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| Product NDC Code | 80610-130 | ||||||
|---|---|---|---|---|---|---|---|
| Drug Name | Zoryve |
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| Type | Brand | ||||||
| Pharm Class | Phosphodiesterase 4 Inhibitor [EPC], Phosphodiesterase 4 Inhibitors [MoA] |
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| Active Ingredients |
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| Route | TOPICAL | ||||||
| Dosage Form | CREAM | ||||||
| RxCUI drug identifier | 2608534, 2608539 |
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| Application Number | NDA215985 | ||||||
| Labeler Name | Arcutis Biotherapeutics, Inc. | ||||||
| Packages |
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| Check if available Online | Get Medication Prices online with Discount |
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The most common adverse reactions (reported in ≥1% of patients) are diarrhea, headache, insomnia, application site pain, upper respiratory tract infections, and urinary tract infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Arcutis Biotherapeutics, Inc. at 1-844-692-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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. In two multicenter, randomized, double-blind, vehicle-controlled trials (DERMIS-1 and DERMIS-2), 881 adult and pediatric subjects 6 years of age or older with plaque psoriasis were treated with ZORYVE cream or vehicle topically once daily for 8 weeks. The median age was 47 years (range 6 to 88). The majority of the subjects were male (64%) and White (82%). The median body surface area (BSA) affected was 5.5% (range 2% to 20%). The proportion of subjects who discontinued treatment due to an adverse reaction was 1.0% for subjects treated with ZORYVE cream and 1.3% for subjects treated with vehicle cream. The most common adverse reaction that led to discontinuation of ZORYVE cream was application site urticaria (0.3%). Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE cream, and for which the rate exceeded the rate for vehicle cream. Table 1. Adverse Reactions Reported in ≥1% of Subjects with Plaque Psoriasis Treated with ZORYVE Cream (and More Frequently than Vehicle Cream) for 8 Weeks in Trials DERMIS-1 and DERMIS-2 Adverse Reaction ZORYVE Cream (N=576) n (%) Vehicle Cream (N=305) n (%) Diarrhea 18 (3.1) 0 (0.0) Headache 14 (2.4) 3 (1.0) Insomnia 8 (1.4) 2 (0.7) Nausea 7 (1.2) 1 (0.3) Application site pain 6 (1.0) 1 (0.3) Upper respiratory tract infection 6 (1.0) 1 (0.3) Urinary tract infection 6 (1.0) 2 (0.7) In 594 subjects who continued treatment with ZORYVE cream for up to 64 weeks in open-label extension trials, the adverse reaction profile was consistent with that observed in vehicle-controlled trials.
| Adverse Reaction | ZORYVE Cream (N=576) n (%) | Vehicle Cream (N=305) n (%) |
|---|---|---|
| Diarrhea | 18 (3.1) | 0 (0.0) |
| Headache | 14 (2.4) | 3 (1.0) |
| Insomnia | 8 (1.4) | 2 (0.7) |
| Nausea | 7 (1.2) | 1 (0.3) |
| Application site pain | 6 (1.0) | 1 (0.3) |
| Upper respiratory tract infection | 6 (1.0) | 1 (0.3) |
| Urinary tract infection | 6 (1.0) | 2 (0.7) |
ZORYVE Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Co-administration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE cream, weigh the potential for increased adverse reactions against benefit. ( 7 ) Drugs that Inhibit Cytochrome P450 (CYP) Enzymes The co-administration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. If these products are co-administered with ZORYVE cream, weigh the potential for increased adverse reactions against benefit [see Clinical Pharmacology (12.3) ] .
