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warnings and cautions
5 WARNINGS AND PRECAUTIONS Methemoglobinemia: Cases of methemoglobinemia have been reported. Discontinue ACZONE gel if signs of methemoglobinemia occur ( 5.1 ). Hematologic Effects: Some subjects with G6PD deficiency using ACZONE Gel developed laboratory changes suggestive of hemolysis. ( 5.2 )( 8.6 ). 5.1 Methemoglobinemia Cases of methemoglobinemia, with resultant hospitalization, have been reported postmarketing in association with ACZONE Gel, 5% treatment. Patients with glucose‐6‐phosphate dehydrogenase deficiency or congenital or idiopathic methemoglobinemia are more susceptible to drug‐induced methemoglobinemia. Avoid use of ACZONE Gel, 5% in those patients with congenital or idiopathic methemoglobinemia. Signs and symptoms of methemoglobinemia may be delayed some hours after exposure. Initial signs and symptoms of methemoglobinemia are characterized by a slate grey cyanosis seen in, e.g., buccal mucous membranes, lips and nail beds. Advise patients to discontinue ACZONE Gel, 5% and seek immediate medical attention in the event of cyanosis. Dapsone can cause elevated methemoglobin levels particularly in conjunction with methemoglobin‐inducing agents. 5.2 Hematologic Effects Oral dapsone treatment has produced dose-related hemolysis and hemolytic anemia. Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are more prone to hemolysis with the use of certain drugs. G6PD deficiency is most prevalent in populations of African, South Asian, Middle Eastern, and Mediterranean ancestry. Some subjects with G6PD deficiency using ACZONE Gel developed laboratory changes suggestive of hemolysis. There was no evidence of clinically relevant hemolysis or anemia in patients treated with ACZONE Gel, 5%, including patients who were G6PD deficient. Discontinue ACZONE Gel, 5%, if signs and symptoms suggestive of hemolytic anemia occur. Avoid use of ACZONE Gel, 5% in patients who are taking oral dapsone or antimalarial medications because of the potential for hemolytic reactions. Combination of ACZONE Gel, 5%, with trimethoprim/sulfamethoxazole (TMP/SMX) may increase the likelihood of hemolysis in patients with G6PD deficiency. 5.3 Peripheral Neuropathy Peripheral neuropathy (motor loss and muscle weakness) has been reported with oral dapsone treatment. No events of peripheral neuropathy were observed in clinical trials with topical ACZONE Gel, 5% treatment. 5.4 Skin Skin reactions (toxic epidermal necrolysis, erythema multiforme, morbilliform and scarlatiniform reactions, bullous and exfoliative dermatitis, erythema nodosum, and urticaria) have been reported with oral dapsone treatment. These types of skin reactions were not observed in clinical trials with topical ACZONE Gel, 5% treatment.
6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 10%) are oiliness/peeling, dryness and erythema at the application site ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies 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. Serious adverse reactions reported in subjects treated with ACZONE Gel, 5%, during clinical trials included but were not limited to the following: Nervous system/Psychiatric – Suicide attempt, tonic clonic movements. Gastrointestinal – Abdominal pain, severe vomiting, pancreatitis. Other – Severe pharyngitis In the clinical trials, a total of 12 out of 4032 subjects were reported to have depression (3 of 1660 treated with vehicle and 9 of 2372 treated with ACZONE Gel, 5%). Psychosis was reported in 2 of 2372 subjects treated with ACZONE Gel, 5%, and in 0 of 1660 subjects treated with vehicle. Combined contact sensitization/irritation studies with ACZONE Gel, 5%, in 253 healthy subjects resulted in at least 3 subjects with moderate erythema. ACZONE Gel, 5%, did not induce phototoxicity or photoallergy in human dermal safety studies. ACZONE Gel, 5%, was evaluated for 12 weeks in four controlled trials for local cutaneous events in 1819 subjects. The most common events reported from these studies include oiliness/peeling, dryness, and erythema. These data are shown by severity in Table 1 below. Table 1 – Application Site Adverse Reactions by Maximum Severity ACZONE ® (N=1819) Vehicle (N=1660) Application Site Event Mild Moderate Severe Mild Moderate Severe Erythema 9% 5% <1% 9% 6% <1% Dryness 14% 3% <1% 14% 4% <1% Oiliness/Peeling 13% 6% <1% 15% 6% <1% The adverse reactions occurring in at least 1% of subjects in either arm in the four vehicle controlled trials are presented in Table 2 . Table 2 – Adverse Reactions Occurring in at Least 1% of Subjects NOS = Not otherwise specified ACZONE ® N=1819 Vehicle N=1660 Application Site Reaction NOS 18% 20% Application Site Dryness 16% 17% Application Site Erythema 13% 14% Application Site Burning 1% 2% Application Site Pruritus 1% 1% Pyrexia 1% 1% Nasopharyngitis 5% 6% Upper Respiratory Tract Inf. NOS 3% 3% Sinusitis NOS 2% 1% Influenza 1% 1% Pharyngitis 2% 2% Cough 2% 2% Joint Sprain 1% 1% Headache NOS 4% 4% One subject treated with ACZONE Gel in the clinical trials had facial swelling which led to discontinuation of medication. In addition, 486 subjects were evaluated in a 12 month safety trial. The adverse event profile in this trial was consistent with that observed in the vehicle-controlled trials. 6.2 Experience with Oral Use of Dapsone Although not observed in the clinical trials with ACZONE Gel (topical dapsone) serious adverse reactions have been reported with oral use of dapsone, including agranulocytosis, hemolytic anemia, peripheral neuropathy (motor loss and muscle weakness), and skin reactions (toxic epidermal necrolysis, erythema multiforme, morbilliform and scarlatiniform reactions, bullous and exfoliative dermatitis, erythema nodosum, and urticaria). 6.3 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of topical dapsone: methemoglobinemia, rash (including erythematous rash, application site rash) and swelling of face (including lip swelling, eye swelling)