FDA Label for Oxymetazoline Hydrochloride

View Indications, Usage & Precautions

Oxymetazoline Hydrochloride Product Label

The following document was submitted to the FDA by the labeler of this product Taro Pharmaceuticals U.s.a., Inc.. The document includes published materials associated whith this product with the essential scientific information about this product as well as other prescribing information. Product labels may durg indications and usage, generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, warnings, inactive ingredients, etc.

1 Indications And Usage

Oxymetazoline hydrochloride cream is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.

2 Dosage And Administration

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.

3 Dosage Forms And Strengths

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.

4 Contraindications

None.

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.

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
Adverse Reaction	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.

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 alpha₁ 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.

Other

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).

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.

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: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1
Distributed by: Taro Pharmaceuticals U.S.A., Inc., Hawthorne, NY 10532

Revised: October 2021
5217318
1021
55

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 mother's clinical need for oxymetazoline hydrochloride and any potential adverse effects on the breastfed child from oxymetazoline hydrochloride or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of oxymetazoline hydrochloride 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 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.

10 Overdosage

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.

11 Description

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 C₁₆H₂₅CIN₂O and its structural formula is:

Chemical Structure - oxymetazoline 01

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.

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.

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 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).

14 Clinical Studies

Oxymetazoline hydrochloride was evaluated for the treatment of persistent erythema associated with rosacea in two identical, randomized, double-blind, vehicle-controlled, parallel-group clinical trials. The trials enrolled 885 subjects aged 18 years and older. Overall, 90% of subjects were Caucasian and 79% were female. Subjects applied either oxymetazoline hydrochloride or vehicle once daily for 29 days.

Disease severity was graded by the clinician using a 5-point clinician erythema assessment (CEA) scale and by the subject on a similar 5-point subject self-assessment (SSA) scale, on which subjects scored either "moderate" or "severe" on both scales.

CEA and SSA were measured over a 12-hour period at equally-spaced timepoints (hours 3, 6, 9, and 12) post-dose on Days 1, 15, and 29. The primary efficacy endpoint was defined as the proportion of subjects with at least a 2-grade reduction in erythema (improvement) from baseline (pre-dose on Day 1) on both the CEA and SSA measured at hours 3, 6, 9, and 12 on Day 29. The results from both trials on the composite endpoint for Day 29 are presented in Table 2.

Table 2: Proportion of Subjects Achieving Composite Success
Composite success is defined as the proportion of subjects achieving at least a 2-grade improvement on both CEA and SSA.
on Day 29
	Trial 1		Trial 2
Time-point (Hour)	Oxymetazoline Hydrochloride Cream (N=222)	Vehicle Cream (N=218)	Oxymetazoline Hydrochloride Cream (N=224)	Vehicle Cream (N=221)
3	12%	6%	14%	7%
6	16%	8%	13%	5%
9	18%	6%	16%	9%
12	15%	6%	12%	6%

16 How Supplied/Storage And Handling

Oxymetazoline hydrochloride cream, 1%, is a white to off-white cream. The product is available in a laminated tube in the following packaging configurations, each with a child-resistant closure:

NDC 51672-1405-2	30 gram tube
NDC 51672-1405-3	60 gram tube

Storage And Handling

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

17 Patient Counseling Information

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Spl Patient Package Insert

This Patient Information has been approved by the U.S. Food and Drug Administration.
PATIENT INFORMATION Oxymetazoline Hydrochloride (ox" i me taz' oh leen hye" droe klor' ride) Cream
Important: Oxymetazoline hydrochloride cream is for skin (topical) use on the face only. Do not use oxymetazoline hydrochloride cream in your eyes, mouth, or vagina. Keep oxymetazoline hydrochloride cream out of the reach of children. Get medical help right away if you, a child, or anyone else swallows oxymetazoline hydrochloride cream.
What is oxymetazoline hydrochloride cream? Oxymetazoline hydrochloride cream is a 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 oxymetazoline hydrochloride cream is safe and effective in children under 18 years of age.
Before you use oxymetazoline hydrochloride 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 a stroke have Sjögren's Syndrome have scleroderma have Raynaud's 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 oxymetazoline hydrochloride cream will harm your unborn baby. are breastfeeding. It is not known if oxymetazoline hydrochloride cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use oxymetazoline hydrochloride 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 oxymetazoline hydrochloride cream with certain other medicines may affect each other and can cause serious side effects.
How should I use oxymetazoline hydrochloride cream? See the detailed Instructions for Use that comes with your oxymetazoline hydrochloride cream tube for information about how to apply oxymetazoline hydrochloride cream correctly. Use oxymetazoline hydrochloride cream exactly as your healthcare provider tells you. Do not use more oxymetazoline hydrochloride cream than prescribed. Oxymetazoline hydrochloride cream is for use on your skin only. Do not use oxymetazoline hydrochloride cream in your eyes, mouth, or vagina. Avoid contact with your lips and eyes. Do not apply oxymetazoline hydrochloride cream to irritated skin or open wounds.
What are the possible side effects of oxymetazoline hydrochloride cream? The most common side effects of oxymetazoline hydrochloride cream include application site reactions of:
	skin reactions (dermatitis) worsening of rosacea pimples	itching redness	pain
These are not all the possible side effects of oxymetazoline hydrochloride cream. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store oxymetazoline hydrochloride cream? Store oxymetazoline hydrochloride cream at room temperature between 68°F to 77°F (20°C to 25°C). Keep oxymetazoline hydrochloride cream and all medicines out of the reach of children.
General information about the safe and effective use of oxymetazoline hydrochloride cream Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use oxymetazoline hydrochloride cream for a condition for which it was not prescribed. Do not give oxymetazoline hydrochloride 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 oxymetazoline hydrochloride cream that is written for health professionals.

What are the ingredients in oxymetazoline hydrochloride cream? Active ingredient: oxymetazoline hydrochloride 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. Manufactured by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1 Distributed by: Taro Pharmaceuticals U.S.A., Inc., Hawthorne, NY 10532 Revised: October 2021 5217318 1021 55

Instructions For Use

Oxymetazoline Hydrochloride (ox" i me taz' oh leen hye" droe klor' ride) Cream
Tube

Important:

Oxymetazoline hydrochloride cream is for skin (topical) use on the face only. Do not use oxymetazoline hydrochloride cream in your eyes, mouth, or vagina.
Keep oxymetazoline hydrochloride cream out of the reach of children.
Get medical help right away if you, a child, or anyone else swallows oxymetazoline hydrochloride cream.

Read and follow the steps below so that you use your tube of oxymetazoline hydrochloride cream correctly:

Step 1: Open the tube by gently squeezing and 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.	Figure - oxymetazoline 02
Note: When the cap is removed, the tube is not child-resistant.
Step 2: To apply oxymetazoline hydrochloride cream to your face, squeeze a pea-sized amount of oxymetazoline hydrochloride cream from the tube onto your fingertip.
Step 3: Apply the pea-sized amount of oxymetazoline hydrochloride cream to cover your entire face (forehead, nose, each cheek, and chin) 1 time each day. Spread the cream smoothly and evenly in a 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 oxymetazoline hydrochloride 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 oxymetazoline hydrochloride cream.
How do I store oxymetazoline hydrochloride cream? Store oxymetazoline hydrochloride cream at room temperature between 68°F to 77°F (20°C to 25°C). Keep oxymetazoline hydrochloride 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.

Manufactured by: Taro Pharmaceuticals Inc.
Brampton, Ontario, Canada L6T 1C1
Distributed by: Taro Pharmaceuticals U.S.A., Inc., Hawthorne, NY 10532