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE4. Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic 3',5'-adenosine monophosphate (cyclic AMP) metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP. The specific mechanism(s) by which roflumilast exerts its therapeutic action is not well defined. 12.2 Pharmacodynamics Pharmacodynamics of ZORYVE cream in the treatment of plaque psoriasis is unknown. 12.3 Pharmacokinetics Absorption The PK of ZORYVE cream was investigated in 18 adult and 6 adolescent (13 to 16 years of age) subjects with plaque psoriasis and a mean ± SD body surface area (BSA) involvement of 26.8 ± 6.80% and 13.0 ± 3.58% in adults and adolescents, respectively. In this study, on average, subjects applied 3 to 6.5 g of ZORYVE cream once daily for 15 days. Plasma concentrations of roflumilast and roflumilast N-oxide (see Metabolism ) were quantifiable in all but two subjects at Day 15. Following application of ZORYVE cream, the plasma concentration versus time profile was relatively flat, generally with a peak-to-trough ratio less than 2. In adults, the mean ± SD systemic exposure (AUC 0-24 ) was 72.7 ± 53.1 and 628 ± 648 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In adolescents, the mean ± SD AUC 0-24 was 25.1 ± 24.0 and 140 ± 179 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. The PK of ZORYVE cream was investigated in 10 pediatric subjects (6 to less than 12 years of age) with at least mild plaque psoriasis and a mean ± SD BSA involvement of 10.9 ± 6.56%. The 14-day mean ± SD extrapolated AUC 0-24 was 75.6 ± 87.3 and 693 ± 986 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In another study, the PK of ZORYVE cream was investigated in 9 pediatric subjects (2 to less than 6 years of age) with at least mild plaque psoriasis and a mean ± SD BSA involvement of 9.44 ± 5.57%. The 14-day mean ± SD extrapolated AUC 0-24 was 51.6 ± 29.9 and 539 ± 372 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. Distribution Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Elimination The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following topical administration, the half-lives of roflumilast and the N-oxide metabolite were 4.0 and 4.6 days, respectively. Metabolism Roflumilast is extensively metabolized via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the only major metabolite observed in the plasma of humans. Following oral administration, roflumilast and roflumilast N-oxide account for the majority (87.5%) of total dose administered in plasma. Roflumilast was not detectable in urine, while roflumilast N-oxide was only a trace metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were detected in urine. While roflumilast is 3 times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro , the plasma AUC of roflumilast N-oxide on average is approximately 8-fold greater than the plasma AUC of roflumilast following topical administration. A similar ratio was observed following intravenous administration, whereas following oral administration the N-oxide metabolite circulated on average about 10-fold higher than the parent drug. Specific Populations Following topical administration, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on age (2 to 88 years), sex, race, or ethnicity. Patients with Hepatic Impairment No studies were conducted with topical roflumilast in subjects with hepatic impairment; however, oral roflumilast 250 mcg once daily for 14 days was studied in subjects with mild to moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh A subjects and by 92% and 41%, respectively, in Child-Pugh B subjects, as compared to age-, weight-, and gender-matched healthy subjects. The C max of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively, in Child-Pugh A subjects and by 26% and 40%, respectively, in Child-Pugh B subjects, as compared to healthy subjects [see Contraindications (4) ] . Patients with Renal Impairment No studies were conducted with topical roflumilast in subjects with renal impairment. Following oral administration in 12 subjects with severe renal impairment, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed. Drug Interaction Studies Clinical Studies Since a major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2, drug interaction studies were performed with oral roflumilast and systemic inhibitors of CYP3A4 and CYP1A2 [see Drug Interactions (7) ] . Erythromycin: In an open-label crossover study in 16 healthy volunteers, the co-administration of CYP3A4 inhibitor erythromycin (500 mg 3 times daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 40% and 70% increase in C max and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in C max and AUC for roflumilast N-oxide, respectively. Ketoconazole: In an open-label crossover study in 16 healthy volunteers, the co-administration of a strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 23% and 99% increase in C max and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in C max and AUC for roflumilast N-oxide, respectively. Fluvoxamine: In an open-label crossover study in 16 healthy volunteers, the co-administration of dual CYP 3A4/1A2 inhibitor fluvoxamine (50 mg daily for 14 days) with a single oral dose of 500 mcg roflumilast showed a 12% and 156% increase in roflumilast C max and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide C max and AUC, respectively. Enoxacin: In an open-label crossover study in 16 healthy volunteers, the co-administration of dual CYP 3A4/1A2 inhibitor enoxacin (400 mg twice daily for 12 days) with a single oral dose of 500 mcg roflumilast resulted in an increased C max and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide C max was decreased by 14% while roflumilast N-oxide AUC was increased by 23%. Cimetidine: In an open-label crossover study in 16 healthy volunteers, the co-administration of a dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for 7 days) with a single oral dose of 500 mcg roflumilast resulted in a 46% and 85% increase in roflumilast C max and AUC; and a 4% decrease in C max and 27% increase in AUC for roflumilast N-oxide, respectively. In Vitro Studies Cytochrome P450 (CYP) Enzymes: In vitro studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human liver microsomes, roflumilast and roflumilast N-oxide in therapeutic plasma concentrations do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11; therefore, there is a low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE4. Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic 3',5'-adenosine monophosphate (cyclic AMP) metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP. The specific mechanism(s) by which roflumilast exerts its therapeutic action is not well defined.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Pharmacodynamics of ZORYVE cream in the treatment of plaque psoriasis is unknown.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Absorption The PK of ZORYVE cream was investigated in 18 adult and 6 adolescent (13 to 16 years of age) subjects with plaque psoriasis and a mean ± SD body surface area (BSA) involvement of 26.8 ± 6.80% and 13.0 ± 3.58% in adults and adolescents, respectively. In this study, on average, subjects applied 3 to 6.5 g of ZORYVE cream once daily for 15 days. Plasma concentrations of roflumilast and roflumilast N-oxide (see Metabolism ) were quantifiable in all but two subjects at Day 15. Following application of ZORYVE cream, the plasma concentration versus time profile was relatively flat, generally with a peak-to-trough ratio less than 2. In adults, the mean ± SD systemic exposure (AUC 0-24 ) was 72.7 ± 53.1 and 628 ± 648 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In adolescents, the mean ± SD AUC 0-24 was 25.1 ± 24.0 and 140 ± 179 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. The PK of ZORYVE cream was investigated in 10 pediatric subjects (6 to less than 12 years of age) with at least mild plaque psoriasis and a mean ± SD BSA involvement of 10.9 ± 6.56%. The 14-day mean ± SD extrapolated AUC 0-24 was 75.6 ± 87.3 and 693 ± 986 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. In another study, the PK of ZORYVE cream was investigated in 9 pediatric subjects (2 to less than 6 years of age) with at least mild plaque psoriasis and a mean ± SD BSA involvement of 9.44 ± 5.57%. The 14-day mean ± SD extrapolated AUC 0-24 was 51.6 ± 29.9 and 539 ± 372 h∙ng/mL for roflumilast and the N-oxide metabolite, respectively. Distribution Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Elimination The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following topical administration, the half-lives of roflumilast and the N-oxide metabolite were 4.0 and 4.6 days, respectively. Metabolism Roflumilast is extensively metabolized via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the only major metabolite observed in the plasma of humans. Following oral administration, roflumilast and roflumilast N-oxide account for the majority (87.5%) of total dose administered in plasma. Roflumilast was not detectable in urine, while roflumilast N-oxide was only a trace metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were detected in urine. While roflumilast is 3 times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro , the plasma AUC of roflumilast N-oxide on average is approximately 8-fold greater than the plasma AUC of roflumilast following topical administration. A similar ratio was observed following intravenous administration, whereas following oral administration the N-oxide metabolite circulated on average about 10-fold higher than the parent drug. Specific Populations Following topical administration, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on age (2 to 88 years), sex, race, or ethnicity. Patients with Hepatic Impairment No studies were conducted with topical roflumilast in subjects with hepatic impairment; however, oral roflumilast 250 mcg once daily for 14 days was studied in subjects with mild to moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh A subjects and by 92% and 41%, respectively, in Child-Pugh B subjects, as compared to age-, weight-, and gender-matched healthy subjects. The C max of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively, in Child-Pugh A subjects and by 26% and 40%, respectively, in Child-Pugh B subjects, as compared to healthy subjects [see Contraindications (4) ] . Patients with Renal Impairment No studies were conducted with topical roflumilast in subjects with renal impairment. Following oral administration in 12 subjects with severe renal impairment, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed. Drug Interaction Studies Clinical Studies Since a major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2, drug interaction studies were performed with oral roflumilast and systemic inhibitors of CYP3A4 and CYP1A2 [see Drug Interactions (7) ] . Erythromycin: In an open-label crossover study in 16 healthy volunteers, the co-administration of CYP3A4 inhibitor erythromycin (500 mg 3 times daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 40% and 70% increase in C max and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in C max and AUC for roflumilast N-oxide, respectively. Ketoconazole: In an open-label crossover study in 16 healthy volunteers, the co-administration of a strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 23% and 99% increase in C max and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in C max and AUC for roflumilast N-oxide, respectively. Fluvoxamine: In an open-label crossover study in 16 healthy volunteers, the co-administration of dual CYP 3A4/1A2 inhibitor fluvoxamine (50 mg daily for 14 days) with a single oral dose of 500 mcg roflumilast showed a 12% and 156% increase in roflumilast C max and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide C max and AUC, respectively. Enoxacin: In an open-label crossover study in 16 healthy volunteers, the co-administration of dual CYP 3A4/1A2 inhibitor enoxacin (400 mg twice daily for 12 days) with a single oral dose of 500 mcg roflumilast resulted in an increased C max and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide C max was decreased by 14% while roflumilast N-oxide AUC was increased by 23%. Cimetidine: In an open-label crossover study in 16 healthy volunteers, the co-administration of a dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for 7 days) with a single oral dose of 500 mcg roflumilast resulted in a 46% and 85% increase in roflumilast C max and AUC; and a 4% decrease in C max and 27% increase in AUC for roflumilast N-oxide, respectively. In Vitro Studies Cytochrome P450 (CYP) Enzymes: In vitro studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human liver microsomes, roflumilast and roflumilast N-oxide in therapeutic plasma concentrations do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11; therefore, there is a low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS ZORYVE cream is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C) [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . Moderate to severe liver impairment (Child-Pugh B or C). ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION ZORYVE (roflumilast) cream, 0.3%, is a white to off-white cream for topical use. The active ingredient, roflumilast, is a phosphodiesterase 4 (PDE4) inhibitor. Roflumilast is described chemically as 3-cyclopropylmethoxy- N -(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide. The empirical formula is C 17 H 14 Cl 2 F 2 N 2 O 3, and the molecular weight is 403.21. The structural formula is represented below: Roflumilast is practically insoluble in water and hexane, sparingly soluble in ethanol, and freely soluble in acetone. Each gram of ZORYVE cream contains 3 mg of roflumilast in a cream base containing ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Apply ZORYVE cream to affected areas once daily and rub in completely. Wash hands after application, unless ZORYVE cream is for treatment of the hands. ZORYVE cream is for topical use only and not for ophthalmic, oral, or intravaginal use. Apply once daily to affected areas. ( 2 ) For topical use only. ( 2 ) Not for ophthalmic, oral, or intravaginal use. ( 2 )
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Cream, 0.3%: 3 mg of roflumilast per gram of white to off-white cream in 60-gram tubes. Cream, 0.3%: 3 mg of roflumilast per gram in 60-gram tubes. ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE ZORYVE ® cream is indicated for topical treatment of plaque psoriasis, including intertriginous areas, in patients 6 years of age and older. ZORYVE cream is a phosphodiesterase 4 inhibitor indicated for topical treatment of plaque psoriasis, including intertriginous areas, in patients 6 years of age and older. ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.ZORYVE roflumilast ROFLUMILAST roflumilast ceteareth-10 phosphate CETOSTEARYL ALCOHOL cetearyl phosphate diethylene glycol monoethyl ether hexylene glycol isopropyl palmitate methylparaben propylparaben WATER sodium hydroxide white petrolatum hydrochloric acid off white
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies were conducted in hamsters and mice with roflumilast to evaluate its carcinogenic potential. In 2-year oral gavage carcinogenicity studies, roflumilast treatment resulted in dose-related, statistically significant increases in the incidence of undifferentiated carcinomas of nasal epithelium in hamsters at doses greater than or equal to 8 mg/kg/day (12 times the MRHD on an AUC basis). The tumorigenicity of roflumilast appears to be attributed to a reactive metabolite of 4-amino-3,5-dichloropyridine N - oxide (ADCP N-oxide). No evidence of tumorigenicity was observed in mice at roflumilast oral doses up to 12 and 18 mg/kg/day in females and males, respectively (11 and 17 times the MRHD, respectively, on an AUC basis). In a 2-year dermal mouse carcinogenicity study, no evidence of carcinogenicity was observed at topical doses of roflumilast cream up to 1% applied at 2 mL/kg/day (4 times the MRHD on an AUC basis). Roflumilast tested positive in an in vivo mouse micronucleus test, but negative in the following assays: the Ames test, an in vitro chromosome aberration assay in human lymphocytes, an in vitro HPRT assay with V79 cells, an in vitro micronucleus test with V79 cells, a DNA adduct formation assay in rat nasal mucosa, liver, and testes, and an in vivo mouse bone marrow chromosome aberration assay. Roflumilast N-oxide was negative in the Ames test and an in vitro micronucleus test with V79 cells. In a human spermatogenesis study, oral roflumilast 500 mcg had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period. In a fertility study, oral roflumilast decreased fertility rates in male rats at 1.8 mg/kg/day (35 times the MRHD on a mg/m 2 basis). The male rats also showed increases in the incidence of tubular atrophy, degeneration in the testis, and spermiogenic granuloma in the epididymides. No effect on rat fertility rate or male reproductive organ morphology was observed at 0.6 mg/kg/day (12 times the MRHD on a mg/m 2 basis). In a female fertility study, no effect on fertility was observed up to the highest roflumilast dose of 1.5 mg/kg/day in rats (29 times the MRHD on a mg/m 2 basis).
