Apremilast Prescribing Information

1.1 Psoriatic Arthritis

Apremilast tablets are indicated for the treatment of adult patients with active psoriatic arthritis.

2.1 Dosage in Psoriatic Arthritis

The recommended initial dosage titration of apremilast tablets 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.

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

Table 1: Dosage Titration Schedule

2.2 Dosage Adjustment in Patients with Severe Renal Impairment

Apremilast tablets dosage should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance (CL cr) 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 apremilast tablets be titrated using only the AM schedule listed in Table 1 and the PM doses be skipped.

5.1 Hypersensitivity

Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported during post marketing surveillance. Avoid the use of apremilast in patients with known hypersensitivity to apremilast or to any of the excipients in the formulation. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue apremilast and institute appropriate therapy.

5.2 Diarrhea, Nausea, and Vomiting

There have been reports of severe diarrhea, nausea, and vomiting associated with the use of apremilast tablets. Most events occurred within the first few weeks of treatment. In some cases, patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting. Patients who reduced dosage or discontinued apremilast tablets generally improved quickly. Consider apremilast tablets dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting.

5.3 Depression

Treatment with apremilast tablets is associated with an increased incidence of depression. Before using apremilast tablets in patients with a history of depression and/or suicidal thoughts or behaviour, prescribers should carefully weigh the risks and benefits of treatment with apremilast tablets. 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 apremilast tablets 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 apremilast tablets reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1,441) of subjects treated with apremilast tablets 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% (3/1,441) of subjects exposed to apremilast tablets, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1,441) of subjects while receiving apremilast tablets, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in apremilast tablets-treated subjects.

5.4 Weight Decrease

During the placebo-controlled period of the trials in psoriatic arthritis (PsA), weight decrease between 5% to 10% of body weight was reported in 10% (49/497) of subjects treated with apremilast tablets 30 mg twice daily compared to 3.3% (16/495) treated with placebo.

Patients treated with apremilast tablets should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of apremilast tablets should be considered [see Adverse Reactions ( 6.1)].

5.5 Drug Interactions

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 apremilast tablets. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with apremilast tablets is not recommended [see Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.3)].

6.1 Clinical Trials Experience

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

Psoriatic Arthritis Clinical Trials

Apremilast was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials (PsA-1, PsA-2, and PsA-3) of similar design in adult subjects with active psoriatic arthritis [see Clinical Studies ( 14.1)] . Across the 3 trials, there were 1,493 subjects randomized equally to placebo, apremilast 20 mg twice daily or apremilast 30 mg twice daily. Titration was used over the first 5 days [see Dosage and Administration ( 2.1)] . Placebo subjects whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either apremilast 20 mg twice daily or 30 mg twice daily at week 16 while apremilast subjects remained on their initial treatment. Subjects 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 subjects taking apremilast were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of subjects with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for subjects taking apremilast 30 mg twice daily and 1.2% for placebo-treated subjects.

Table 2: Adverse Reactions Reported in ≥ 2% of Subjects on Apremilast 30 mg Twice Daily and ≥ 1% Than That Observed in Subjects on Placebo up to Day 112 (Week 16)

aOf the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in apremilast 30 mg twice daily; 1 subject treated with apremilast 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 subject treated with apremilast 30 mg twice daily experienced a serious adverse reaction of headache.
bOf the reported adverse drug reactions none were serious.
cn (%) indicates number of subjects and percent.
dBID = twice daily.

Other adverse reactions reported in subjectson apremilast inpsoriatic arthritis clinicaltrials are:
• Gastrointestinal Disorders: Gastroesophageal reflux disease
• Immune System Disorders: Hypersensitivity
• Investigations: Weight decrease
• Metabolism and Nutrition Disorders: Decreasedappetite*
• Nervous System Disorders: Migraine
• Respiratory, Thoracic, and Mediastinal Disorders: Cough
• Skin and Subcutaneous Tissue Disorders: Rash
*1 subjecttreated with apremilast 30 mg twice daily experienced a serious adverse reaction.

