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Arctic > Foam > Flashcards

Foam Flashcards

1
Q

Indications and usage

A

ZORYVE foam, 0.3% is indicated for the treatment of seborrheic dermatitis in adult and pediatric patients 9 years of age and older

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2
Q

Dosage and administration

A
  1. Shake can prior to use. Apply a thin layer of ZORYVE foam, 0.3%, once daily to affected areas on skin and/or scalp when they are not wet. Rub in completely.
  2. Wash hands after application
  3. Avoid fire, flame, and smoking during and immediately following application
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3
Q

Dosage and strengths

A

Topical foam, 0.3%: 3 mg of roflumilast per gram of white to off-white foam in 60-gram pressurized cans

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4
Q

Contraindications

A

ZORYVE foam, 0.3% is contraindicated in patients with moderate-to-severe liver impairment (Child-Pugh B or C)

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5
Q

warnings and precautions

A

5.1 Flammability: The propellants in ZORYVE foam, 0.3%, are flammable. Avoid fire, flame, and smoking during and immediately following application

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6
Q

Most common ARs in ≥1% of patients with SD treated with foam 0.3% for 8 weeks

A
  1. Nasopharyngitis (1.5%)
  2. Nausea (1.3%)
  3. Headache (1.1%)
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7
Q

The following additional ARs were reported in fewer than 1% of patients with foam:

A

diarrhea, insomnia

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8
Q

in 408 patients who continued treatment with foam, for up to 24 to 52 weeks in an open-label, long-term trial, the AR profile was

A

consistent with that observed in vehicle-controlled trials

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9
Q

drug interactions

A

no drug interaction studies were conducted

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10
Q

drug reactions: the coadministration of rofl with ____ or _____ may increase rofl exposure and result in increased ARs.

A

CYP3A4 inhibitors, dual inhibitors of 3a4 and 1A2

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11
Q

data in pregnant women

A

There are insufficient data available on the use of ZORYVE foam, 0.3% in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes

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12
Q

data in pregnant rats and rabbits

A
  1. produced no fetal structural abnormalities at doses up to 30- and 26-times the MRHD, respectively
  2. Roflumilast induced post-implantation loss in rats at oral doses ≥10-times the MRHD
  3. Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 16- and 49-times the MRHD, respectively
  4. Roflumilast has been shown to adversely affect pup postnatal development when dams were treated with oral dose 49-times the MRHD during pregnancy and lactation periods in mice
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13
Q

Data in labor and delivery

A

avoid using ZORYVE foam, 0.3%, during labor and delivery. There are no human studies that have investigated effects of ZORYVE foam, 0.3%, on preterm labor or labor at term; however, animal studies showed that oral roflumilast disrupted the labor and delivery process in mice

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14
Q

data in lactation

A

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

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15
Q

data in lactation (rats)

A

Roflumilast and/or its metabolites are excreted into the milk of lactating rats. 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 foam, 0.3%, and any potential adverse effects on the breastfed infant from ZORYVE foam, 0.3%, or from the underlying maternal condition

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16
Q

clinical guidance on use in lactation

A

To minimize potential exposure to the breastfed infant via breastmilk, use ZORYVE foam, 0.3%, on the smallest area of the skin and for the shortest duration possible while breastfeeding. To avoid direct infant exposure, advise breastfeeding women not to apply ZORYVE foam, 0.3% directly to the nipple or areola. If applied to the patient’s chest, avoid exposure via direct contact with the infant’s skin

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17
Q

pediatric use?

A
  1. The safety and effectiveness of ZORYVE foam, 0.3%, for the treatment of seborrheic dermatitis have been established in pediatric patients ≥9 years of age
  2. The safety and effectiveness of ZORYVE foam, 0.3%, in pediatric patients below the age of 9 years have not been established
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18
Q

what data supports pediatric use?

A

Use of ZORYVE foam, 0.3%, in this age group is supported by data from two 8-week, vehicle-controlled trials which included 32 pediatric patients 9 to 17 years of age, of whom 17 received ZORYVE foam, 0.3%, and from open-label trials of up to 52 weeks which included 23 pediatric patients treated with ZORYVE foam, 0.3%

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19
Q

difference between adult and pediatric ARs

A

The adverse reaction profile was consistent with that observed in adults

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20
Q

geriatric use?