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies were conducted in hamsters and mice with roflumilast to evaluate its carcinogenic potential. In 2-year oral gavage carcinogenicity studies, roflumilast treatment resulted in dose-related, statistically significant increases in the incidence of undifferentiated carcinomas of nasal epithelium in hamsters at doses greater than or equal to 8 mg/kg/day (12 times the MRHD on an AUC basis). The tumorigenicity of roflumilast appears to be attributed to a reactive metabolite of 4-amino-3,5-dichloropyridine N - oxide (ADCP N-oxide). No evidence of tumorigenicity was observed in mice at roflumilast oral doses up to 12 and 18 mg/kg/day in females and males, respectively (11 and 17 times the MRHD, respectively, on an AUC basis). In a 2-year dermal mouse carcinogenicity study, no evidence of carcinogenicity was observed at topical doses of roflumilast cream up to 1% applied at 2 mL/kg/day (4 times the MRHD on an AUC basis). Roflumilast tested positive in an in vivo mouse micronucleus test, but negative in the following assays: the Ames test, an in vitro chromosome aberration assay in human lymphocytes, an in vitro HPRT assay with V79 cells, an in vitro micronucleus test with V79 cells, a DNA adduct formation assay in rat nasal mucosa, liver, and testes, and an in vivo mouse bone marrow chromosome aberration assay. Roflumilast N-oxide was negative in the Ames test and an in vitro micronucleus test with V79 cells. In a human spermatogenesis study, oral roflumilast 500 mcg had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period. In a fertility study, oral roflumilast decreased fertility rates in male rats at 1.8 mg/kg/day (35 times the MRHD on a mg/m 2 basis). The male rats also showed increases in the incidence of tubular atrophy, degeneration in the testis, and spermiogenic granuloma in the epididymides. No effect on rat fertility rate or male reproductive organ morphology was observed at 0.6 mg/kg/day (12 times the MRHD on a mg/m 2 basis). In a female fertility study, no effect on fertility was observed up to the highest roflumilast dose of 1.5 mg/kg/day in rats (29 times the MRHD on a mg/m 2 basis).
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 60 g Tube Carton NDC 80610-130-60 ZORYVE ® (roflumilast) cream 0.3% For Topical Use Only Not for oral, ophthalmic, or intravaginal use Rx Only Net Wt. 60 g ARCUTIS ® PRINCIPAL DISPLAY PANEL - 60 g Tube Carton
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Indications and Usage ( 1 ) 10/2023
| Indications and Usage ( | 10/2023 |
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.© 2024 Arcutis Biotherapeutics, Inc. All rights reserved. v3
ZORYVE: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information). Lactation Advise patients to use ZORYVE cream on the smallest area of skin and for the shortest duration possible while breastfeeding. Instruct patients who are breastfeeding not to apply ZORYVE cream directly to the nipple and areola to avoid direct infant exposure. Instruct patients to avoid inadvertent contact of treated areas with infant skin [see Use in Specific Populations (8.2) ] .
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.Patient Information ZORYVE ® (zor-EEV) (roflumilast) cream This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 10/2023 v2 Important information: ZORYVE cream is for use on the skin (topical use) only. Do not use ZORYVE cream in or on your eyes, mouth, or vagina. What is ZORYVE cream? ZORYVE cream is a prescription medicine used on the skin (topical), including in areas with skin folds, to treat plaque psoriasis in people 6 years of age and older. It is not known if ZORYVE cream is safe and effective in children under 6 years of age. Do not use ZORYVE cream if you have certain liver problems. Before using ZORYVE cream, tell your healthcare provider about all of your medical conditions, including if you: have liver problems. are pregnant or plan to become pregnant. It is not known if ZORYVE cream will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if ZORYVE cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with ZORYVE cream. Breastfeeding women using ZORYVE cream should use it on the smallest area of the skin and for the shortest time needed. Do not apply ZORYVE cream directly to the nipple or areola to avoid contact with your baby. Tell your healthcare provider about the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I use ZORYVE cream? Use ZORYVE cream exactly as your healthcare provider tells you to use it. Apply ZORYVE cream to the affected areas 1 time a day. Rub the cream in completely until you no longer see it on your skin. Wash your hands after applying ZORYVE cream, unless your hands are being treated. If someone else applies ZORYVE cream for you, they should wash their hands after applying it. What are the possible side effects of ZORYVE cream? The most common side effects of ZORYVE cream include: diarrhea headache trouble sleeping nausea application site pain upper respiratory tract infections urinary tract infections (UTIs) These are not all of the possible side effects of ZORYVE cream. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Arcutis Biotherapeutics, Inc. by calling 1-844-692-6729. How should I store ZORYVE cream? Store ZORYVE cream at room temperature from 68°F to 77°F (20°C to 25°C). Keep ZORYVE cream and all medicines out of the reach of children. General Information about the safe and effective use of ZORYVE cream. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZORYVE cream for a condition for which it was not prescribed. Do not give ZORYVE cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about ZORYVE cream that is written for health professionals. What are the ingredients in ZORYVE cream? Active ingredient: roflumilast Inactive ingredients: ceteareth-10 phosphate, cetearyl phosphate, cetostearyl alcohol, diethylene glycol monoethyl ether, hexylene glycol, isopropyl palmitate, methylparaben, propylparaben, purified water, sodium hydroxide, and white petrolatum. Hydrochloric acid may have been added to adjust pH. Marketed by: Arcutis Biotherapeutics, Inc. Westlake Village, CA 91361 For more information, call 1-844-692-6729 or visit http://www.zoryve.com.
