|Warnings and Precautions, Methemoglobinemia (5.1) ||7/2015 |
1 INDICATIONS AND USAGE ACZONE ® Gel, 5%, is indicated for the topical treatment of acne vulgaris. ACZONE ® Gel is indicated for the topical treatment of acne vulgaris (1).
3 DOSAGE FORMS AND STRENGTHS Gel, 5%. Each gram of ACZONE ® gel contains 50 mg of dapsone in a white to pale yellow gel. Gel, 5% (3).
4 CONTRAINDICATIONS None. None (4).
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 1-800-433-8871 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 patients 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 patients 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 patients treated with ACZONE ® Gel, 5%, and in 0 of 1660 patients 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 studies for local cutaneous events in 1819 patients. 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 patients in either arm in the four vehicle controlled studies are presented in Table 2. Table 2 – Adverse Reactions Occurring in at Least 1% of Patients 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 patient treated with ACZONE ® Gel in the clinical trials had facial swelling which led to discontinuation of medication. In addition, 486 patients were evaluated in a 12 month safety study. The adverse event profile in this study was consistent with that observed in the vehicle-controlled studies. 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 The following adverse reactions have been identified during post-approval use of ACZONE ® Gel, 5%. 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. Methemoglobinemia has been identified during postmarketing use of ACZONE ® Gel, 5% [see Warnings and Precautions (5.1)].
7 DRUG INTERACTIONS Trimethoprim/sulfamethoxazole (TMP/SMX) increases the level of dapsone and its metabolites (7.1). Topical benzoyl peroxide used at the same time as ACZONE ® may result in temporary local yellow or orange skin discoloration (7.2). 7.1 Trimethoprim-Sulfamethoxazole A drug-drug interaction study evaluated the effect of the use of ACZONE ® Gel, 5%, in combination with double strength (160 mg/800 mg) trimethoprim-sulfamethoxazole (TMP/SMX). During co-administration, systemic levels of TMP and SMX were essentially unchanged. However, levels of dapsone and its metabolites increased in the presence of TMP/SMX. Systemic exposure (AUC0-12) of dapsone and N-acetyl-dapsone (NAD) were increased by about 40% and 20% respectively in the presence of TMP/SMX. Notably, systemic exposure (AUC0-12) of dapsone hydroxylamine (DHA) was more than doubled in the presence of TMP/SMX. Exposure from the proposed topical dose is about 1% of that from the 100 mg oral dose, even when co-administered with TMP/SMX. 7.2 Topical Benzoyl Peroxide Topical application of ACZONE ® Gel followed by benzoyl peroxide in subjects with acne vulgaris resulted in a temporary local yellow or orange discoloration of the skin and facial hair (reported by 7 out of 95 subjects in a clinical study) with resolution in 4 to 57 days. 7.3 Drug Interactions with Oral Dapsone Certain concomitant medications (such as rifampin, anticonvulsants, St. John's wort) may increase the formation of dapsone hydroxylamine, a metabolite of dapsone associated with hemolysis. With oral dapsone treatment, folic acid antagonists such as pyrimethamine have been noted to possibly increase the likelihood of hematologic reactions. 7.4 Concomitant Use with Drugs that Induce Methemoglobinemia Concomitant use of ACZONE ® with drugs that induce methemoglobinemia such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para‐aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine may increase the risk for developing methemoglobinemia [see Warnings and Precautions (5.1)].
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well controlled studies in pregnant women. Dapsone has been shown to have an embryocidal effect in rats and rabbits when administered orally in doses of 75 mg/kg/day and 150 mg/kg/day (approximately 800 and 500 times the systemic exposure observed in human females as a result of use of the maximum recommended topical dose, based on AUC comparisons), respectively. These effects were probably secondary to maternal toxicity. ACZONE ® Gel, 5%, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Although systemic absorption of dapsone following topical application of ACZONE ® Gel, 5%, is minimal relative to oral dapsone administration, it is known that dapsone is excreted in human milk. Because of the potential for oral dapsone to cause adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue ACZONE ® Gel, 5%, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy was evaluated in 1169 children aged 12-17 years old treated with ACZONE ® Gel, 5%, in the clinical studies. The adverse event rate for ACZONE ® Gel, 5%, was similar to the vehicle control group. Safety and efficacy was not studied in pediatric patients less than 12 years of age, therefore ACZONE ® Gel, 5%, is not recommended for use in this age group. 8.5 Geriatric Use Clinical studies of ACZONE ® Gel, 5%, did not include sufficient number of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 G6PD Deficiency ACZONE ® Gel, 5% and vehicle were evaluated in a randomized, double-blind, cross-over design clinical study of 64 patients with G6PD deficiency and acne vulgaris. Subjects were Black (88%), Asian (6%), Hispanic (2%) or of other racial origin (5%). Blood samples were taken at Baseline, Week 2, and Week 12 during both vehicle and ACZONE ® Gel, 5% treatment periods. There were 56 out of 64 subjects who had a Week 2 blood draw and applied at least 50% of treatment applications. Table 3 contains results from testing of relevant hematology parameters for these two treatment periods. ACZONE ® Gel was associated with a 0.32 g/dL drop in hemoglobin after two weeks of treatment, but hemoglobin levels generally returned to baseline levels at Week 12. Table 3 – Mean Hemoglobin, Bilirubin, and Reticulocyte Levels in Acne Subjects with G6PD Deficiency in ACZONE®/Vehicle Cross-Over Study ACZONE ® Vehicle N Mean N Mean Hemoglobin (g/dL) Pre-treatment 53 13.44 56 13.36 2 weeks 53 13.12 55 13.34 12 weeks 50 13.42 50 13.37 Bilirubin (mg/dL) Pre-treatment 54 0.58 56 0.55 2 weeks 53 0.65 55 0.56 12 weeks 50 0.61 50 0.62 Reticulocytes (%) Pre-treatment 53 1.30 55 1.34 2 weeks 53 1.51 55 1.34 12 weeks 50 1.48 50 1.41 There were no changes from baseline in haptoglobin or lactate dehydrogenase during ACZONE ® or vehicle treatment at either the 2-week or 12-week time point. The proportion of subjects who experienced decreases in hemoglobin ≥1 g/dL was similar between ACZONE ® Gel, 5% and vehicle treatment (8 of 58 subjects had such decreases during ACZONE ® treatment compared to 7 of 56 subjects during vehicle treatment among subjects with at least one on-treatment hemoglobin assessment). Subgroups based on gender, race, or G6PD enzyme activity did not display any differences in laboratory results from the overall study group. There was no evidence of clinically significant hemolytic anemia in this study. Some of these subjects developed laboratory changes suggestive of hemolysis.