help if your glaucoma worsens. have irritated skin or open sores on the face are pregnant or plan to become pregnant. It is not known if RHOFADE cream will harm your unborn baby. are breastfeeding. It is not known if RHOFADE cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use RHOFADE cream.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, skin products, vitamins, and herbal supplements. Using RHOFADE cream with certain other medicines may affect each other and can cause serious side effects. How should use RHOFADE creamSee the detailed Instructions for Use that comes with your RHOFADE cream tube or pump for information about how to apply RHOFADE cream correctly. Use RHOFADE cream exactly as your healthcare provider tells you. Do not use more RHOFADE cream than prescribed. RHOFADE cream is for use on your skin only. Do not use RHOFADE cream in your eyes, mouth, or vagina. Avoid contact with your lips and eyes. Do not apply RHOFADE cream to irritated skin or open wounds. What are the possible side effects of RHOFADE creamThe most common side effects of RHOFADE cream include application site reactions of: skin reactions (dermatitis)o itchingo paino worsening of rosacea pimpleso rednessThese are not all the possible side effects of RHOFADE cream. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store RHOFADE creamStore RHOFADE cream at room temperature between 68F to 77F (20C to 25C).Keep RHOFADE cream and all medicines out of the reach of children. General information about the safe and effective use of RHOFADE creamMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use RHOFADE cream for condition for which it was not prescribed. Do not give RHOFADE cream to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about RHOFADE cream that is written for health professionals.What are the ingredients in RHOFADE cream Active ingredient: oxymetazoline hydrochlorideInactive ingredients: sodium citrate dihydrate, citric acid anhydrous, disodium edetate dihydrate, butylated hydroxytoluene, anhydrous lanolin, medium chain triglycerides, diisopropyl adipate, oleyl alcohol, polyethylene glycol 300, PEG-6 stearate, glycol stearate, PEG-32 stearate, cetostearyl alcohol, ceteareth-6, stearyl alcohol, ceteareth-25, methylparaben, propylparaben, phenoxyethanol, and purified water Distributed by: Allergan USA, Inc.Madison, NJ 07940 (C) 2018 Allergan. All rights reserved.All trademarks are the property of their respective owners.Patented. See www.allergan.com/patents This Patient Information has been approved by the U.S. Food and Drug Administration Approved: 01/2017v1.0PPI5300. RHOFADE is for topical use only. RHOFADE pumps require priming before initial use and discard product from the first three pumps. Do not to apply RHOFADE to irritated skin or open wounds. Avoid contact with the eyes and lips. Wash hands immediately after application. Keep RHOFADE out of reach of children.. have heart, blood vessel, or blood pressure problems. Call your healthcare provider or get medical help if these conditions worsen. have problems with blood circulation or have had stroke have Sjogrens Syndrome have scleroderma have Raynauds phenomenon have thromboangiitis obliterans have narrow-angle glaucoma. Call your healthcare provider or get medical help if your glaucoma worsens. have irritated skin or open sores on the face are pregnant or plan to become pregnant. It is not known if RHOFADE cream will harm your unborn baby. are breastfeeding. It is not known if RHOFADE cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use RHOFADE cream.. See the detailed Instructions for Use that comes with your RHOFADE cream tube or pump for information about how to apply RHOFADE cream correctly. Use RHOFADE cream exactly as your healthcare provider tells you. Do not use more RHOFADE cream than prescribed. RHOFADE cream is for use on your skin only. Do not use RHOFADE cream in your eyes, mouth, or vagina. Avoid contact with your lips and eyes. Do not apply RHOFADE cream to irritated skin or open wounds. Store RHOFADE cream at room temperature between 68F to 77F (20C to 25C).

