WARNINGS AND PRECAUTIONS---------------
`---------------
`­
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`Hematological Effects: Some subjects with G6PD deficiency
`
`
`
`These highlights do not include all the information needed to
`
`
`
`
`using ACZONE Gel developed laboratory changes suggestive of
`
`
`use ACZONE safely and effectively. See full prescribing
`
`mild hemolysis. (5.1 )(8.6)
`
`information for ACZONE.
`
`ACZONE™ (dapsone) Gel, 5%
`
`
`For topical use only
`
`
`Initial U.S. Approval: 1955
`
`The following are seen with oral dapsone treatment:
`
`
`
`• Hematological Effects ( 5 .1 ).
`
`
`• Peripheral Neuropathy (5.2).
`
`• Skin Reactions (5.3).
`--------------------IND I
`CATIONS AND USA GE------------------­
`
`
`
`
`A CZONE Gel is indicated for the topical treatment of acne
`----------------------
`ADVERSE REACTIONS----------------------­
`
`
`vulgaris ( 1 ).
`
`
`
`Most common adverse reactions (incidence 2: 10%) are
`
`
`
`
`oiliness/peeling, dryness and erythema at the application site (6).
`DOSAGE AND ADMINISTRATION-------------
`-----------------
`
`• Apply twice daily (2).
`To report SUSPECTED ADVERSE REACTIONS, contact
`
`• Apply approximately a pea-sized amount of ACZONE
`
`
`
`QLT USA, Inc. at 1-800-[ACZONE Call Number] or FDA at
`
`
`Gel, 5%, in a thin layer to the acne aflected area (2 ).
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`• If there is no improvement after 12 weeks, treatment with
`
`---------------------------------------------
`
`
`ACZONE Gel, 5%, should be reassessed (2).
`DRUG INTERACTIONS
`
`
`• Trimethoprim/sulfamethoxazole (TMP/SMX) increases the
`For topical use only. Not for oral, ophthalmic, or intravaginal
`
`
`
`
`level of dapsone and its metabolites. (7.1)
`use (2).
`
`
`
`• Topical benzoyl peroxide used at the same time as
`
`
`ACZONE may result in temporary local yellow or orange
`DOSAGE FORMS AND STRENGTHS------------
`--------------
`­
`
`skin discoloration. (7.2)
`
`
`
`ACZONE (dapsone) Gel, 5%, is supplied in the following size
`tubes:
`
`USE IN SPECIFIC POPULATI0NS--------------
`---------------
`­
`• Professional Sample: 3 gram laminate tube (3).
`
`
`
`
`G6PD Deficiency (8.6).
`
`
`• Commercially: 30 gram laminate tube (3).
`
`See 17 for PATIENT COUNSELING INFORMATION and
`-----------------------
`
`--------------------­
`
`FDA-approved patient labeling.
`CONTRAINDICATIONS
`N one.
`
`
`
`Version: 03/2008
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`12.4 Microbiology
`13 NONCLINICAL TOXICOLOGY
`
`
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Information for Patients
`
`
`17.2 FDA-Approved Patient Labeling
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`*Sections or subsections omitted from the full prescribing
`
`
`
`
`information are not listed.
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5 .1 Hematological Eflects
`
`5.2 Peripheral Neuropathy
`5.3 Skin
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2 Experience with Oral Use ofDapsone
`7 DRUG INTERACTIONS
`7 .1 Trimethoprim-Sulfamethoxazole
`7.2 Topical Benzoyl Peroxide
`7.3 Drug Interactions with Oral Dapsone
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`8.6 G6PD Deficiency
`
`March 2008
`
`1 of 7
`
`Almirall EXHIBIT 2044
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`5.3 Skin
`
`ACZONE Gel, 5%, is indicated for the topical treatment of acne
`vulgaris.
`
`2 DOSAGE AND ADMINISTRATION
`
`For topical use only. Not for oral, ophthalmic, or intravaginal
`use.
