PSORIASIX

Apremilast, also known as Otezla, is a phosphodiesterase 4 (PDE4) inhibitor used to treat various types of symptoms resulting from certain inflammatory autoimmune diseases.

It belongs to the same drug class as Roflumilast and Crisaborole. 11, 12 Initially approved in 2014, it is marketed by Celgene.

In July 2019, apremilast was granted a new FDA approval for the treatment of oral ulcers associated with Behcet's disease, an autoimmune condition that causes recurrent skin, blood vessel, and central nervous system inflammation.

Apremilast is indicated for the treatment of adults with active psoriatic arthritis and adults with oral ulcers associated with Behcet's Disease.

In addition, apremilast is indicated for the treatment of plaque psoriasis, of any severity, in adult patients who are candidates for phototherapy or systemic therapy.

Apremilast reduces but does not completely inhibit various inflammatory cytokines such as IL-1α, IL-6, IL-8, IL-10 MCP-1, MIP-1β, MMP-3, and TNF-α, relieving the symptoms of psoriasis and Behcet's disease, which are caused by an increase in these inflammatory mediators. 6, 13 This drug has also been proven to be effective in relieving the pain associated with oral ulcers in Behcet's disease.

Apremilast may cause unwanted weight loss and worsen depression, leading to suicidal thoughts or actions.

It is advisable to monitor for symptoms of depression and seek medical attention if they occur, especially in patients with pre-existing depression.

The need for apremilast should be carefully assessed along with the risk of worsening depression and suicide.

If weight loss occurs, the degree of weight loss should be evaluated, and consideration should be made for the possible discontinuation of apremilast.

An oral dose of apremilast is well-absorbed and the absolute bioavailability is approximately 73%.

Tmax is approximately 2.5 hours and Cmax has been reported to be approximately 584 ng/mL in one pharmacokinetic study.

Food intake does not appear to affect apremilast absorption.

The average apparent volume of distribution (Vd) is about 87 L, suggesting that apremilast is distributed in the extravascular compartment.

Apremilast is heavily metabolized by various pathways, which include oxidation, hydrolysis, in addition to conjugation.

About 23 metabolites are produced from its metabolism.

CYP3A4 primarily mediates the oxidative metabolism of this drug, with smaller contributions from CYP1A2 and CYP2A6 enzymes.

The main metabolite of apremilast, M12, is an inactive glucuronide conjugate form of the O-demethylated drug.

Some other major metabolites, M14 and M16, are significantly less active in the inhibition of PDE4 and inflammatory mediators than their parent drug, apremilast.

After an oral dose, unchanged apremilast (45%) and the inactive metabolite, O-desmethyl apremilast glucuronide (39%) are found in the plasma.

Minor metabolites

M7 and M17 are active, but are only present in about 2% or less of apremilast concentrations, and likely not significant contributors to the actions of apremilast.

Hover over products below to view reaction partners Apremilast O-desmethyl Apremilast O-desmethyl apremilast glucuronide.

Only 3% and 7% of an apremilast dose are detected in the urine and feces as unchanged drug, respectively, indicating extensive metabolism and high absorption.

The average elimination half-life of this drug ranges from 6-9 hours. 7, 14.

In healthy patients, the plasma clearance of apremilast is about 10 L/hour.

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The oral

LD50 in mice was greater than 2000 mg/kg in mice.

In rats, oral LD50 was 2000 mg/kg males and 300 mg/kg in females.

Overdose information

In healthy subjects receiving a maximum dose of 100 mg (given as 50 mg twice daily) for about 5 days, no significant toxicity was observed.

In cases of an overdose, supportive and symptomatic treatment should be administered.

Contact the local poison control center for the most recent overdose management for apremilast.

is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation.

Known hypersensitivity to apremilast or to any of the excipients in the formulation.

To reduce the risk of gastrointestinal symptoms, titrate to recommended dosage as follows: Adults with Psoriatic Arthritis, Plaque Psoriasis, or Behçet's Disease See Table for the initial titration schedule.

Recommended maintenance dosage is

OTEZLA 30 mg twice daily or OTEZLA XR 75 mg once daily Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis or Moderate to Severe Plaque Psoriasis See Table for the initial titration schedule For patients weighing 50 kg or more: Recommended maintenance dosage is OTEZLA 30 mg twice daily or OTEZLA XR 75 mg once daily For patients weighing 20 kg to less than 50 kg: Recommended maintenance dosage is OTEZLA 20 mg twice daily Dosage in Patients with Severe Renal Impairment: Adult Patients: For initial dosage titration, titrate using only morning schedule listed in Table and skip afternoon doses.