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USERHOFADE(TM) (roe fayd)(oxymetazoline hydrochloride) creamTubeImportant:RHOFADE cream is for skin (topical) use on the face only. Do not use RHOFADE cream in your eyes, mouth, or vagina. Keep RHOFADE cream out of the reach of children.Get medical help right away if you, child, or anyone else swallows RHOFADE cream.Read and follow the steps below so that you use your tube of RHOFADE cream correctly: Step 1: Open the tube of RHOFADE cream by gently pressing down on the child-resistant cap and twisting it counterclockwise until the cap is removed. Do not squeeze the tube while opening or closing.Note: When the cap is removed, the tube is not child-resistant.Step 2: To apply RHOFADE cream to your face, squeeze pea-sized amount of RHOFADE cream from the tube onto your fingertip.Step 3: Apply the pea-sized amount of RHOFADE cream to cover your entire face (forehead, nose, each cheek, and chin) time each day. Spread the cream smoothly and evenly in thin layer over your face. Avoid contact with your eyes and lips. Do not apply cream to irritated skin or open wounds. Step 4: To close your RHOFADE cream tube, place the cap back on the tube. Press down on the child-resistant cap and twist clockwise until it stops. The tube is child-resistant again.Step 5: Wash your hands right away after applying RHOFADE cream.How do store RHOFADE creamStore RHOFADE cream at room temperature between 68F to 77F (20C to 25C).Keep RHOFADE cream and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Allergan USA, Inc.Madison, NJ 07940 (C) 2018 Allergan. All rights reserved.All trademarks are the property of their respective owners.Patented. See www.allergan.com/patentsApproved: 01/2017v1.0IFUTube5300. RHOFADE cream is for skin (topical) use on the face only. Do not use RHOFADE cream in your eyes, mouth, or vagina. Keep RHOFADE cream out of the reach of children.. Get medical help right away if you, child, or anyone else swallows RHOFADE cream.. Avoid contact with your eyes and lips. Do not apply cream to irritated skin or open wounds.. Store RHOFADE cream at room temperature between 68F to 77F (20C to 25C).. Step 1: Open the tube of RHOFADE cream by gently pressing down on the child-resistant cap and twisting it counterclockwise until the cap is removed. Do not squeeze the tube while opening or closing.. Step 2: To apply RHOFADE cream to your face, squeeze pea-sized amount of RHOFADE cream from the tube onto your fingertip.. Step 4: To close your RHOFADE cream tube, place the cap back on the tube. Press down on the child-resistant cap and twist clockwise until it stops. The tube is child-resistant again.

LACTATION SECTION.

8.2 Lactation No clinical data are available to assess the effects of oxymetazoline on the quantity or rate of breastmilk production, or to establish the level of oxymetazoline present in human breastmilk post-dose. Oxymetazoline was detected in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for RHOFADE and any potential adverse effects on the breastfed child from RHOFADE or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Oxymetazoline is an alpha1A adrenoceptor agonist. Oxymetazoline acts as vasoconstrictor.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, 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 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).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 0023-5300-30Rhofade(oxymetazoline hydrochloride) cream, 1%30 gRx Only. PRINCIPAL DISPLAY PANELNDC 0023-5300-30Rhofade(oxymetazoline hydrochloride) cream, 1%30 gRx Only.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe pharmacokinetics of oxymetazoline was evaluated following topical administration of RHOFADE in 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 (Cmax) and area under the concentration-time curves from time to 24 hours (AUC0-24hr) were 60.5 +- 53.9 pg/mL and 895 +-798 pghr/mL, respectively. Following once daily applications for 28 days, the mean +- SD Cmax and AUC0-24hr were 66.4 +- 67.1 pg/mL and 1050 +- 992 pghr/mL, respectively. Following twice daily applications (twice the recommended frequency of application) for 28 days, the mean +- SD Cmax and AUC0-24hr were 68.8 +- 61.1 pg/mL and 1530 +- 922 pghr/mL, respectively.DistributionAn in vitro study demonstrated that oxymetazoline is 56.7% to 57.5% bound to human plasma proteins.MetabolismIn 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 120-minute incubation with human liver microsomes. ExcretionThe excretion of oxymetazoline following administration of RHOFADE has not been characterized in humans.Drug InteractionIn 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on RHOFADE use in pregnant women to inform drug-associated risk for major birth defects and miscarriage. literature article describing intranasal decongestant use in pregnant women identified 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 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 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 2-4% and 15-20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsFollowing repeated use of oxymetazoline hydrochloride solution nasal spray for the treatment of nasal congestion at dose times higher than recommended, one case of fetal distress was reported in 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- to18-fold higher than plasma exposures after topical administration of RHOFADE.DataHuman DataNo adequate and well-controlled trials of RHOFADE have been conducted in pregnant women. Across all clinical trials of RHOFADE, two pregnancies were reported. One pregnancy resulted in the delivery of healthy child. One pregnancy resulted in spontaneous abortion, which was considered to be unrelated to the trial medication. literature article summarizing the results of exploratory analyses of intranasal decongestant use during pregnancy identified potential association between second-trimester exposure to oxymetazoline hydrochloride solution (with no decongestant exposure in the first trimester) and renal collecting system anomalies.Animal DataEffects 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 organogeneisis (3 times the MRHD on an AUC comparison basis). Oxymetazoline hydrochloride did not cause adverse effects to the fetus at oral doses up to mg/kg/day in pregnant rabbits during the period of organogeneisis (73 times the MRHD on an AUC comparison basis). Maternal toxicity, such as decreased maternal body weight, was produced at the high dose of mg/kg/day in pregnant rabbits and was associated with findings of delayed skeletal ossification. In rat perinatal and postnatal development study, oxymetazoline hydrochloride was orally administered to pregnant rats once daily from gestation day 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 times the MRHD on an AUC comparison basis, respectively). Oxymetazoline hydrochloride did not have any adverse effects on fetal development at dose of 0.05 mg/kg/day (one-half of the MRHD on an AUC comparison basis).