`
`After the skin is gently washed and patted dry, apply
`approximately a pea-sized amount of ACZONE Gel, 5%, in a
`thin layer to the acne affected areas twice daily. Rub in
`ACZONE Gel, 5%, gently and completely. ACZONE Gel, 5%,
`is gritty with visible drug substance particles. Wash hands after
`application of ACZONE Gel, 5%.
`
`If there is no improvement after 12 weeks, treatment with
`ACZONE Gel, 5%, should be reassessed.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`ACZONE (dapsone) Gel, 5%, is supplied in the following size
`tubes:
`• Professional Sample: 3 gram laminate tube
`• Commercially: 30 gram laminate tube
`
`4 CONTRAINDICATIONS
`
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hematological 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.
`
`There was no evidence of clinically relevant hemolysis or
`anemia in patients treated with ACZONE Gel, 5%, including
`patients who were G6PD deficient. Some subjects with G6PD
`deficiency using ACZONE Gel developed laboratory changes
`suggestive of mild hemolysis.
`
`If signs and symptoms suggestive of hemolytic anemia occur,
`ACZONE Gel, 5% should be discontinued. ACZONE Gel, 5%
`should not be used 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.
`
`5.2 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.
`
`March 2008
`
`2
`
`erythema
`epidermal necrolysis,
`(toxic
`reactions
`Skin
`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
`
`6.1 Clinical Studies Experience
`
`trials are conducted under prescribed
`Because clinical
`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 O 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� l819
`Application Mild Moderate
`Site Event
`
`Vehicle
`( N� l660
`Severe Mild Moderate
`
`Erythema
`
`Dryness
`
`Oiliness/
`Peeling
`
`9%
`
`14%
`
`13%
`
`5%
`
`3%
`
`6%
`
`<1%
`
`9%
`
`<1%
`
`14%
`
`<1%
`
`15%
`
`6%
`
`4%
`
`6%
`
`Severe
`
`<1%
`
`<1%
`
`<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.
`
`2 of 7
`
`

`

`Table 2 - Adverse Reactions Occurring in at least 1 % of
`Patients
`
`Application Site Reaction NOS
`Application Site Dryness
`Application Site Erythema
`Application Site Burning
`Application Site Pruritus
`Pyrexia
`N asooharvrn1:itis
`Upper Respiratory Tract Inf.
`NOS
`Sinusitis NOS
`Influenza
`Pharvrn1:itis
`Cough
`Joint Sprain
`Headache NOS
`NOS � Not otherwise specified
`
`ACZONE
`N� l819
`18%
`16%
`13%
`1%
`1%
`1%
`5%
`3%
`
`2%
`1%
`2%
`2%
`1%
`4%
`
`Vehicle
`N� l660
`20%
`17%
`14%
`2%
`1%
`1%
`6%
`3%
`
`1%
`1%
`2%
`2%
`1%
`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 ofDapsone
`
`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).
`
`7 DRUG INTERACTIONS
`
`7.1 Trimethoprim-Sulfomethoxazole
`
`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 presence
`(AUC0_12) of
`of TMP/SMX. Notably, systemic exposure
`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
`
`March 2008
`
`3
`
`(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
`
`rifampin,
`as
`(such
`concomitant medications
`Certain
`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.
`
`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 eflect
`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 eflicacy 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 diflerently 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
`
`3 of 7
`
`

`

`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
`
`Hemoglobin (g/dL) Pre-treatment
`2 weeks
`12 weeks
`
`Vehicle
`ACZONE
`N Mean N Mean
`53
`13.44
`56
`13.36
`53
`13.1 2
`55
`13.34
`50
`13.42
`50
`13.37
`
`Bilirubin (mg/dL)
`
`Pre-treatment
`2 weeks
`12 weeks
`
`54
`53
`50
`
`0.58
`0.65
`0.61
`
`56
`55
`50
`
`Reticulocytes (%)
`
`Pre-treatment
`2 weeks
`12 weeks
`
`55
`1.30
`53
`53 I.SI 55
`50
`1.48
`50
`
`0.55
`0.56
`0.6 2
`
`1.34
`1.34
`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 c::l 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 mild hemolysis.