OTEZLA 30 mg once daily Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis or Moderate to Severe Plaque Psoriasis: For initial dosage titration, titrate using only morning schedule for appropriate body weight category in Table and skip afternoon doses For patients weighing 50 kg or more: Recommended maintenance dosage is OTEZLA 30 mg once daily For patients weighing 20 kg to less than 50 kg: Recommended maintenance dosage is OTEZLA 20 mg once daily 2.1 Recommended Dosage in Adult and Pediatric Patients with Psoriatic Arthritis, Plaque Psoriasis, and Behçet's Disease Adult Patients with Psoriatic Arthritis, Plaque Psoriasis, or Behçet's Disease The recommended initial dosage titration from Day to Day is shown in Table 1.

Following the 5-day titration with OTEZLA, the recommended maintenance dosage is OTEZLA 30 mg twice daily or OTEZLA XR 75 mg once daily taken orally starting on Day 6.

This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.

Table 1.

Dosage Titration Schedule for Adult Patients with Psoriatic Arthritis, Plaque Psoriasis, or Behçet's Disease OTEZLA Dosage Titration OTEZLA tablets should be used for the initial titration regardless of whether OTEZLA or OTEZLA XR will be used for the maintenance dosage.

OTEZLA/OTEZLA XR Maintenance Dosage Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 & thereafter AM AM PM AM PM AM PM AM PM BID = twice daily; QD = once daily 10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg OTEZLA 30 mg BID OR OTEZLA XR 75 mg QD Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis Moderate to Severe Plaque Psoriasis The recommended dosage for pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis or moderate to severe plaque psoriasis is based on body weight.

Following the appropriate initial titration schedule shown in Table 2, the recommended maintenance dosage is: For pediatric patients who weigh at least 50 kg: OTEZLA 30 mg twice daily or OTEZLA XR 75 mg once daily taken orally For pediatric patients who weigh from 20 kg to less than 50 kg: OTEZLA 20 mg twice daily taken orally The initial titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.

Table 2.

Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis or Moderate to Severe Plaque Psoriasis OTEZLA Dosage Titration OTEZLA tablets should be used for the initial titration regardless of whether OTEZLA or OTEZLA XR will be used for the maintenance dosage.

OTEZLA/OTEZLA XR Maintenance Dosage Body Weight Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 & thereafter AM AM PM AM PM AM PM AM PM BID = twice daily; QD = once daily 50 kg or more 10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg OTEZLA 30 mg BID OR OTEZLA XR 75 mg QD 20 kg to less than 50 kg 10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 20 mg OTEZLA 20 mg BID 2.2 Switching Between OTEZLA and OTEZLA XR Patients treated with OTEZLA 30 mg twice daily may be switched to OTEZLA XR 75 mg once daily the day following the last dose of OTEZLA 30 mg. Patients treated with OTEZLA XR 75 mg once daily may be switched to OTEZLA 30 mg twice daily the day following the last dose of OTEZLA XR 75 mg. 2.3 Dosage Adjustment in Adult and Pediatric Patients with Severe Renal Impairment Adult Patients with Psoriatic Arthritis, Plaque Psoriasis, or Behçet's Disease For initial dosage titration in adult patients with severe renal impairment (creatinine clearance [CLcr] of less than 30 mL per minute estimated by the Cockcroft–Gault equation), titrate OTEZLA using only the AM schedule listed in Table and skip the PM doses.

The recommended maintenance dosage in this group is OTEZLA 30 mg once daily.

XR is not recommended for adult patients with severe renal impairment; the appropriate dosage for these patients has not been determined.

Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis or Moderate to Severe Plaque Psoriasis For initial dosage titration in pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis or moderate to severe plaque psoriasis and severe renal impairment (CLcr of less than 30 mL per minute estimated by the Cockcroft–Gault equation), titrate OTEZLA using only the AM schedule listed in Table for the appropriate body weight category and skip the PM doses.

The recommended maintenance dosage is

For pediatric patients who weigh at least 50 kg: OTEZLA 30 mg once daily taken orally For pediatric patients who weigh 20 kg to less than 50 kg: OTEZLA 20 mg once daily taken orally OTEZLA XR is not recommended for pediatric patients with severe renal impairment; the appropriate dosage for these patients has not been determined. 2.4 Important Administration Instructions Administer OTEZLA/OTEZLA XR with or without food.

