Apremilast

Apremilast
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]

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Overview

Apremilast is a Phosphodiesterase Inhibitor that is FDA approved for the treatment of active psoriatic arthritis, moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Common adverse reactions include diarrhea, nausea, and headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

Psoriatic Arthritis

• OTEZLA is indicated for the treatment of adult patients with active psoriatic arthritis.

Psoriasis

• OTEZLA is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Dosage

Dosage in Psoriatic Arthritis and Psoriasis

• The recommended initial dosage titration of OTEZLA from Day 1 to Day 5 is shown in TABLE 1. Following the 5-day titration, the recommended maintenance dosage is 30 mg twice daily taken orally starting on Day 6. This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.

• OTEZLA can be administered without regard to meals. Do not crush, split, or chew the tablets.

Dosage Adjustment in Patients With Severe Renal Impairment

• OTEZLA dosage should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance (CLcr) of less than 30 mL per minute estimated by the Cockcroft–Gault equation) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. For initial dosage titration in this group, it is recommended that OTEZLA be titrated using only the AM schedule listed in TABLE 1 and the PM doses be skipped.

DOSAGE FORMS AND STRENGTHS

• OTEZLA 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Apremilast in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Apremilast in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Apremilast in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Apremilast in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Apremilast in pediatric patients.

Contraindications

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

Warnings

Depression

• Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur.

Psoriatic arthritis

• During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects.

Psoriasis

• During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects(0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide.

Weight Decrease

• During the controlled period of the studies in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo [see Adverse Reactions (6.1)].

• During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo.

• Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered.

Adverse Reactions

Clinical Trials Experience

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Psoriatic Arthritis Clinical Trials

• OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials [Studies PsA-1, PsA-2, and PsA-3] of similar design in adult patients with active psoriatic arthritis [see Clinical Studies (14.1)]. Across the 3 studies, there were 1493 patients randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1)]. Placebo patients whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA patients remained on their initial treatment. Patients ranged in age from 18 to 83 years, with an overall median age of 51 years.

• The majority of the most common adverse reactions presented in TABLE 2 occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.

Other adverse reactions reported in patients on OTEZLA in clinical studies including extension studies: Immune system disorders: Hypersensitivity Investigations: Weight decrease Gastrointestinal Disorders: Frequent bowel movement, gastroesophageal reflux disease, dyspepsia Metabolism and Nutrition Disorders: Decreased appetite* Nervous System Disorders: Migraine Respiratory, Thoracic, and Mediastinal Disorders: Cough Skin and Subcutaneous Tissue Disorders: Rash

• 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.

Psoriasis Clinical Trials

• The safety of OTEZLA® was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1)]. Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years.

Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for subjects treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated subjects.

• Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Apremilast in the drug label.

Drug Interactions

Strong CYP450 Inducers

• Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see Warnings and Precautions (5.3) and Clinical Pharmacology
• Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

• Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972.

Risk Summary

Adequate and well-controlled studies with OTEZLA have not been conducted in pregnant women. In animal embryo-fetal development studies, the administration of apremilast to cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures 2.1-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. In mice, there were no apremilast induced malformations up to exposures 4.0-times the MRHD. The incidences of malformations and pregnancy loss in human pregnancies have not been established for OTEZLA. However, all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Labor or delivery The effects of OTEZLA on labor and delivery in pregnant women are unknown. In mice, dystocia was noted at doses corresponding to ≥4.0-times the MRHD (on an AUC basis at doses ≥80 mg/kg/day) of apremilast.

Animal Data Monkey embryo-fetal development: In an embryo-fetal developmental study, cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1000 mg/kg/day during the period of organogenesis (gestation Days 20 through 50). There was a dose-related increase in spontaneous abortions, with most abortions occurring during weeks 3 to 4 of dosing in the first trimester, at doses approximately 2.1-times the MRHD and greater (on an 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.

Mouse embryo-fetal development: In an embryo-fetal development study, apremilast was administered at doses of 250, 500, or 750 mg/kg/day to dams during organogenesis (gestation Day 6 through 15). In a combined fertility and embryo-fetal development study, apremilast was administered at doses of 10, 20, 40 or 80 mg/kg/day starting 15 days before cohabitation and continuing through gestation Day 15. No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in postimplantation loss at doses corresponding to a systemic exposure of 2.3-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).

Mouse pre- and postnatal development: 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 6 of gestation through Day 20 of lactation, with weaning on day 21. Dystocia, reduced viability, and reduced birth weights occurred at doses corresponding to ≥4.0-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).
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Apremilast in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Apremilast during labor and delivery.

Nursing Mothers

• It is not known whether OTEZLA or its metabolites are present in human milk; however apremilast was detected in milk of lactating mice. Because many drugs are present in human milk, caution should be exercised when OTEZLA is administered to a nursing woman.

Pediatric Use

• The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established.

Geriatic Use

• Of the 1493 subjects who enrolled in Studies PsA-1, PsA-2, and PsA-3 a total of 146 psoriatic arthritis subjects were 65 years of age and older, including 19 subjects 75 years and older. No overall differences were observed in the safety profile of elderly subjects ≥65 years of age and younger adult subjects <65 years of age in the clinical studies.