`
`10 OVERDOSAGE
`
`ACZONE Gel, 5%, is not for oral use. If oral ingestion occurs,
`medical advice should be sought.
`
`11 DESCRIPTION
`
`ACZONE Gel, 5%, contains dapsone, a sulfone, in an aqueous
`gel base for topical dermatologic use. ACZONE Gel, 5% is a
`gritty translucent material with visible drug substance particles.
`Chemically, dapsone has an empirical formula of C12H12N202S.
`It is a white, odorless crystalline powder that has a molecular
`weight
`of
`248.
`Dapsone's
`chemical
`name
`1s
`4,4'-diaminodiphenylsulfone and its structural formula is:
`
`,iH,--Q-so, --Q-
`
`NH2
`
`Each gram of ACZONE Gel, 5%, contains 50 mg of
`dapsone, USP, in a gel of carbomer 980; diethylene glycol
`monoethyl ether, NF; methylparaben, NF; sodium hydroxide,
`NF; and purified water, USP.
`
`March 2008
`
`4
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`The mechanism of action of dapsone gel m treating acne
`vulgaris is not known.
`
`12.3 Pharmacokinetics
`
`An open-label study compared the pharmacokinetics of dapsone
`after ACZONE Gel, 5%, (110 ± 60 mg/day) was applied twice
`daily (-BSA 22.5%) for 14 days (n=l 8) with a single 100 mg
`dose of oral dapsone administered to a subgroup of patients
`(n=l O) in a crossover design. On Day 14 the mean dapsone
`AUC0_24 h was 415 ± 224 ng•h/mL for ACZONE Gel, 5%,
`whereas following a single 100 mg dose of oral dapsone the
`AUC0_ infinity was 52,641 ± 36,223 ng•h/mL. Exposure after the
`oral dose of 100 mg dapsone was approximately 100 times
`greater than after the topical ACZONE Gel, 5% dose, twice a
`day.
`
`In a long-term safety study of ACZONE Gel, 5% treatment,
`periodic blood samples were collected up to 12 months to
`determine systemic exposure of dapsone and its metabolites in
`approximately 500 patients. Based on the measurable dapsone
`concentrations from 408 patients (M=l92, F=216), obtained at
`month 3, neither gender, nor race appeared to aflect the
`pharmacokinetics of dapsone. Similarly, dapsone exposures
`were approximately the same between the age groups of 12-15
`years (N=l 55) and those greater than or equal to 16 years
`(N=253). There was no evidence of increasing systemic
`exposure to dapsone over the study year in these patients.
`
`12.4 Microbiology
`
`In Vivo Activity: No microbiology or inmmnology studies were
`
`conducted during dapsone gel clinical trials.
`
`Drug Resistance: No dapsone resistance studies were conducted
`during dapsone gel clinical trials. Because no microbiology
`studies were done, there are no data available as to whether
`dapsone treatment may have resulted in decreased susceptibility
`
`
`of Propionibacterium acnes, an organism associated with acne,
`to other antimicrobials that may be used to treat acne.
`Therapeutic resistance to dapsone has been reported for
`
`
`Mycobacterium leprae, when patients have been treated with
`oral dapsone.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Dapsone was not mutagenic in a bacterial reverse mutation
`
`
`assay (Ames test) using S. typhimurium and E. coli, with and
`without metabolic activation and was negative in a micronucleus
`assay conducted in mice. Dapsone increased both numerical and
`structural aberrations
`in a chromosome aberration assay
`conducted with Chinese hamster ovary (CHO) cells.
`
`Dapsone was not carcinogenic to rats when orally administered
`to females for 92 weeks or males for 100 weeks at dose levels
`up to 15 mg/kg/day (approximately 160 times the systemic
`exposure observed in human males and 300 times the systemic
`exposure observed in human females as a result of use of the
`
`4 of 7
`
`

`

`on the Global Acne Assessment Score (no or minimal acne) and
`in the percent reduction in inflammatory, non-inflammatory, and
`total lesions.
