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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
ZORYVE (NDA-215985)
(ROFLUMILAST)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
06/29/2026 (SUPPL-15)
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
…
Plaque Psoriasis
…
In 644 subjects 6 years of age and older with plaque psoriasis who continued treatment with ZORYVE cream, 0.3%, for up to 64 weeks in open-label extension trials, the adverse reaction profile was consistent with that observed in vehicle-controlled trials.
Pediatric Subjects 2 to 5 Years of Age
The safety of ZORYVE cream, 0.3%, once daily was assessed in an open-label trial for up to 24 weeks. The adverse reaction profile in pediatric subjects 2 years to 5 years of age with plaque psoriasis was consistent with that observed in adult and pediatric subjects 6 years of age and older.
…
8 Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined:
Plaque Psoriasis
The safety and effectiveness of ZORYVE cream, 0.3%, for the topical treatment of plaque psoriasis, including intertriginous areas, have been established in pediatric patients 2 years of age and older. Use of ZORYVE cream, 0.3%, for this indication is supported by data from:
Two 8-week, vehicle-controlled, safety and efficacy trials in adults and 18 subjects 6 to
17 years of age, of whom 11 received ZORYVE cream, 0.3%;
One open-label, safety trial in 21 pediatric subjects 2 to 5 years of age with up to 25% BSA involvement who applied ZORYVE cream, 0.3%, up to 24 weeks;
With additional safety and pharmacokinetic (PK) data from:
Open-label trials of 2- and 24-weeks duration which included 25 subjects 12 to 17 years of age treated with ZORYVE cream, 0.3%;
Two 4-week, open-label, safety and PK studies which included 20 pediatric subjects 6 to 11 years of age and 10 pediatric subjects 2 to 5 years of age, treated with ZORYVE cream, 0.3% [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].
The safety and effectiveness of ZORYVE cream, 0.3%, have not been established in pediatric patients younger than 2 years of age.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONAdditions and/or revisions underlined:
…
What is ZORYVE cream?
ZORYVE cream 0.3% is a prescription medicine used on the skin (topical), including in areas with skin folds, to treat plaque psoriasis in adults and children 2 years of age and older.
It is not known if ZORYVE cream 0.3% is safe and effective in children with plaque psoriasis younger than 2 years of age.
ZORYVE cream 0.15% is a prescription medicine used on the skin (topical) to treat mild to moderate eczema (atopic dermatitis) in adults and children 6 years of age and older.
It is not known if ZORYVE cream 0.15% is safe and effective in children with mild to moderate eczema (atopic dermatitis) younger than 6 years of age.
ZORYVE cream 0.05% is a prescription medicine used on the skin (topical) to treat mild to moderate eczema (atopic dermatitis) in children 2 to 5 years of age.
It is not known if ZORYVE cream 0.05% is safe and effective in children with mild to moderate eczema (atopic dermatitis) younger than 2 years of age and older than 6 years of age.
…
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. Avoid direct skin contact of treated areas with your baby if ZORYVE cream is applied to your chest.
…
10/04/2025 (SUPPL-12)
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
…
Plaque Psoriasis
Adult and Pediatric Subjects 6 Years of Age and Older
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, 0.3%, or vehicle cream once daily for 8 weeks [see Clinical Studies (14.1)].
The proportion of subjects who discontinued treatment due to an adverse reaction was 1.0% for subjects treated with ZORYVE cream, 0.3%, and 1.3% for subjects treated with vehicle cream. The most common adverse reaction that led to discontinuation of ZORYVE cream, 0.3%, was application site urticaria (0.3%).
Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE cream, 0.3%, and for which the rate exceeded the rate for vehicle cream.