Of the 1257 subjects who enrolled in two placebo-controlled psoriasis trials (PSOR 1 and PSOR 2), a total of 108 psoriasis subjects were 65 years of age and older, including 9 subjects who were 75 years of age and older. No overall differences were observed in the efficacy and safety in elderly subjects ≥65 years of age and younger adult subjects <65 years of age in the clinical trials.

Gender

There is no FDA guidance on the use of Apremilast with respect to specific gender populations.

Race

There is no FDA guidance on the use of Apremilast with respect to specific racial populations.

Renal Impairment

• OTEZLA pharmacokinetics were not characterized in subjects with mild (creatinine clearance of 60-89 mL per minute estimated by the Cockcroft–Gault equation) or moderate (creatinine clearance of 30-59 mL per minute estimated by the Cockcroft–Gault equation) renal impairment. The dose of OTEZLA should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockcroft–Gault equation)

Hepatic Impairment

• Apremilast pharmacokinetics were characterized in subjects with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. No dose adjustment is necessary in these patients.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Apremilast in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Apremilast in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

Monitoring

There is limited information regarding Apremilast Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Apremilast and IV administrations.

Overdosage

• In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should there be an overdose.

Pharmacology

There is limited information regarding Apremilast Pharmacology in the drug label.

Mechanism of Action

• Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action in psoriatic arthritis patients and psoriasis patients is not well defined.

Structure

• The active ingredient in OTEZLA tablets is apremilast. Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Apremilast is known chemically as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide. Its empirical formula is C22H24N2O7S and the molecular weight is 460.5.

The chemical structure is:

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Apremilast Pharmacodynamics in the drug label.

Pharmacokinetics

Absorption Apremilast when taken orally is absorbed with an absolute bioavailability of ~73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of ~2.5 hours. Co-administration with food does not alter the extent of absorption of apremilast.

Distribution Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L.

Metabolism Following oral administration in humans, apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6.

Elimination The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively.

Specific Populations

Hepatic Impairment: The pharmacokinetics of apremilast is not affected by moderate or severe hepatic impairment.

Renal Impairment: In 8 subjects with severe renal impairment administered a single dose of 30 mg apremilast, the AUC and Cmax of apremilast increased by approximately 88% and 42%, respectively. [See Use in Specific Populations (8.6) and Dosage and Administration (2.2)].

Age: A single oral dose of 30-mg apremilast was studied in young adults and elderly healthy subjects. The apremilast exposure in elderly subjects (65 to 85 years of age) was about 13% higher in AUC and about 6% higher in Cmax than in young subjects (18 to 55 years of age). [See Use in Specific Populations (8.5)].

Gender: In pharmacokinetic studies in healthy volunteers, the extent of exposure in females was about 31% higher and Cmax was about 8% higher than that in male subjects.

Race and Ethnicity: The pharmacokinetics of apremilast in Chinese and Japanese healthy male subjects is comparable to that in Caucasian healthy male subjects. In addition, apremilast exposure is similar among Hispanic Caucasians, non-Hispanic Caucasians, and African Americans.

Drug Interactions In vitro data: Apremilast is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and not an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4. Apremilast is a substrate, but not an inhibitor of P-glycoprotein (P-gp) and is not a substrate or an inhibitor of organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP).

Drug interaction studies were performed with apremilast and CYP3A4 substrates (oral contraceptive containing ethinyl estradiol and norgestimate), CYP3A and P-gp inhibitor (ketoconazole), CYP450 inducer (rifampin) and frequently co-administered drug in this patient population (methotrexate).

No significant pharmacokinetic interactions were observed when 30-mg oral apremilast was administered with either oral contraceptive, ketoconazole, or methotrexate. Co-administration of the CYP450 inducer rifampin (600 mg once daily for 15 days) with a single oral dose of 30-mg apremilast resulted in reduction of apremilast AUC and Cmax by 72% and 43%, respectively

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Long-term studies were conducted in mice and rats with apremilast to evaluate its carcinogenic potential. No evidence of apremilast-induced tumors was observed in mice at oral doses up to 8.8-times the Maximum Recommended Human Dose (MRHD) on an AUC basis (1000 mg/kg/day) or in rats at oral doses up to approximately 0.08- and 1.1-times the MRHD, (20 mg/kg/day in males and 3 mg/kg/day in females, respectively).

Apremilast tested negative in the Ames assay, in vitro chromosome aberration assay of human peripheral blood lymphocytes, and the in vivo mouse micronucleus assay.

In a fertility study of male mice, apremilast at oral doses up to approximately 3-times the MRHD based on AUC (up to 50 mg/kg/day) produced no effects on male fertility. In a fertility study of female mice, apremilast was administered at oral doses of 10, 20, 40, or 80 mg/kg/day. At doses ≥1.8-times the MRHD (≥20 mg/kg/day), estrous cycles were prolonged, due to lengthening of diestrus which resulted in a longer interval until mating. Mice that became pregnant at doses of 20 mg/kg/day and greater also had increased incidences of early postimplantation losses. There was no effect of apremilast approximately 1.0-times the MRHD (10 mg/kg/day).

Clinical Studies

There is limited information regarding Apremilast Clinical Studies in the drug label.

How Supplied

There is limited information regarding Apremilast How Supplied in the drug label.

Storage

There is limited information regarding Apremilast Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Apremilast Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Apremilast interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Apremilast Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Apremilast Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.