A

Of the 683 patients with seborrheic dermatitis exposed to ZORYVE foam, 0.3%, or vehicle for up to 8 weeks in the controlled clinical trials, 98 (14%) were ≥65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity in some older individuals cannot be ruled out

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21
Q

hepatic impairment

A

Oral roflumilast 250 mcg once daily for 14 days was studied in patients with hepatic impairment. The systemic exposure of roflumilast and roflumilast N-oxide were increased in patients with moderate (Child-Pugh B) hepatic impairment. ZORYVE foam, 0.3%, is contraindicated in patients with moderate-to-severe liver impairment (Child-Pugh B or C)

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22
Q

dose adjustment for mild hepatic impairment (Child-Pugh A)

A

No dosage adjustment is needed in patients with mild (Child-Pugh A) hepatic impairment

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23
Q

MoA

A

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

24
Q

Pharmacodynamics

A

Pharmacodynamics of ZORYVE foam, 0.3% in the treatment of seborrheic dermatitis is unknown

25
Q

PK: absorption

A

The PK of ZORYVE foam, 0.3%, was investigated in 10 adult and 10 pediatric (11 to 16 years of age) patients with seborrheic dermatitis. In this study, a mean dose of approximately 4.1 g of ZORYVE foam, 0.3%, was applied once daily for 15 days to a mean ± SD BSA involvement of 6.5 ± 1.08% and 5.5 ± 1.27% in adult and pediatric patients, respectively. Plasma concentrations of roflumilast were quantifiable in all but 2 patients at Day 15. Plasma concentrations of roflumilast N-oxide were quantifiable in all patients at Day 15.
Following application of ZORYVE foam, 0.3%, the plasma concentration versus time profile was relatively flat, with mean peak-to-trough ratios of 1.68 and 1.62 for roflumilast and roflumilast N-oxide, respectively

26
Q

PK: absorption (continued)

A
  1. In adults, the mean ± SD Cmax was 2.2 ± 1.6 and 13.8 ± 9.0 ng/mL for roflumilast and roflumilast N-oxide metabolite, respectively. The mean systemic exposure (AUC0-24) was 36.6 ± 23.7 and 261 ± 190 h*ng/mL for roflumilast and the N-oxide metabolite, respectively
  2. In pediatric patients, the extrapolated mean ± AUC0-24 (based on pre-dose concentration) was 25.1 ± 30.2 and 253 ± 404 h*ng/mL for roflumilast and the N-oxide, respectively
27
Q

PK: distribution

A

Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively

28
Q

PK: Elimination

A

The plasma clearance after short-term IV 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

29
Q

PK: metabolism

A

Roflumilast is extensively metabolized via Phase I (CYP450) 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 the total dose administered in plasma. Roflumilast was not detectable in urine, while roflumilast N-oxide was only a trace metabolite (<1%). Other conjugated metabolites, such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were detected in urine

30
Q

PK: metabolism (continued)

A

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 7-fold greater than the plasma AUC of roflumilast following topical administration. A similar ratio was observed following IV administration, whereas following oral administration the N-oxide metabolite circulated on average about 10-fold higher than the parent drug

31
Q

PK: specific populations

A

Following topical administration, no clinically significant differences in the PK of roflumilast and roflumilast N-oxide were observed based on age (2 to 88 years), sex, race, or ethnicity

32
Q

PK: hepatic impairment

A

No studies were conducted with topical roflumilast in patients with hepatic impairment; however, oral roflumilast 250 mcg once daily for 14 days was studied in patients with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 patients in each group)
The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh A patients and 92% and 41%, respectively in Child-Pugh B patient, as compared to age-, weight-, and gender-matched healthy participants
The Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively, in Child-Pugh A patients and by 26% and 40%, respectively, in Child-Pugh B patients, as compared to healthy participants

33
Q

PK: renal impairment

A

Patients with Renal Impairment: No studies were conducted with topical roflumilast in patients with renal impairment. Following oral administration in 12 patients with severe renal impairment, no clinically significant differences in the PK of roflumilast and roflumilast N-oxide were observed

34
Q

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, including

A

erythromycin, ketoconazole, fluvoxamine, enoxacin, cimedtidine

35
Q

cimetidine use

A

heartburn, stomach ulcers, reflux disease

36
Q

enoxacin use

A

treatment of gonorrhea, cystitis, complicated urinary-tract infections, and skin and skin structure infections

37
Q

fluvoxamine use

A

treatment of obsessive-compulsive disorder and is used for other conditions, including depression.

38
Q

ketoconazole use

A

Athlete’s foot (tinea pedis; ringworm of the foot);
Ringworm of the body (tinea corporis);
Ringworm of the groin (tinea cruris; jock itch);
Seborrheic dermatitis;
“Sun fungus” (tinea versicolor; pityriasis versicolor); and.
Yeast infection of the skin (cutaneous candidiasis).

39
Q

erythromycin use

A

Erythromycin is used to prevent and treat infections in many different parts of the body, including respiratory tract infections, skin infections, diphtheria, intestinal amebiasis, acute pelvic inflammatory disease, Legionnaire’s disease, pertussis, and syphilis.