Table 1: Adverse Reactions Reported in greater than or equal to 1% of Adult and Pediatric Subjects 6 Years of Age and Older with Plaque Psoriasis Treated with ZORYVE Cream, 0.3%, (and More Frequently than Vehicle Cream) for 8 Weeks in Trials DERMIS-1 and DERMIS-2
…
Atopic Dermatitis
Adult and Pediatric Subjects 6 Years of Age and Older
In two multicenter, randomized, double-blind, vehicle-controlled trials (INTEGUMENT-1 and INTEGUMENT-2), 1336 adult and pediatric subjects 6 years of age or older with mild to moderate atopic dermatitis were treated with ZORYVE cream, 0.15%, or vehicle cream once daily for 4 weeks [see Clinical Studies (14.2)].
The proportion of subjects who discontinued treatment due to an adverse reaction was 1.6% for subjects treated with ZORYVE cream, 0.15%, and 1.1% for subjects treated with vehicle cream.
Table 2 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE cream, 0.15%, and for which the rate exceeded the rate for vehicle cream.
Table 2: Adverse Reactions Reported in greater than or equal to 1% of Adult and Pediatric Subjects 6 Years of Age and Older with Atopic Dermatitis Treated with ZORYVE Cream, 0.15%, (and More Frequently than Vehicle Cream) for 4 Weeks in Trials INTEGUMENT-1 and INTEGUMENT-2
…
Pediatric Subjects 2 to 5 Years of Age
In a multicenter, randomized, double-blind, vehicle-controlled trial (INTEGUMENT-PED), 652 pediatric subjects 2 to 5 years of age with mild to moderate atopic dermatitis were treated with ZORYVE cream, 0.05%, or vehicle cream once daily for 4 weeks [see Clinical Studies (14.2)].
Table 3 presents adverse reactions that occurred in at least 1% of subjects treated with ZORYVE cream, 0.05%, and for which the rate exceeded the rate for vehicle cream.
Table 3: Adverse Reactions Reported in greater than or equal to 1% of Pediatric Subjects 2 to 5 Years of Age with Atopic Dermatitis Treated with ZORYVE Cream, 0.05%, (and More Frequently than Vehicle) for 4 Weeks in Trial INTEGUMENT-PED
Please refer to label for complete information
Adult and Pediatric Subjects 2 Years of Age and Older
The long-term safety of ZORYVE cream, 0.15%, and ZORYVE cream, 0.05%, was assessed in an open-label extension trial of 1219 subjects 2 years of age and older with mild to moderate atopic dermatitis who had completed one of the 4-week vehicle-controlled trials. The safety profile observed in the open-label extension trial was generally consistent with the safety profile observed at Week 4.
7 Drug Interactions
7.1 Effects of Other Drugs on ZORYVE Cream
Subsection title revised
Additions and/or revisions underlined:
Drugs that Inhibit Cytochrome P450 (CYP) Enzymes
No formal drug-drug interaction studies were conducted with ZORYVE cream; however, the 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 [see Clinical Pharmacology (12.3)].
Oral Contraceptives Containing Gestodene and Ethinyl Estradiol
The co-administration of roflumilast with oral contraceptives containing gestodene and ethinyl estradiol 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)].
8 Use in Specific Populations
8.2 Lactation
Additions and/or revisions underlined:
…
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. The concentration of roflumilast in animal milk does not necessarily predict the concentration of drug in human milk.
8.3 Females and Males of Reproductive Potential
Newly added subsection:
Infertility
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.
8.4 Pediatric Use
Additions and/or revisions underlined:
…
Atopic Dermatitis
ZORYVE Cream, 0.15%
The safety and effectiveness of ZORYVE cream, 0.15%, for the topical treatment of mild to moderate atopic dermatitis have been established in pediatric patients 6 years of age and older. Use of ZORYVE cream, 0.15%, in this age group is supported by data from two 4-week, vehicle- controlled, safety and efficacy trials which included 615 subjects 6 to 17 years of age, of whom 406 received ZORYVE cream, 0.15%, [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Use of ZORYVE cream, 0.15%, in pediatric patients 6 years of age and older is also supported by data from 481 pediatric subjects treated with ZORYVE cream, 0.15%, in open-label trials, of which 104 were treated for 52 weeks.
