5.1 Potential Impacts on Cardiovascular Disease

Alpha-adrenergic agonists may impact blood pressure. RHOFADE cream 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 cream should be used with caution in patients with cerebral or coronary insufficiency, Raynaud's phenomenon, thromboangitis 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

RHOFADE cream 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 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.

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.

8.1 Pregnancy

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 RHOFADE cream and any potential adverse effects on the breastfed child from RHOFADE cream or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of RHOFADE cream 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 cream (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 cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

Oxymetazoline is an alpha1A adrenoceptor agonist. Oxymetazoline acts as a vasoconstrictor.

12.2 Pharmacodynamics

The pharmacodynamics of RHOFADE cream has not been studied.

12.3 Pharmacokinetics

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 genotoxicity 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).

Storage: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30ºC (59°F- 86ºF) [see USP Controlled Room Temperature].