SPL UNCLASSIFIED SECTION.

5.1 Potential Impacts on Cardiovascular Disease Alpha-adrenergic agonists may impact blood pressure. RHOFADE 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on RHOFADE use in pregnant women to inform drug-associated risk for major birth defects and miscarriage. literature article describing intranasal decongestant use in pregnant women identified 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 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 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 2-4% and 15-20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsFollowing repeated use of oxymetazoline hydrochloride solution nasal spray for the treatment of nasal congestion at dose times higher than recommended, one case of fetal distress was reported in 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- to18-fold higher than plasma exposures after topical administration of RHOFADE.DataHuman DataNo adequate and well-controlled trials of RHOFADE have been conducted in pregnant women. Across all clinical trials of RHOFADE, two pregnancies were reported. One pregnancy resulted in the delivery of healthy child. One pregnancy resulted in spontaneous abortion, which was considered to be unrelated to the trial medication. literature article summarizing the results of exploratory analyses of intranasal decongestant use during pregnancy identified potential association between second-trimester exposure to oxymetazoline hydrochloride solution (with no decongestant exposure in the first trimester) and renal collecting system anomalies.Animal DataEffects 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 organogeneisis (3 times the MRHD on an AUC comparison basis). Oxymetazoline hydrochloride did not cause adverse effects to the fetus at oral doses up to mg/kg/day in pregnant rabbits during the period of organogeneisis (73 times the MRHD on an AUC comparison basis). Maternal toxicity, such as decreased maternal body weight, was produced at the high dose of mg/kg/day in pregnant rabbits and was associated with findings of delayed skeletal ossification. In rat perinatal and postnatal development study, oxymetazoline hydrochloride was orally administered to pregnant rats once daily from gestation day 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 times the MRHD on an AUC comparison basis, respectively). Oxymetazoline hydrochloride did not have any adverse effects on fetal development at dose of 0.05 mg/kg/day (one-half of the MRHD on an AUC comparison basis).. 8.2 Lactation No clinical data are available to assess the effects of oxymetazoline on the quantity or rate of breastmilk production, or to establish the level of oxymetazoline present in human breastmilk post-dose. Oxymetazoline was detected in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for RHOFADE and any potential adverse effects on the breastfed child from RHOFADE or from the underlying maternal condition. 8.4 Pediatric Use. Safety and effectiveness of RHOFADE have not been established in pediatric patients below the age of 18 years.. 8.5 Geriatric Use. One hundred and ninety-three subjects aged 65 years and older received treatment with RHOFADE (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 RHOFADE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Alpha-adrenergic agonists as 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, Raynauds phenomenon, thromboangiitis obliterans, scleroderma, or Sjogrens 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). Alpha-adrenergic agonists as 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, Raynauds phenomenon, thromboangiitis obliterans, scleroderma, or Sjogrens 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. RHOFADE 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 RHOFADE should be used with caution in patients with cerebral or coronary insufficiency, Raynauds phenomenon, thromboangiitis obliterans, scleroderma, or Sjogrens 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 RHOFADE 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.