`
`The Global Acne Assessment Score was a 5-point scale as
`follows:
`0 None: no evidence of facial acne vulgaris
`1 Minimal: few non-inflammatory lesions (comedones) are
`present; a few inflammatory lesions (papules/pustules) may
`be present
`lesions
`to many non-inflanunatory
`2 Mild:
`several
`( comedones) are present; a few inflammatory lesions
`(papules/pustules) are present
`( comedones) and
`3 Moderate: many non-inflanunatory
`inflammatory lesions (papules/pustules) are present; no
`nodulo-cystic lesions are allowed
`inflammatory disease;
`Severe: significant degree of
`papules/pustules are a predominant feature; a few nodulo­
`cystic lesions may be present; comedones may be present.
`
`4
`
`The success rates on the Global Acne Assessment Score (no or
`minimal acne) at Week 12 are presented in Table 4.
`
`Table 4 - Success (No or Minimal Acne) on the Global Acne
`Assessment Score at Week 12
`
`Study 2*
`ACZONE
`N�7 29
`253 (35%)
`
`Vehicle
`N�738
`206
`(28%)
`
`Subjects with
`No or Minimal
`Acne
`* Analysis excludes subJects classified with mmrmal acne at
`baseline
`
`Study 1 *
`ACZONE
`N�699
`291 (42%)
`
`Vehicle
`N�687
`223
`(3 2%)
`
`. ..
`
`Table 5 presents the mean percent reduction in inflammatory,
`non-inflammatory, and total lesions from baseline to Week 12.
`
`Table 5 - Percent Reduction in Lesions from Baseline to Week
`12
`
`Study 1
`ACZONE
`N�745
`46%
`31%
`
`Vehicle
`N�740
`42%
`24%
`
`Study 2
`ACZONE
`N�761
`48%
`30%
`
`Vehicle
`N�764
`40%
`21%
`
`38%
`
`3 2%
`
`37%
`
`29%
`
`Inflammatory
`Non-
`Inflammatory
`Total
`
`The clinical studies enrolled about equal proportions of male
`and female subjects. Female patients tended to have greater
`percent reductions in lesions and greater success on the Global
`Acne Assessment Score than males. The breakdown by race in
`the clinical studies was about 73% Caucasian, 14% Black, 9%
`Hispanic, and 2% Asian. Efficacy results were similar across
`the racial subgroups.
`
`recommended
`maximum
`comparisons).
`
`topical dose, based on AUC
`
`No evidence of potential to induce carcinogenicity was obtained
`in a dermal study in which dapsone gel was topically applied to
`Tg.AC transgenic mice for approximately 26 weeks. Dapsone
`concentrations of 3%, 5%, and 10% were evaluated; 3%
`material was judged to be the maximum tolerated dosage.
`
`ACZONE Gel, 5%, did not increase the rate of formation of
`ultra violet light-induced skin tumors when topically applied to
`hairless mice in a 12-month photocarcinogenicity study.
`
`The effects of dapsone on fertility and general reproduction
`performance were assessed in male and female rats following
`oral (gavage) dosing. Dapsone reduced sperm motility at
`dosages of 3 mg/kg/day or greater (approximately 17 times the
`systemic exposure observed in human males as a result of use of
`the maximum recommended topical dose, based on AUC
`comparisons). The mean numbers of embryo implantations and
`viable embryos were significantly reduced in untreated females
`mated with males that had been dosed at 12 mg/kg/day or
`greater (approximately 70 times the systemic exposure observed
`in human males as a result of use of
`the maximum
`recommended topical dose, based on AUC comparisons),
`presumably due to reduced numbers or effectiveness of sperm,
`indicating impairment of fertility. Dapsone had no effect on
`male fertility at dosages of 2 mg/kg/day or less (approximately
`13 times the systemic exposure observed in human males as a
`result of use of the maximum recommended topical dose, based
`on AUC comparisons). When administered to female rats at a
`dosage of 75 mg/kg/day (approximately 800 times the systemic
`exposure observed in human females as a result of use of the
`maximum
`recommended
`topical dose, based on AUC
`comparisons) for 15 days prior to mating and for 17 days
`thereafter, dapsone reduced the mean number of implantations,
`increased the mean early resorption rate, and reduced the mean
`litter size. These effects were probably secondary to maternal
`toxicity.