Swallow tablets whole.

Do not crush, split, or chew.

is available as diamond-shaped, film-coated tablets in the following dosage strengths: 10 mg pink tablet engraved with "APR" on one side and "10" on the other side; 20 mg brown tablet engraved with "APR" on one side and "20" on the other side; 30 mg beige tablet engraved with "APR" on one side and "30" on the other side.

Tablets are supplied in the strengths and package configurations listed in Table 14.

Table 14.

OTEZLA Package Configurations Package configuration Tablet strength NDC number Configurations for 30 mg BID Dosage 28-day treatment initiation pack 55-tablet blister pack including tablets for titration and maintenance dosage: 4 tablets (10 mg each), 4 tablets (20 mg each), and 47 tablets (30 mg each) 55513-369-55 60-count bottle 30 mg 55513-137-60 Configurations for 20 mg BID Dosage 28-day treatment initiation pack 55-tablet blister pack including tablets for titration and maintenance dosage: 4 tablets (10 mg each) and 51 tablets (20 mg each) 55513-508-55 60-count bottle 20 mg 55513-497-60 OTEZLA XR is available as 75 mg round, biconvex, pink, film-coated extended-release tablets with "APR 75" printed in black on one side and a hole or indentation on either side of the tablet, which may or may not be visible.

Tablets are supplied in the strengths and package configurations listed in Table 15.

Table 15.

OTEZLA XR Package Configurations Package configuration Tablet strength NDC number 28-day treatment initiation pack 41-tablet blister titration pack including tablets for titration and maintenance dosage: OTEZLA: 4 tablets (10 mg each), 4 tablets (20 mg each), and 19 tablets (30 mg each) and OTEZLA XR: 14 tablets (75 mg each) 55513-516-41 Bottles of 30 OTEZLA XR: 30 tablets (75 mg each) 55513-519-30 Storage and Handling Store OTEZLA tablets below 30°C (86°F).

XR tablets between 20°C and 25°C (68°F and 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) .

OTEZLA tablets below 30°C (86°F).

XR tablets between 20°C and 25°C (68°F and 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) .

Risk Summary Available data with

OTEZLA use in pregnant women have not identified a drug-associated risk of major birth defects or adverse maternal or fetal outcomes.

In animal embryo-fetal development studies, the administration of apremilast to pregnant cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures approximately 2-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD.

When apremilast was administered to pregnant mice during organogenesis, there were no apremilast-induced malformations up to exposures 4-times the MRHD.

Based on findings from animal reproduction studies, OTEZLA/OTEZLA XR may increase the risk for fetal loss.

Advise pregnant women of the potential risk of fetal loss.

The background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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.

Data Human Data A pregnancy registry conducted by the Organization of Teratology Information Specialists (OTIS) in the United States and Canada assessed the risk of major birth defects in liveborn infants of women with psoriatic arthritis, psoriasis, or Behçet's Disease exposed to apremilast in the first trimester.

The study compared pregnant women treated with apremilast (n = 15) with disease matched pregnant women who were not exposed to apremilast (n = 106).

In the apremilast-exposed cohort, there were no reports of liveborn infants with major birth defects nor miscarriages.

One stillbirth was reported in the apremilast exposed cohort.

These data are limited by the small sample size of apremilast-exposed pregnancies.

In an embryo-fetal developmental study, pregnant cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1000 mg/kg/day during the period of organogenesis (gestation Days [GD] 20 through 50).

There was a dose -related increase in spontaneous abortions, with most abortions occurring during Weeks to 4 of dosing in the first trimester, at doses approximately 2-times the MRHD and greater (on an area under the curve [AUC] basis at doses ≥ 50 mg/kg/day).

No abortifacient effects were observed at a dose approximately 1.4-times the MRHD (on an AUC basis at a dose of 20 mg/kg/day).

Although there was no evidence for a teratogenic effect at doses of 20 mg/kg/day and greater when examined at Day 100, aborted fetuses were not examined.

In an embryo-fetal development study in mice, apremilast was administered at doses of 250, 500, or 750 mg/kg/day to dams during organogenesis (GD 6 through 15).

In a combined fertility and embryo-fetal development study in mice, apremilast was administered at doses of 10, 20, 40, or 80 mg/kg/day starting 15 days before cohabitation and continuing through GD 15.