| Patient Information ZORYVE® (zor-EEV) (roflumilast) cream | |||
|---|---|---|---|
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Issued: 10/2023 | ||
| v2 | |||
| ZORYVE cream is a prescription medicine used on the skin (topical), including in areas with skin folds, to treat plaque psoriasis in people 6 years of age and older. | |||
| It is not known if ZORYVE cream is safe and effective in children under 6 years of age. | |||
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| These are not all of the possible side effects of ZORYVE cream. | |||
| Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | |||
| You may also report side effects to Arcutis Biotherapeutics, Inc. by calling 1-844-692-6729. | |||
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| Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZORYVE cream for a condition for which it was not prescribed. Do not give ZORYVE cream to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about ZORYVE cream that is written for health professionals. | |||
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES Two multicenter, randomized, double-blind, vehicle-controlled trials (DERMIS-1 [NCT04211363] and DERMIS-2 [NCT04211389]) enrolled a total of 881 adult and pediatric subjects with mild to severe plaque psoriasis. Subjects were randomized 2:1 to receive ZORYVE cream or vehicle cream applied topically once daily for 8 weeks. The median age of the trial population was 47 years (range 6 to 88 years of age). The trial population was 64% male and 36% female; 82.3% were White, 7.1% Asian, 3.6% Black or African American, 0.9% Native Hawaiian or Other Pacific Islander, 0.7% American Indian or Alaska Native, 0.5% more than one race, 3.3% Other, and missing in 1.6% of subjects. For ethnicity, 75.7% of subjects identified as Not Hispanic or Latino, 24.1% identified as Hispanic or Latino, and 0.2% were unknown. The median body surface area (BSA) affected of the trial population was 5.5% (range 2% to 20%). At baseline, 16% of subjects had an Investigator's Global Assessment (IGA) score of 2 (mild), 76% had an IGA score of 3 (moderate), and 8% had an IGA score of 4 (severe). One hundred seventy-nine (20%) subjects had a baseline intertriginous IGA (I-IGA) score of 2 or higher (mild), and 678 (77%) subjects had a baseline Worst Itch-Numeric Rating Scale (WI-NRS) score of 4 or higher on a scale of 0 to 10. The primary endpoint was the proportion of subjects who achieved IGA treatment success at Week 8 (Table 2). Success was defined as a score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade improvement from baseline. Table 2: IGA Treatment Success at Week 8 in Subjects with Mild to Severe Plaque Psoriasis in Trials DERMIS-1 and DERMIS-2 DERMIS-1 DERMIS-2 ZORYVE Cream Vehicle Cream ZORYVE Cream Vehicle Cream Number of subjects randomized N=286 N=153 N=290 N=152 Abbreviations: CI = Confidence Interval IGA success IGA treatment success was defined as an IGA score of "Clear" (0) or "Almost Clear" (1), plus a 2-grade IGA score improvement from baseline at Week 8 (Multiple Imputation). 41.5% 5.8% 36.7% 7.1% Difference from vehicle (95% CI) Treatment difference and 95% CI are based on the CMH method stratified by site, baseline IGA, and baseline intertriginous involvement. 39.7% (32.4%, 47.0%) 29.5% (21.5%, 37.6%) Secondary endpoints included the proportion of subjects that achieved I-IGA success at Week 8 and WI-NRS success sequentially at Weeks 8, 4, and 2 (see Figure 1 ). WI-NRS success was defined as a reduction of at least 4 points from baseline in subjects with a baseline WI-NRS score of at least 4. Figure 1: WI-NRS Success Over Time in Subjects with Mild to Severe Plaque Psoriasis in Trials DERMIS-1 and DERMIS-2 WI-NRS success is a reduction of at least 4 points in subjects with a WI-NRS score of 4 or higher at baseline. † The treatment difference at Week 2 in DERMIS-1 was not statistically significant. Among subjects with an I-IGA score of at least 2 (mild) at baseline (approximately 22% of subjects in DERMIS-1 and 19% in DERMIS-2), there was a higher percentage of subjects who achieved I-IGA success at Week 8 in the group who received ZORYVE cream compared to the group who received vehicle cream (DERMIS-1: 71.5% vs. 13.8%; DERMIS-2: 67.5% vs. 17.4%). Figure 1
| DERMIS-1 | DERMIS-2 | |||
|---|---|---|---|---|
| ZORYVE Cream | Vehicle Cream | ZORYVE Cream | Vehicle Cream | |
| Number of subjects randomized | N=286 | N=153 | N=290 | N=152 |
| Abbreviations: CI = Confidence Interval | ||||
| IGA success | 41.5% | 5.8% | 36.7% | 7.1% |
| Difference from vehicle (95% CI) | 39.7% (32.4%, 47.0%) | 29.5% (21.5%, 37.6%) | ||
| Figure 1: WI-NRS Success Over Time in Subjects with Mild to Severe Plaque Psoriasis in Trials DERMIS-1 and DERMIS-2 |
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| †The treatment difference at Week 2 in DERMIS-1 was not statistically significant. |
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Of the 881 subjects with psoriasis exposed to ZORYVE cream or vehicle for up to 8 weeks in 2 controlled clinical trials, 106 were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3) ] .