`
`Dapsone was assessed for effects on perinatal/postnatal pup
`development and postnatal maternal behavior and function in a
`study in which dapsone was orally administered to female rats
`daily beginning on the seventh day of gestation and continuing
`until the twenty-seventh day postpartum. Maternal toxicity
`(decreased body weight
`and
`food consumption) and
`developmental effects (increase in stillborn pups and decreased
`pup weight) were seen at a dapsone dose of 30 mg/kg/day
`(approximately 500 times the systemic exposure observed in
`human females as a result of use of the maximum recommended
`topical dose, based on AUC comparisons). No effects were
`observed on the viability, physical development, behavior,
`learning ability, or reproductive function of surviving pups.
`
`14 CLINICAL STUDIES
`
`Two randomized, double blind, vehicle controlled, clinical
`studies were conducted to evaluate ACZONE Gel, 5%, for the
`treatment of patients with acne vulgaris (N=l 475 and 1525).
`The studies were designed to enroll patients 12 years of age and
`older with 20 to 50 inflammatory and 20 to 100 non­
`inflammatory lesions at baseline. In these studies patients
`applied either ACZONE Gel, 5%, or vehicle control twice daily
`for up to 12 weeks. Efficacy was evaluated in terms of success
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`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`ACZONE (dapsone) Gel, 5%, is supplied in the following size
`tubes:
`
`Professional Sample
`5 % NDC XXXX-XXXX-XX
`3 gram laminate tube
`
`Commercially Available as:
`5 % NDC XXXX-XXXX-XX
`30 gram laminate tube
`
`Product Code 500503
`
`Product Code 500530
`
`KEEP OUT OF THE REACH OF CHILDREN LESS
`THAN 12 YEARS OLD.
`
`Storage conditions:
`Store at controlled room temperature, 20-25°C (68-76°F),
`excursions permitted to 15-30°C
`(59-86°F). Protect from
`freezing.
`
`17 PATIENT COUNSELING INFORMATION
`
`See FDA Approved-Patient Labeling (17.2)
`
`17.1 Information for Patients
`
`1. Patients should use ACZONE Gel, 5%, as directed by the
`physician. ACZONE Gel, 5%, is for external topical use
`only. ACZONE Gel, 5%, is not for oral, ophthalmic or
`intravaginal use.
`2. Patients should not use this medication for any disorder
`other than that for which it was prescribed.
`3. Patients should report any signs of adverse reactions to
`their physician.
`4. Protect ACZONE Gel, 5%, from freezing.
`5. See Patient Labeling for additional information on safety,
`efficacy, general use, and storage of ACZONE Gel, 5%.
`
`17.2 FDA-Approved Patient Labeling
`
`ACZONE™ (dapsone) Gel 5%
`
`important information before you start using
`this
`Read
`ACZONE (AK-zon) Gel and each time you refill your
`prescription. There may be new information that you need to
`know. This summary is not meant to take the place of your
`doctor's advice. If you have any questions or want more
`information about ACZONE Gel, ask your doctor or pharmacist.
`
`What is A CZ ONE Gel?
`ACZONE Gel is a prescription medicine used on your skin
`(topical) to treat acne in people 12 years and older.
`
`ACZONE Gel has not been studied in children under 12 years of
`age.
`
`Who should not use A CZ ONE Gel?
`Do not use ACZONE Gel if you are allergic to any of the
`ingredients in ACZONE Gel or if you are younger than 12 years
`of age.
`
`Active ingredient: dapsone.
`Inactive
`ingredients: Carbomer 980, diethylene glycol
`monoethyl ether (DGME), methylparaben, sodium hydroxide,
`and purified water.