No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in post-implantation loss at doses corresponding to a systemic exposure of approximately 2-times the MRHD and greater (≥ 20 mg/kg/day).

At doses of ≥ 20 mg/kg/day skeletal variations included incomplete ossification sites of tarsals, skull, sternebra, and vertebrae.

No effects were observed at a dose approximately 1.3-times the MRHD (10 mg/kg/day).

Apremilast distributed across the placenta into the fetal compartment in mice and monkeys.

In a pre and postnatal study in mice, apremilast was administered to pregnant female mice at doses of 10, 80, or 300 mg/kg/day from Day of gestation through Day of lactation, with weaning on Day 21.

Dystocia, reduced viability, and reduced birth weights occurred at doses corresponding to ≥ 4-times the MRHD (on an AUC basis at doses ≥ 80 mg/kg/day).

No adverse effects occurred at a dose 1.3-times the MRHD (10 mg/kg/day).

There was no evidence for functional impairment of physical development, behavior, learning ability, immune competence, or fertility in the offspring at doses up to 7.5-times the MRHD (on an AUC basis at a dose of 300 mg/kg/day).

OTEZLA Plaque Psoriasis The safety and effectiveness of OTEZLA have been established in pediatric patients 6 years of age and older and weighing at least 20 kg with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Use of

OTEZLA in these patients is supported by evidence from a 52-week adequate and well-controlled clinical trial (PSOR-6) in 245 pediatric subjects 6 years of age and older with moderate to severe plaque psoriasis.

Weight loss in

OTEZLA-treated pediatric subjects was comparable to weight loss observed in adults.

Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA.

Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

The safety and effectiveness of

OTEZLA have not been established in pediatric patients below the age of 6 years or weighing less than 20 kg with moderate to severe plaque psoriasis.

Psoriatic Arthritis The safety and effectiveness of OTEZLA have been established for pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis.

OTEZLA in these patients is supported by evidence from adequate and well controlled trials of OTEZLA in adults with psoriatic arthritis, pharmacokinetic data from adult patients with psoriatic arthritis, adult patients with psoriasis, and pediatric patients with psoriasis, and safety data from a clinical trial in 245 pediatric patients 6 years of age and older with psoriasis.

Steady-state exposure of

OTEZLA in pediatric patients with psoriatic arthritis is estimated to be comparable to adults with psoriatic arthritis and pediatric patients with psoriasis.

Closely monitor growth (height and weight) in OTEZLA-treated pediatric patients.

OTEZLA have not been established in pediatric patients below the age of 6 years or weighing less than 20 kg with psoriatic arthritis.

Behçet's Disease The safety and effectiveness of OTEZLA have not been established in pediatric patients with psoriatic arthritis or oral ulcers associated with Behçet's Disease.

OTEZLA XR Plaque Psoriasis and Psoriatic Arthritis The safety and effectiveness of OTEZLA XR have been established for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in pediatric patients 6 years of age and older and weighing at least 50 kg. Use of OTEZLA XR in these patients is supported by pharmacokinetic data from healthy adults demonstrating comparable PK exposure between OTEZLA XR 75 mg once daily and OTEZLA 30 mg twice daily, which is the recommended OTEZLA dosage for pediatric patients weighing at least 50 kg.

Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA XR.

The safety and effectiveness of OTEZLA

XR have not been established in pediatric patients below the age of 6 years or weighing less than 50 kg with moderate to severe plaque psoriasis or psoriatic arthritis.

Behçet's Disease The safety and effectiveness of OTEZLA XR have not been established in pediatric patients with oral ulcers associated with Behçet's Disease.

Of the 1493 patients who enrolled in Trials PsA-1, PsA-2, and PsA-3, a total of 146 (9.8%) psoriatic arthritis patients were 65 years of age and older, including 19 (1.3%) patients 75 years and older.

No overall differences were observed in the safety profile of geriatric patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical trials.

Of the 1257 subjects who enrolled in two placebo-controlled plaque psoriasis trials (PSOR-1 and PSOR-2), a total of 108 (8.6%) plaque psoriasis patients were 65 years of age and older, including 9 (0.7%) patients who were 75 years of age and older.

No overall differences were observed in the safety or effectiveness in geriatric patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical trials.

Because patients 65 years of age or older may be at a higher risk of complications such as volume depletion or hypotension from severe diarrhea, nausea, or vomiting, monitor geriatric patients closely for such complications.