OXYMETAZOLINE: 4,555 Adverse Event Reports & Safety Profile

RHOFADE ® (oxymetazoline hydrochloride) cream, 1% contains oxymetazoline hydrochloride, an alpha 1A adrenoceptor agonist. RHOFADE is a white to off-white cream. It has a chemical name of 3-[(4,5-Dihydro1H-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 ClN 2 O 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.

Chemical

Structure

Directions adults and children 6 to under 12 years of age (with adult supervision): 2 or 3 sprays in each nostril not more often than every 10 to 12 hours. Do not exceed 2 doses in any 24-hour period. children under 6 years of age: consult a doctor. Shake well before use. Remove safety seal. To open, rotate cap to align the marks. Squeeze cap on both sides in a counter-clockwise turn and pull off to remove. To spray, remove clamp and hold bottle with thumb at base and nozzle between first and second fingers. Without tilting the head, insert nozzle into nostril. Fully depress rim with a firm, even stroke and sniff deeply. Wipe nozzle clean after use and snap cap back onto bottle.

AND ADMINISTRATION For topical use only. RHOFADE cream is not for oral, ophthalmic, or intravaginal use. Prime the RHOFADE cream 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 cream tubes do not require priming. Apply a pea-sized amount of RHOFADE 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 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 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 )

None. None. ( 4 )

REACTIONS 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 EPI Health, LLC at 1-800-499-4468 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 RHOFADE cream 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 RHOFADE cream 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 RHOFADE cream 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 RHOFADE 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.

AND PRECAUTIONS Ptosis may be associated with neurologic or orbital diseases such as stroke and/or cerebral aneurysm, Horner syndrome, myasthenia gravis, external ophthalmoplegia, orbital infection and orbital masses. Consideration should be given to these conditions in the presence of ptosis with decreased levator muscle function and/or other neurologic signs. ( 5.1 ) 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. ( 5.2 ) Use with caution in patients with cerebral or coronary insufficiency or Sjögren’s syndrome and advise patients to seek medical care if signs and symptoms of potentiation of vascular insufficiency develop. ( 5.3 ) Advise patients to seek immediate medical care if pain, redness, blurred vision and photophobia occur (signs and symptoms of acute angle closure). ( 5.4 )

5.1 Ptosis as Presenting Sign of Serious Neurologic Disease Ptosis may be associated with neurologic or orbital diseases such as stroke and/or cerebral aneurysm, Horner syndrome, myasthenia gravis, external ophthalmoplegia, orbital infection and orbital masses. Consideration should be given to these conditions in the presence of ptosis with decreased levator muscle function and/or other neurologic signs.

5.2 Potential Impacts on Cardiovascular Disease Alpha-adrenergic agonists may impact blood pressure. UPNEEQ should be used with caution in patients with severe or unstable 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.

5.3 Potentiation of Vascular Insufficiency UPNEEQ should be used with caution in patients with cerebral or coronary insufficiency, or Sjögren’s syndrome. Advise patients to seek immediate medical care if signs and symptoms of potentiation of vascular insufficiency develop.

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

5.5 Risk of Contamination Patients should not touch the tip of the single patient-use container to their eye or to any surface, in order to avoid eye injury or contamination of the solution.

5.2 Potential Impacts on Cardiovascular Disease Alpha-adrenergic agonists may impact blood pressure. UPNEEQ should be used with caution in patients with severe or unstable 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.

5.3 Potentiation of Vascular Insufficiency UPNEEQ should be used with caution in patients with cerebral or coronary insufficiency, or Sjögren’s syndrome. Advise patients to seek immediate medical care if signs and symptoms of potentiation of vascular insufficiency develop.

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

5.5 Risk of Contamination Patients should not touch the tip of the single patient-use container to their eye or to any surface, in order to avoid eye injury or contamination of the solution.

INTERACTIONS

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 adrenergic receptor antagonists such as in the treatment of cardiovascular disease, or benign prostatic hypertrophy.

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

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 adrenergic receptor antagonists such as in the treatment of cardiovascular disease, or benign prostatic hypertrophy.

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

Active ingredient Oxymetazoline hydrochloride 0.05% Purpose: Nasal Decongestant Uses: ■ temporarily relieves nasal congestion due to: ■ a cold ■ hay fever or other upper respiratory allergies ■ promotes nasal and/or sinus drainage; temporarily relieves sinus congestion and pressure ■ helps clear nasal passages; shrinks swollen membranes

Inactive ingredients No Drip Original benzalkonium chloride solution, benzyl alcohol, edetate disodium, flavor, microcrystalline cellulose and carboxymethylcellulose sodium, polyethylene glycol, povidone, purified water, sodium phosphate dibasic, sodium phosphate monobasic No Drip Night benzalkonium chloride solution, benzyl alcohol, dibasic sodium phosphate, edetate disodium, flavor, glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, monobasic sodium phosphate, polyethylene glycol, povidone, purified water