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use The safety and effectiveness of ZORYVE cream for the treatment of plaque psoriasis have been established in pediatric patients 6 years of age and older. Use of ZORYVE cream in pediatric patients 6 to less than 18 years of age is supported by data from two 8-week, vehicle-controlled safety and efficacy trials which included 18 pediatric subjects 6 to 17 years of age, of whom 11 received ZORYVE cream. Use of ZORYVE cream in pediatric patients 12 to 17 years of age is also supported by data from open-label trials of 2 and 24 weeks duration which included 18 pediatric subjects 12 to 17 years of age treated with ZORYVE cream. Use of ZORYVE cream in pediatric patients 6 to less than 12 years of age is also supported by data from one 4-week, open-label, safety and pharmacokinetic (PK) study which included 20 pediatric subjects 6 to less than 12 years of age. The adverse reaction profile in subjects 6 to less than 18 years of age was consistent with that observed in adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14) ] . The safety and effectiveness of ZORYVE cream in pediatric patients below the age of 6 years have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary There are insufficient data available on the use of ZORYVE cream in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, roflumilast administered orally to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities at doses up to 36 and 31 times the maximum recommended human dose (MRHD), respectively. Roflumilast induced post-implantation loss in rats at oral doses greater than or equal to 12 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 19 and 59 times the MRHD, respectively. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with an oral dose 59 times the MRHD during pregnancy and lactation periods in mice (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Labor and delivery Avoid using ZORYVE cream during labor and delivery. There are no human studies that have investigated effects of ZORYVE cream on preterm labor or labor at term; however, animal studies showed that oral roflumilast disrupted the labor and delivery process in mice. Data Animal data In an embryo-fetal development study, pregnant rats were dosed orally during the period of organogenesis with up to 1.8 mg/kg/day roflumilast (36 times the MRHD on a mg/m 2 basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast did not affect embryo-fetal development at a maternal oral dose of 0.2 mg/kg/day (4 times the MRHD on a mg/m 2 basis). In a fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day roflumilast for 10 weeks and females for 2 weeks prior to pairing and throughout the organogenesis period. Roflumilast induced pre- and post-implantation loss at maternal oral doses greater than or equal to 0.6 mg/kg/day (12 times the MRHD on a mg/m 2 basis). Roflumilast did not cause fetal structural abnormalities at maternal oral doses up to 1.8 mg/kg/day (35 times the MRHD on a mg/m 2 basis). In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0.8 mg/kg/day roflumilast during the period of organogenesis. Roflumilast did not cause fetal structural abnormalities at the maternal oral doses of 0.8 mg/kg/day (31 times the MRHD on a mg/m 2 basis). In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day roflumilast during the period of organogenesis and lactation. Roflumilast induced stillbirth and decreased pup viability at maternal oral doses greater than 2 mg/kg/day and 6 mg/kg/day, respectively (19 and 59 times the MRHD on a mg/m 2 basis, respectively). Roflumilast induced delivery retardation in pregnant mice at maternal oral doses greater than 2 mg/kg/day (19 times the MRHD on a mg/m 2 basis). Roflumilast decreased pup rearing frequencies at a maternal oral dose of 6 mg/kg/day during pregnancy and lactation (59 times the MRHD on a mg/m 2 basis). Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at a maternal oral dose of 12 mg/kg/day (116 times the MRHD on a mg/m 2 basis).
