Oxymetazoline hydrochloride

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# Overview
Oxymetazoline hydrochloride is a alpha1A adrenoceptor agonist that is FDA approved for the topical treatment of persistent facial erythema associated with rosacea in adults.   Common adverse reactions include application site dermatitis, worsening inflammatory lesions of rosacea, application site pruritis, application site erythema, and application site pain.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Oxymetazoline hydrochlorine cream is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.
- For topical use only. Oxymetazoline hydrochlorine is not for oral, ophthalmic, or intravaginal use.
- Prime the oxymetazoline hydrochlorine 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.
- Oxymetazoline hydrochlorine tubes do not require priming.
- Apply a pea-sized amount of oxymetazoline hydrochlorine 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 hydrochlorine cream.
- Oxymetazoline hydrochlorine (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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding oxymetazoline hydrochlorine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding oxymetazoline hydrochlorine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Oxymetazoline hydrochloride FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding oxymetazoline hydrochlorine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding oxymetazoline hydrochlorine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- None.

# Warnings
- Alpha-adrenergic agonists may impact blood pressure. Oxymetazoline hydrochlorine 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.
- Oxymetazoline hydrochlorine 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.
- Oxymetazoline hydrochlorine 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.

# Adverse Reactions

## Clinical Trials 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 hydrochlorine 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 hydrochlorine once daily for up to one year in a long-term (openlabel) clinical trial. Adverse reactions that occurred in at least 1% of subjects treated with oxymetazoline hydrochlorine through 4 weeks of treatment are presented in Table 1 below.
- 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.

## Postmarketing Experience
There is limited information regarding Oxymetazoline hydrochloride Postmarketing Experience in the drug label.

# Drug Interactions
- Anti-hypertensives/Cardiac Glycosides
- Monoamine Oxidase Inhibitors
- 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.
- Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- There are no available data on oxymetazoline hydrochlorine 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. 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). 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 2-4% and 15-20%, respectively.
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- to18-fold higher than plasma exposures after topical administration of oxymetazoline hydrochlorine.
Human
- No adequate and well-controlled trials of oxymetazoline hydrochlorine have been conducted in pregnant women. Across all clinical trials of oxymetazoline hydrochlorine, 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
- 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 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 1 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 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).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxymetazoline hydrochloride in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Oxymetazoline hydrochloride during labor and delivery.

### Nursing Mothers
- 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 oxymetazoline hydrochlorine and any potential adverse effects on the breastfed child from oxymetazoline hydrochlorine or from the underlying maternal condition.

### Pediatric Use
- Safety and effectiveness of oxymetazoline hydrochlorine have not been established in pediatric patients below the age of 18 years.

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

### Gender
There is no FDA guidance on the use of Oxymetazoline hydrochloride with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Oxymetazoline hydrochloride with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Oxymetazoline hydrochloride in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Oxymetazoline hydrochloride in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxymetazoline hydrochloride in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Oxymetazoline hydrochloride in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- For topical use only. Oxymetazoline hydrochlorine is not for oral, ophthalmic, or intravaginal use.
- Prime the oxymetazoline hydrochlorine 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.
- Oxymetazoline hydrochlorine tubes do not require priming.
- Apply a pea-sized amount of oxymetazoline hydrochlorine 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 hydrochlorine cream.

### Monitoring
- Nasal congestion: Relief of nasal congestion may indicate efficacy.
- Rosacea: Reduction in facial erythema due to rosacea may indicate efficacy.

# IV Compatibility
There is limited information regarding the compatibility of Oxymetazoline hydrochloride and IV administrations.

# Overdosage
- Oxymetazoline hydrochlorine 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 hydrochlorine out of reach of children.

# Pharmacology

## Mechanism of Action
- Oxymetazoline is an alpha1A adrenoceptor agonist. Oxymetazoline acts as a vasoconstrictor.

## Structure

## Pharmacodynamics
- The pharmacodynamics of oxymetazoline hydrochlorine has not been studied.

## Pharmacokinetics
- The pharmacokinetics of oxymetazoline was evaluated following topical administration of oxymetazoline hydrochlorine 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 (Cmax) and area under the concentration-time curves from time 0 to 24 hours (AUC0-24hr) were 60.5  53.9 pg/mL and 895 798 pg*hr/mL, respectively. Following once daily applications for 28 days, the mean  SD Cmax and AUC0-24hr 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 Cmax and AUC0-24hr were 68.8  61.1 pg/mL and 1530  922 pg*hr/mL, respectively.
- An in vitro study demonstrated that oxymetazoline is 56.7% to 57.5% bound to human plasma proteins.
- 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.
- The excretion of oxymetazoline following administration of oxymetazoline hydrochlorine has not been characterized in humans.
- 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.

## Nonclinical Toxicology
- 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).

# Clinical Studies
- Oxymetazoline hydrochlorine 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 hydrochlorine 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) postdose 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.

# How Supplied
- Oxymetazoline hydrochlorine (oxymetazoline hydrochloride) cream, 1%, is a white to off-white cream. The product is available in a laminated tube and an airless pump polypropylene bottle in the following packaging configurations, each with a child-resistant closure:
- NDC 0023-5300-30 30 gram tube
- NDC 0023-5300-60 60 gram tube
- NDC 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).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling.
- Advise patients of the following:
- Oxymetazoline hydrochlorine is for topical use only.
- Oxymetazoline hydrochlorine pumps require priming before initial use and discard product from the first three pumps.
- Do not to apply oxymetazoline hydrochlorine to irritated skin or open wounds.
- Avoid contact with the eyes and lips.
- Wash hands immediately after application.
- Keep oxymetazoline hydrochlorine out of reach of children.

# Precautions with Alcohol
Alcohol-Oxymetazoline hydrochloride interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
- Rhofade

# Look-Alike Drug Names
There is limited information regarding Oxymetazoline hydrochloride Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price