40
Q

DI: erythromycin

A

in an open-label crossover study in 16 healthy participants, the coadministration of CYP3A4 inhibitor erythromycin (500 mg TID for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in Cmax and AUC for roflumilast N-oxide, respectively

41
Q

DI: ketoconazole

A

in an open-label crossover study in 16 healthy participants, the coadministration of a strong CYP3A4 inhibitor ketoconazole (200 mg BID for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in Cmax and AUC for roflumilast N-oxide, respectively

42
Q

DI: fluvoxamine

A

in an open-label crossover study in 16 healthy participants, the coadministration of dual CYP3A4/1A2 inhibitor fluvoxamine (50 mg QD for 14 days) with a single oral dose of 500 mcg roflumilast showed a 12% and 156% increase in roflumilast Cmax and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide Cmax and AUC, respectively

43
Q

DI: enoxacin

A

in an open-label crossover study in 16 healthy participants, the coadministration of dual CYP3A4/1A2 inhibitor enoxacin (400 mg BID for 12 days) with a single oral dose of 500 mcg roflumilast resulted in an increased Cmax and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide Cmax was decreased by 14% while AUC increased by 23%

44
Q

DI: cimetidine

A

: in an open-label crossover study in 16 healthy participants, the coadministration of a dual CYP3A4/1A2 inhibitor cimetidine (400 mg BID for 7 days) with a single oral dose of 500 mcg roflumilast resulted in a 46% and 85% increase in roflumilast Cmax and AUC; and a 4% decrease in Cmax and 27% increase in AUC for roflumilast N-oxide, respectively

45
Q

in vitro studies: CYP enzymes

A

in vitro studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further invitro 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 CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only weak induction of CYP2B6 by roflumilast

46
Q

long-term carcinogenesis, mutagenesis, and fertility impairment

A

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 the nasal epithelium in hamsters at doses ≥8 mg/kg/day (20-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 (18- and 27-times the MRHD, respectively, on an AUC basis)

47
Q

semen and reproductive hormone changes

A

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

48
Q

clinical studies

A

Two randomized, DB, vehicle-controlled trials (STRATUM [NCT04973228] and Trial 203 [NCT04091646]) enrolled a total of 683 adult and pediatric patients with seborrheic dermatitis involving the scalp, face, and/or body with an IGA of moderate or severe (IGA of 3 or 4 on a 5-point scale from 0 to 4)
In each trial, patients were randomized 2:1 to receive ZORYVE foam, 0.3%, or vehicle foam applied once daily for 8 weeks
The combined trial population included 79% White, 11% Black, and 5% Asian; for ethnicity, 79% identified as non-Hispanic/Latino and 21% identified as Hispanic/Latino. Fifty percent (50%) were male and 50% were female.

49
Q

STRATUM description

A

In the Trial STRATUM, the trial population ranged in age from 9 to 87 years, including 7% of patients who were 9 to 17 years of age and 12% of patients who were ≥65 years. At baseline, 94% of patients had an IGA score of 3 (moderate), and 6% had an IGA score of 4 (severe). At baseline, 67% of patients had a WI-NRS score of 4 or higher on a scale of 0 to 10

50
Q

203 description

A

In Trial 203, the trial population ranged in age from 18 to 85 years, including 18% who were ≥65 years. At baseline, 93% of patients had an IGA score of 3 (moderate), and 7% had an IGA score of 4 (severe). At baseline, 81% of patients had a WI-NRS score of 4 or higher on a scale of 0 to 10

51
Q

how supplied

A

ZORYVE (roflumilast) topical foam, 0.3%, is a white to off-white foam. It is supplied in a 60-gram pressurized aluminum can (NDC 80610-430-60)

52
Q

storage and handling

A
  1. Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [See USP Controlled Room Temperature]
  2. Do not freeze
  3. Store upright
  4. Flammable. Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at room temperatures above 49C (120F)
53
Q

counseling information: flammability

A

Because the propellants in ZORYVE foam, 0.3%, are flammable, instruct the patient to avoid fire, flame, and smoking during and immediately following application

54
Q

counseling information: lactation

A

Advise patients to use ZORYVE foam, 0.3%, on the smallest area of skin and for the shortest duration possible while breastfeeding. Instruct patients who are breastfeeding not to apply ZORYVE foam, 0.3%, directly to the nipple and areola to avoid direct infant exposure. Instruct patients to avoid inadvertent contact of treated areas with infant skin

55
Q

patient information: How should I use ZORYVE foam?

A

Before applying ZORYVE foam for the first time, gently pull back the nozzle to break the plastic piece at the base
Shake the can well before each use
Turn the can upside down and press the nozzle to dispense a small amount into your hand
Apply a thin layer of ZORYVE foam 1 time a day to cover the affected areas on the scalp and skin when they are not wet. If you are treating your scalp, part the hair so that ZORYVE foam can be applied directly to the affected area on the skin. Rub the foam in completely
Wash your hands after applying ZORYVE foam. If someone else applies it to you, they should wash their hands after applying it

56
Q
A

Arctic (12 decks)

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