In an open-label PK trial in 36 pediatric subjects 2 to 16 years of age, following topical administration of roflumilast cream, 0.15%, once daily for 2 weeks, mean systemic exposure of roflumilast and roflumilast N-oxide in subjects 2 to 5 years of age was approximately 3.2-fold and 5.2-fold higher, respectively, compared to subjects 12 to 16 years of age, and approximately 2- fold and 2.3-fold higher, respectively, compared to subjects 6 to 11 years of age.
The safety and effectiveness of ZORYVE cream, 0.15%, have not been established in pediatric patients younger than 6 years of age.
ZORYVE Cream, 0.05%
The safety and effectiveness of ZORYVE cream, 0.05%, for the topical treatment of mild to moderate atopic dermatitis have been established in pediatric patients 2 to 5 years of age. Use of ZORYVE cream, 0.05%, in this age group is supported by data from one 4-week, vehicle- controlled, safety and efficacy trial which included 652 subjects 2 to 5 years of age, of whom 437 received ZORYVE cream, 0.05%, [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Use of ZORYVE cream, 0.05%, in pediatric patients 2 to 5 years of age is also supported by data from 572 pediatric subjects treated with ZORYVE cream, 0.05%, in open-label trials, of whom 353 were treated for 52 weeks.
The safety and effectiveness of ZORYVE cream, 0.05%, have not been established in pediatric patients younger than 2 years of age and older than 6 years of age.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
…
What is ZORYVE cream?
ZORYVE cream 0.3% is a prescription medicine used on the skin (topical), including in areas with skin folds, to treat plaque psoriasis in adults and children 6 years of age and older.
It is not known if ZORYVE cream 0.3% is safe and effective in children with plaque psoriasis under 6 years of age.
ZORYVE cream 0.15% is a prescription medicine used on the skin (topical) to treat mild to moderate eczema (atopic dermatitis) in adults and children 6 years of age and older.
It is not known if ZORYVE cream 0.15% is safe and effective in children with mild to moderate eczema (atopic dermatitis) under 6 years of age.
ZORYVE cream 0.05% is a prescription medicine used on the skin (topical) to treat mild to moderate eczema (atopic dermatitis) in children 2 to 5 years of age.
It is not known if ZORYVE cream 0.05% is safe and effective in children with mild to moderate eczema (atopic dermatitis) under 2 years of age and 6 years of age and older.
…
What are the possible side effects of ZORYVE cream?
The most common side effects of ZORYVE cream 0.3% in adults and children 6 years of age and older treated for plaque psoriasis include:
…
The most common side effects of ZORYVE cream 0.15% in adults and children 6 years of age and older treated for atopic dermatitis include:
…
The most common side effects of ZORYVE cream 0.05% in children 2 to 5 years of age treated for atopic dermatitis include:
upper respiratory tract infections
stuffy or runny nose
red or swollen eyes (like “pink eye”)
diarrhea
headache
vomiting
…
Additions and/or revisions underlined:
Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information).
Administration Instructions
Advise patients or caregivers that ZORYVE cream is for topical use only and is not for ophthalmic, oral, or intravaginal use.
Instruct patients and caregivers to wash hands after applying ZORYVE cream.
Lactation
Advise the patient to use ZORYVE cream on the smallest area of skin and for the shortest duration possible while breastfeeding. Instruct the patient who is breastfeeding not to apply ZORYVE cream directly to the nipple or areola to avoid direct infant exposure. Instruct the patient to avoid inadvertent contact of treated areas with infant skin [see Use in Specific Populations (8.2)].
07/09/2024 (SUPPL-7)
6 Adverse Reactions
6.1 Clinical Trials Experience
Extensive changes; please refer to label for complete information.8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
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).
…
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/m2 basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast didnot affect embryo-fetal development at a maternal oral dose of 0.2 mg/kg/day (4 times the MRHD on a mg/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 basis).