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are insufficient data available on the use of ZORYVE cream in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, roflumilast administered orally to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities at doses up to 36 and 31 times the maximum recommended human dose (MRHD), respectively. Roflumilast induced post-implantation loss in rats at oral doses greater than or equal to 12 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 19 and 59 times the MRHD, respectively. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with an oral dose 59 times the MRHD during pregnancy and lactation periods in mice (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Labor and delivery Avoid using ZORYVE cream during labor and delivery. There are no human studies that have investigated effects of ZORYVE cream on preterm labor or labor at term; however, animal studies showed that oral roflumilast disrupted the labor and delivery process in mice. Data Animal data In an embryo-fetal development study, pregnant rats were dosed orally during the period of organogenesis with up to 1.8 mg/kg/day roflumilast (36 times the MRHD on a mg/m 2 basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast did not affect embryo-fetal development at a maternal oral dose of 0.2 mg/kg/day (4 times the MRHD on a mg/m 2 basis). In a fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day roflumilast for 10 weeks and females for 2 weeks prior to pairing and throughout the organogenesis period. Roflumilast induced pre- and post-implantation loss at maternal oral doses greater than or equal to 0.6 mg/kg/day (12 times the MRHD on a mg/m 2 basis). Roflumilast did not cause fetal structural abnormalities at maternal oral doses up to 1.8 mg/kg/day (35 times the MRHD on a mg/m 2 basis). In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0.8 mg/kg/day roflumilast during the period of organogenesis. Roflumilast did not cause fetal structural abnormalities at the maternal oral doses of 0.8 mg/kg/day (31 times the MRHD on a mg/m 2 basis). In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day roflumilast during the period of organogenesis and lactation. Roflumilast induced stillbirth and decreased pup viability at maternal oral doses greater than 2 mg/kg/day and 6 mg/kg/day, respectively (19 and 59 times the MRHD on a mg/m 2 basis, respectively). Roflumilast induced delivery retardation in pregnant mice at maternal oral doses greater than 2 mg/kg/day (19 times the MRHD on a mg/m 2 basis). Roflumilast decreased pup rearing frequencies at a maternal oral dose of 6 mg/kg/day during pregnancy and lactation (59 times the MRHD on a mg/m 2 basis). Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at a maternal oral dose of 12 mg/kg/day (116 times the MRHD on a mg/m 2 basis). 8.2 Lactation Risk Summary There are no data on the presence of roflumilast or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Roflumilast and/or its metabolites are excreted into the milk of lactating rats (see Data ) . When a drug is present in animal milk, it is likely that the drug will present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZORYVE cream and any potential adverse effects on the breastfed infant from ZORYVE cream or from the underlying maternal condition. Clinical Considerations To minimize potential exposure to the breastfed infant via breast milk, use ZORYVE cream on the smallest area of skin and for the shortest duration possible while breastfeeding. To avoid direct infant exposure, advise breastfeeding women not to apply ZORYVE cream directly to the nipple or areola. If applied to the patient's chest, avoid exposure via direct contact with the infant's skin. Data Animal data Roflumilast and/or its metabolite concentrations measured 8 hours after an oral dose of 1 mg/kg given to lactating rats were 0.32 and 0.02 mcg/g in the milk and pup liver, respectively. 8.4 Pediatric Use The safety and effectiveness of ZORYVE cream for the treatment of plaque psoriasis have been established in pediatric patients 6 years of age and older. Use of ZORYVE cream in pediatric patients 6 to less than 18 years of age is supported by data from two 8-week, vehicle-controlled safety and efficacy trials which included 18 pediatric subjects 6 to 17 years of age, of whom 11 received ZORYVE cream. Use of ZORYVE cream in pediatric patients 12 to 17 years of age is also supported by data from open-label trials of 2 and 24 weeks duration which included 18 pediatric subjects 12 to 17 years of age treated with ZORYVE cream. Use of ZORYVE cream in pediatric patients 6 to less than 12 years of age is also supported by data from one 4-week, open-label, safety and pharmacokinetic (PK) study which included 20 pediatric subjects 6 to less than 12 years of age. The adverse reaction profile in subjects 6 to less than 18 years of age was consistent with that observed in adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14) ] . The safety and effectiveness of ZORYVE cream in pediatric patients below the age of 6 years have not been established. 8.5 Geriatric Use Of the 881 subjects with psoriasis exposed to ZORYVE cream or vehicle for up to 8 weeks in 2 controlled clinical trials, 106 were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3) ] . 8.6 Hepatic Impairment Oral roflumilast 250 mcg once daily for 14 days was studied in subjects with hepatic impairment. The systemic exposure of roflumilast and roflumilast N-oxide were increased in subjects with moderate (Child-Pugh B) hepatic impairment. ZORYVE cream is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C). No dosage adjustment is needed in patients with mild (Child-Pugh A) hepatic impairment [see Contraindications (4) , Clinical Pharmacology (12.3) ] .
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ZORYVE (roflumilast) cream is a white to off-white cream containing 3 mg (0.3%) of roflumilast per gram and is supplied in 60-gram aluminum tubes (NDC 80610-130-60). Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature]
Storage and handling
Information about safe storage and handling of the drug product.Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature]
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API