7.1 Strong CYP450 Inducers

Apremilast exposure is decreased when apremilast is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see Warnings and Precautions ( 5.5) and Clinical Pharmacology ( 12.3)].

8.1 Pregnancy

Risk Summary

Available pharmacovigilance data with apremilast use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, but these data are extremely limited. Based on findings from animal reproduction studies, apremilast may increase the risk for fetal loss. 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 2.1-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. When administered to pregnant mice, during organogenesis there were no apremilast-induced malformations up to exposures 4.0-times the MRHD (see Data). Advise pregnant women of the potential risk of fetal loss. Consider pregnancy planning and prevention for females of reproductive potential.

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

Animal Data

In an embryo-fetal developmental study, pregnant cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1,000 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 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 (gestation Day 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 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).

Apremilast distributed across the placenta into the fetal compartment in mice and monkeys.
In a pre- and post-natal 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).

8.2 Lactation

Risk Summary

There are no data on the presence of apremilast in human milk, the effects on the breastfed infant, or the effects on milk production. However, apremilast was detected in the milk of lactating mice. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for apremilast and any potential adverse effects on the breastfed infant from apremilast or from the underlying maternal condition.

Data

In mice, following a single oral administration of 10 mg/kg to dams on postpartum Day 13, apremilast concentrations in milk were approximately 1.5-times that of simultaneously collected blood samples.

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 1,493 patients who enrolled in Trials PsA-1, PsA-2, and PsA-3, a total of 146 psoriatic arthritis patients were 65 years of age and older, including 19 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.

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 [see Warning and Precautions ( 5.2)].

8.6 Renal Impairment

Apremilast pharmacokinetics were characterized in subjects with mild, moderate, and severe renal impairment as defined by a creatinine clearance of 60 to 89, 30 to 59, and less than 30 mL per minute, respectively, by the Cockcroft–Gault equation. While no dosage adjustment is needed in patients with mild or moderate renal impairment, the dosage of apremilast should be reduced to 30 mg once daily in patients with severe renal impairment [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)].

8.7 Hepatic Impairment

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

12.1 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 is not well defined.

12.3 Pharmacokinetics

Absorption

Apremilast when taken orally is absorbed with an absolute bioavailability of ~73%, with peak plasma concentrations (C max) occurring at a median time (t max) 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 to 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

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

Patients with Renal Impairment:The pharmacokinetics of apremilast is not affected by mild or moderate renal impairment. In 8 subjects with severe renal impairment administered a single dose of 30 mg apremilast, the AUC and C maxof apremilast increased by approximately 88% and 42%, respectively [see Dosage and Administration ( 2.2) and Use in Specific Populations ( 8.6)].

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 C maxthan in young subjects (18 to 55 years of age) [see Use in Specific Populations ( 8.5)].

Gender:In pharmacokinetic trials in healthy volunteers, the extent of exposure in females was about 31% higher and C maxwas 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 trials 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 C maxby 72% and 43%, respectively [see Warnings and Precautions ( 5.5) and Drug Interactions ( 7.1)] .

13.1 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 (1,000 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 vitrochromosome aberration assay of human peripheral blood lymphocytes, and the in vivomouse 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).

14.1 Psoriatic Arthritis

The safety and efficacy of apremilast was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials (PsA-1 [NCT01172938], PsA-2 [NCT01212757], and PsA-3 [NCT01212770]) of similar design. A total of 1,493 adult subjects with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior or current treatment with disease-modifying antirheumatic drug (DMARD) therapy were randomized. Subjects enrolled in these trials had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skin lesion of at least 2 cm in diameter was required in Trial PsA-3. Previous treatment with a biologic, including TNF-blockers was allowed (up to 10% could be TNF-blocker therapeutic failures). Across the 3 trials, subjects were randomly assigned to placebo (n=496), apremilast 20 mg (n=500), or apremilast 30 mg (n=497) given orally twice daily. Titration was used over the first 5 days [see Dosage and Administration ( 2.1)] . Subjects were allowed to receive stable doses of concomitant methotrexate [MTX (≤25 mg/week)], sulfasalazine [SSZ (≤2 g/day)], leflunomide [LEF (≤20 mg/day)], low dose oral corticosteroids (equivalent to ≤10 mg of prednisone a day), and/or nonsteroidal anti-inflammatory drugs (NSAIDs) during the trial. Treatment assignments were stratified based on small-molecule DMARD use at baseline in Trials PsA-1, PsA-2 and PsA-3. There was an additional stratification of body surface area (BSA) > 3% with psoriasis in Trial PsA-3. The subjects who were therapeutic failures of >3 agents for PsA (small molecules or biologics), or >1 biologic TNF blocker were excluded.

