Brimonidine

Brimonidine topical gel, 0.33% is an alpha adrenergic agonist indicated for the topical treatment of persistent (nontransient) erythema of rosacea in adults 18 years of age or older. Brimonidine topical gel, 0.33% is an alpha adrenergic agonist indicated for the topical treatment of persistent (nontransient) facial erythema of rosacea in adults 18 years of age or older.

Apply a pea-sized amount once daily to each of the five areas of the face: central forehead, chin, nose, each cheek. Brimonidine topical gel should be applied smoothly and evenly as a thin layer across the entire face avoiding the eyes and lips. Wash hands after applying brimonidine topical gel.

Brimonidine topical gel is for topical use only and not for oral, ophthalmic, or intravaginal use. • Apply a pea-sized amount once daily to each of the five areas of the face (forehead, chin, nose, each cheek) avoiding the eyes and lips. • Hands should be washed immediately after applying brimonidine topical gel. • For topical use only • Not for oral, ophthalmic, or intravaginal use.

5 WARNINGS AND PRECAUTIONS • Potentiation of Vascular Insufficiency • Severe Cardiovascular Disease • Serious Adverse Reactions Following Ingestion of brimonidine topical gel • Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists • Local Vasomotor Adverse Reactions • Hypersensitivity

5.1Potentiation of Vascular Insufficiency Brimonidine

topical gel should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, thrombangiitis obliterans, scleroderma, or Sjögren’s syndrome.

5.2Severe Cardiovascular Disease Alpha-2

adrenergic agonists can lower blood pressure. Brimonidine topical gel should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease.

5.3Serious Adverse Reactions Following Ingestion

of Brimonidine Topical Gel Two young children of a subject in a clinical trial experienced serious adverse reactions following accidental ingestion of brimonidine topical gel. Adverse reactions experienced by one or both children included lethargy, respiratory distress with apneic episodes (requiring intubation), sinus bradycardia, confusion, psychomotor hyperactivity, and diaphoresis. Both children were hospitalized overnight and discharged the following day without sequelae.

Keep brimonidine topical gel out of the reach of children.

5.4Systemic Adverse Reactions of Alpha

2-adrenergic agonists Postmarketing cases of bradycardia, hypotension (including orthostatic hypotension) and dizziness have been reported. Some cases required hospitalization. Some cases involved application of brimonidine topical gel in unapproved dosing regimens and for unapproved indications, including the application of brimonidine topical gel following laser procedures.

Avoid applying brimonidine topical gel to irritated skin or open wounds.

5.5Local Vasomotor Adverse Reactions Erythema

Some subjects in the clinical trials discontinued use of brimonidine topical gel because of erythema. Some subjects in the clinical trials reported a rebound phenomenon, where erythema was reported to return worse compared to the severity at baseline. Erythema appeared to resolve after discontinuation of brimonidine topical gel . The treatment effect of brimonidine topical gel may begin to diminish hours after application.

From postmarketing reports, some patients have experienced erythema involving areas of the face that were previously not affected by erythema and in areas (e.g., neck and chest) outside of the treatment sites. Flushing Some subjects in the clinical trials discontinued use of brimonidine topical gel because of flushing. Intermittent flushing occurred in some subjects treated with brimonidine topical gel in the clinical trials.

The onset of flushing relative to application of brimonidine topical gel varied, ranging from approximately 30 minutes to several hours . Flushing appeared to resolve after discontinuation of brimonidine topical gel. From postmarketing reports, some patients have experienced increased frequency of flushing and/or increased depth of erythema with the flushing. Additionally, some patients reported new onset of flushing.

Pallor and Excessive Whitening From postmarketing reports, some patients have experienced pallor or excessive whitening at or outside the application site following treatment with brimonidine topical gel.

5.6Hypersensitivity Allergic

contact dermatitis was reported in the clinical trials for brimonidine topical gel . Events reported post marketing with the use of brimonidine topical gel include angioedema, throat tightening, tongue swelling, and urticarial . Institute appropriate therapy and discontinue brimonidine topical gel, if clinically significant hypersensitivity reaction occurs.

Brimonidine topical gel is contraindicated in patients who have experienced a hypersensitivity reaction to any component. Reactions have included angioedema, urticarial, and contact dermatitis . Known hypersensitivity to any component of brimonidine topical gel

8.1Pregnancy Pregnancy Category B. There

are no adequate and well-controlled studies of brimonidine topical gel in pregnant women. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Brimonidine topical gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Brimonidine tartrate was not teratogenic when given at oral doses up to 2.5 mg/kg/day in pregnant rats during gestation days 6 through 15 and 5 mg/kg/day in pregnant rabbits during gestation days 6 through 18.

8.3Nursing Mothers It

is not known whether brimonidine tartrate is excreted in human milk, although in animal studies, brimonidine tartrate has been shown to be excreted in breast milk. Because of the potential for serious adverse reactions from brimonidine topical gel in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The following adverse drug reactions are discussed in greater detail in other sections of the label: • Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists • Local Vasomotor Adverse Reactions • Hypersensitivity In controlled clinical trials with brimonidine topical gel the most common adverse reactions (incidence ≥ 1%) included erythema, flushing, skin burning sensation, and contact dermatitis. To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because

clinical trials are conducted under widely 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. During clinical trials, 1210 subjects were exposed to brimonidine topical gel. A total of 833 subjects were treated for persistent (nontransient) erythema associated with rosacea, and 330 of those were treated once daily for 29 days in vehicle-controlled trials.

Adverse reactions that occurred in at least 1% of subjects treated with brimonidine topical gel once daily for 29 days and for which the rate for brimonidine topical gel exceeded the rate for vehicle are presented in Table 1. Table 1 - Adverse Reactions Reported in Clinical Trials by at Least 1% of Subjects Treated for 29 Days Preferred Term Brimonidine Topical Gel (N=330) n (%) Vehicle Gel (N=331) n (%) Subjects with at least one adverse reaction, Number (%) of Subjects 109 91 Erythema 12 (4%) 3 (1%) Flushing 9 (3%) 0 Skin burning sensation 5 (2%) 2 (1%) Dermatitis contact 3 (1%) 1 (˂1%) Dermatitis 3 (1%) 1 (˂1%) Skin warm 3 (1%) 0 Paraesthesia 2 (1%) 1 (˂1%) Acne 2 (1%) 1 (˂1%) Pain of skin 2 (1%) 0 Vision blurred 2 (1%) 0 Nasal congestion 2 (1%) 0 Open-label, Long-term Study An open-label study of brimonidine topical gel when applied once daily for up to one year was conducted in subjects with persistent (nontransient) facial erythema of rosacea. Subjects were allowed to use other rosacea therapies.

A total of 276 subjects applied brimonidine topical gel for at least one year. The most common adverse events (≥ 4% of subjects) for the entire study were flushing (10%), erythema (8%), rosacea (5%), nasopharyngitis (5%), skin burning sensation (4%), increased intraocular pressure (4%), and headache (4%). Allergic contact dermatitis Allergic contact dermatitis to brimonidine topical gel was reported in approximately 1% of subjects across the clinical development program.

Two subjects underwent patch testing with individual product ingredients. One subject was found to be sensitive to brimonidine tartrate, and one subject was sensitive to phenoxyethanol (a preservative).

6.2Postmarketing Experience The

following adverse reactions have been identified during post-approval use of brimonidine topical gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular disorders: bradycardia, hypotension (including orthostatic hypotension) Immune system disorders: angioedema, hypersensitivity, lip swelling, swollen tongue, throat tightness, urticaria Nervous system disorders: dizziness Skin and subcutaneous disorders: pallor