BRIMONIDINE 5 mg/g Gel — NDC 63629-9616-1 (Billing 63629-9616-01)

5 WARNINGS AND PRECAUTIONS • Potentiation of Vascular Insufficiency ( 5.1 ) • Severe Cardiovascular Disease ( 5.2 ) • Serious Adverse Reactions Following Ingestion of brimonidine topical gel ( 5.3 ) • Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists ( 5.4 ) • Local Vasomotor Adverse Reactions ( 5.5 ) • Hypersensitivity ( 5.6 )

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 [ see Adverse Reactions ( 6.1 ) ].

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 [ see Adverse Reactions ( 6.1 ) ]. 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 [ see Adverse Reactions ( 6.1 ) ]. Events reported post marketing with the use of brimonidine topical gel include angioedema, throat tightening, tongue swelling, and urticarial [ see Adverse Reactions ( 6.2 ) ]. Institute appropriate therapy and discontinue brimonidine topical gel, if clinically significant hypersensitivity reaction occurs.

6 ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: • Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists [ see Warnings and Precautions ( 5.4 ) ] • Local Vasomotor Adverse Reactions [ see Warnings and Precautions ( 5.5 ) ] • Hypersensitivity [ see Warnings and Precautions ( 5.6 ) ] In controlled clinical trials with brimonidine topical gel the most common adverse reactions (incidence ≥ 1%) included erythema, flushing, skin burning sensation, and contact dermatitis.

( 6 ) 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 (33) 91 (28) 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

7 DRUG INTERACTIONS

7.1Anti-hypertensives/Cardiac Glycosides Alpha-2 agonists, as a class, may reduce blood pressure. Caution in using drugs such as beta-blockers, anti-hypertensives and/or cardiac glycosides is advised.

7.2CNS Depressants Although specific drug-drug interactions studies have not been conducted with brimonidine topical gel, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.

7.3Monoamine Oxidase Inhibitors Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.