The primary endpoint was the percentage of subjects achieving American College of Rheumatology (ACR) 20 response at Week 16. Placebo-controlled efficacy data were collected and analyzed through Week 24. Subjects whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at Week 16. Placebo non-responders were re-randomized 1:1 in a blinded fashion to either apremilast 20 mg twice daily or 30 mg twice daily following the titration schema [see Dosage and Administration ( 2.1)] . Apremilast subjects remained on their initial treatment. At Week 24, all remaining placebo subjects were re-randomized to either 20 mg twice daily or 30 mg twice daily.

Subjects with subtypes of PsA were enrolled across the 3 trials, including symmetric polyarthritis (62%), asymmetric oligoarthritis (27.0%), distal interphalangeal (DIP) joint arthritis (6.0%), arthritis mutilans (3.0%), and predominant spondylitis (2.1%). The median duration of PsA disease was 5 years. Subjects received concomitant therapy with at least one DMARD (65.0%), MTX (55.0%), SSZ (9.0%), LEF (7.0%), low dose oral corticosteroids (14.0%), and NSAIDs (71.0%). Prior treatment with small-molecule DMARDs only was reported in 76.0% of subjects and prior treatment with biologic DMARDs was reported in 22.0% of subjects, which includes 9.0% who had failed prior biologic DMARD treatment.

Clinical Response in Subjects with Psoriatic Arthritis
The percent of subjects achieving ACR 20, 50 and 70 responses in Trials PsA-1, PsA-2, and PsA-3 are presented in Table 5 below. Apremilast ± DMARDs, compared with Placebo ± DMARDs resulted in a greater improvement in signs and symptoms of psoriatic arthritis as demonstrated by the proportion of subjects with an ACR 20 response at Week 16.

Table 5: Proportion of Subjects With ACR Responses in Trials PsA-1, PsA-2 and PsA-3

aN is number of randomized and treated subjects.
bStatistically significantly different from placebo (p<0.05).

Apremilast 30 mg twice daily resulted in improvement for each ACR component, compared to placebo at Week 16 in Trial PsA-1 (Table 6). Consistent results were observed in Trials PsA-2 and PsA-3.

Table 6: ACR Components Mean Change from Baseline at Week 16 in Trial PsA-1

Mean changes from baseline are least square means from analyses of covariance.
aScale 0 to 78.
bScale 0 to 76.
cVAS=Visual Analog Scale; 0=best, 100=worst.
dHAQ-DI = Health Assessment Questionnaire-Disability Index; 0=best, 3=worst; measures the subject’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
e CRP = C-reactive protein; Reference range 0 to 0.5 mg/dL.
* N reflects randomized subjects; actual number of subjects evaluable for each endpoint may vary by timepoint.

Treatment with apremilast resulted in improvement in dactylitis and enthesitis in subjects with pre-existing dactylitis or enthesitis.

Physical Function Response

Apremilast 30 mg twice daily demonstrated a greater improvement compared to placebo in mean change from baseline for the Health Assessment Questionnaire Disability Index (HAQ-DI) score at Week 16 [-0.244 vs. -0.086, respectively; 95% CI for the difference was (-0.26, -0.06)] in Trial PsA-1. The proportions of HAQ-DI responders (≥ 0.3 improvement from baseline) at Week 16 for the apremilast 30 mg twice daily group were 38%, compared to 27%, for the placebo group in Trial PsA-1. Consistent results were observed in Trials PsA-2 and PsA-3.