`
`What should I tell my doctor before using A CZ ONE Gel?
`Tell your doctor about all of your medical conditions,
`including if you:
`• are pregnant or planning to become pregnant. It is not
`known if ACZONE Gel may harm your unborn baby. You
`and your doctor will need to decide if ACZONE is right for
`you.
`• are breastfeeding. ACZONE Gel passes into your milk and
`may harm your baby. You should choose either to use
`ACZONE Gel, or breastfeed, but not both. Talk to your
`doctor about the best way to feed your baby while using
`ACZONE Gel.
`• have glucose-6-phoshate dehydrogenase deficiency.
`
`Tell your doctor about all the medicines you are taking
`including prescription and nonprescription medicines,
`vitamins and herbal supplements. Especially, tell your doctor
`if you are using any other medicines applied to the skin, such as
`acne medicines with benzoyl peroxide.
`
`How do I use A CZ ONE Gel?
`• Use ACZONE Gel exactly as prescribed by your doctor.
`ACZONE Gel is usually used on your affected skin twice a
`day, once in the morning and once in the evening.
`• Wash the areas of your skin where you will apply ACZONE
`Gel. Gently pat your skin dry with a clean towel.
`• Apply a thin layer of ACZONE Gel to the areas of your skin
`that have acne. A pea-sized amount of ACZONE Gel will
`usually be enough.
`• Rub the medicine in gently and completely
`• Make sure to put the cap back on the ACZONE Gel tube.
`Close it tightly.
`• Wash your hands after applying ACZONE Gel.
`• Keep ACZONE Gel away from your mouth and eyes. Do
`not swallow ACZONE Gel. If you swallow ACZONE Gel,
`call your doctor or poison control center right away.
`• If your acne does not get better after using ACZONE Gel for
`12 weeks, talk to your doctor about other treatments for acne.
`
`What are the possible side effects of A CZ ONE Gel?
`Like all medicines, ACZONE Gel can cause some side effects.
`The most common side effects of ACZONE Gel are dryness,
`redness, oiliness and peeling of the skin being treated.
`
`When the active ingredient of ACZONE Gel (called dapsone)
`is taken orally as a pill, it has been related to the abnormal
`breakdown of red blood cells (hemolytic anemia). If you have
`glucose-6-phoshate dehydrogenase deficiency, you may have a
`greater risk for lowering your hemoglobin level. However, using
`ACZONE Gel on the skin is not expected to put enough dapsone
`in the blood to cause clinical symptoms of hemolytic anemia.
`You are advised to be alert for signs and symptoms suggestive
`of
`this type of anemia
`(sudden onset of: back pam,
`breathlessness, tiredness/weakness with daily activities, dark-
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`brown urine, high fever and yellow or pale skin). If you
`experience these signs and symptoms, stop use and call your
`doctor immediately.
`
`Use of benzoyl peroxide together with ACZONE Gel at the
`same time may cause your skin to temporarily tum yellow or
`orange at the site of application.
`
`This is not a complete list of all the possible side effects. Call
`your doctor if you have any side effects that do not go away or
`bother you. If you have any questions, ask your doctor or
`pharmacist.
`
`
`How should I store A CZ ONE Gel?
`Store ACZONE Gel at room temperature 68 to 76°F. Do not
`freeze ACZONE Gel.
`
`Keep ACZONE Gel out of the reach of children less than 12
`years of age.
`
`Where can !find 11Wre information about A CZ ONE Gel?
`
`
`
`If you have any questions or want more information about
`ACZONE Gel, ask your doctor or pharmacist. Your doctor or
`pharmacist can also give you a copy of the ACZONE Gel
`Package Insert written for health professionals. Ask them to
`explain anything you do not understand.
`
`You may call 1-800-[ACZONE Call Number] to obtain more
`information about ACZONE™ Gel.
`
`ACZONE™ (dapsone) Gel, 5%
`Manufactured by Tohnar, Inc. Fort Collins, CO 80526 for QLT,
`USA, Inc., Fort Collins, CO 80525
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