8.4 Pediatric Use
Additions and/or revisions underlined:
Plaque Psoriasis
The safety and effectiveness of ZORYVE cream, 0.3%, for the topical treatment of plaque psoriasis, including intertriginous areas, have been established in pediatric patients 6 years of age and older. Use of ZORYVE cream, 0.3%, in pediatric patients 6 years of age and older is supported by data from two 8-week, vehicle-controlled, safety and efficacy trials which included 18 subjects 6 to 17 years of age, of whom 11 received ZORYVE cream, 0.3%. Use of ZORYVE cream, 0.3%, in pediatric patients 12 years of age and older is also supported by data from open-label trials of 2 and 24 weeks duration which included 18 subjects 12 to 17 years of age treated with ZORYVE cream, 0.3%. Use of ZORYVE cream, 0.3%, 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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].
The safety and effectiveness of ZORYVE cream, 0.3%, have not been established in pediatric patients younger than 6 years of age.
Atopic Dermatitis
The safety and effectiveness of ZORYVE cream, 0.15%, for the topical treatment of mild to moderate atopic dermatitis have been established in pediatric patients 6 years of age and older. Use of ZORYVE cream, 0.15%, in this age group is supported by data from two 4-week, vehicle-controlled, safety and efficacy trials which included 615 subjects 6 to 17 years of age, of whom 406 received ZORYVE cream, 0.15%. Use of ZORYVE cream, 0.15%, in pediatric patients 6 years of age and older is also supported by data from 481 pediatric subjects treated with ZORYVE cream, 0.15%, in open-label trials, of which 104 were treated for 52 weeks [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
The safety and effectiveness of ZORYVE cream, 0.15%, have not been established in pediatric patients younger than 6 years of age.
8.5 Geriatric Use
Additions and/or revisions underlined:
There were 184 patients 65 years of age and older in clinical studies for plaque psoriasis and atopic dermatitis [see Clinical Studies (14.1, 14.2)].
Plaque Psoriasis
Of the 576 patients treated with ZORYVE cream, 0.3%, in the 2 controlled clinical studies for plaque psoriasis, 56 (9.7%) were 65 to 74 years of age and 21 (3.7%) were 75 years of age and 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.
Atopic Dermatitis
Of the 885 patients treated with ZORYVE cream, 0.15%, in the 2 controlled clinical studies for atopic dermatitis, 36 (4.1%) were 65 to 74 years of age and 8 (0.9%) were 75 years of age and 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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions and/or revisions underlined:
What is ZORYVE cream?
ZORYVE cream 0.3% 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 0.3% is safe and effective in children with plaque psoriasis under 6 years of age.
- ZORYVE cream 0.15% is a prescription medicine used on the skin (topical) to treat mild to moderate eczema (atopic dermatitis) in people 6 years of age and older.
It is not known if ZORYVE cream 0.15% is safe and effective in children with mild to moderate eczema (atopic dermatitis) under 6 years of age.
…
The most common side effects of ZORYVE cream 0.3% in people treated for plaque psoriasis include:
diarrhea
application site pain
headache
upper respiratory tract infections
trouble sleeping
urinary tract infections (UTIs)
- nausea
The most common side effects of ZORYVE cream 0.15% in people treated for atopic dermatitis include:
headache
diarrhea
nausea
vomiting
application site pain
10/05/2023 (SUPPL-2)
4 Contraindications
(Additions and/or revisions underlined)
ZORYVE cream is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
6 Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
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.
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.
8 Use in Specific Populations
8.1 Pregnancy
Risk Summary
(Additions and/or revisions underlined)
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 9 and 8 times the maximum recommended human dose (MRHD), respectively. Roflumilast induced post-implantation loss in rats at oral doses greater than or equal to 3 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 5 and 15 times the MRHD, respectively. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with an oral dose 15 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.
8.2 Lactation
Risk Summary
(Additions and/or revisions underlined)
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
(Additions and/or revisions underlined)
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), and 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
(Additions and/or revisions underlined)
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
(Additions and/or revisions underlined)
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) and Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
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)].