Label: OTEZLA- apremilast   OTEZLA- apremilast tablet, film coated 

  • Label RSS
  • NDC Code(s): 59572-630-27, 59572-630-99, 59572-631-06, 59572-631-28
  • Packager: Celgene Corporation
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated 05/14

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use OTEZLA safely and effectively. See full prescribing information for OTEZLA.

    OTEZLA® (apremilast) tablets, for oral use
    Initial U.S. Approval: 2014

    INDICATIONS AND USAGE

    OTEZLA, an inhibitor of phosphodiesterase 4 (PDE4), is indicated for the treatment of adult patients with active psoriatic arthritis (1.1)

    DOSAGE AND ADMINISTRATION

    • To reduce risk of gastrointestinal symptoms, titrate to recommended dose of 30 mg twice daily according to the following schedule (2.1)
      • Day 1: 10 mg in morning
      • Day 2: 10 mg in morning and 10 mg in evening
      • Day 3: 10 mg in morning and 20 mg in evening
      • Day 4: 20 mg in morning and 20 mg in evening
      • Day 5: 20 mg in morning and 30 mg in evening
      • Day 6 and thereafter: 30 mg twice daily
    • Dosage in Severe Renal Impairment:
      • Recommended dose is 30 mg once daily (2.1)
      • For initial dosage titration, titrate using only morning schedule listed in Table 1 and skip afternoon doses (2.2)

    DOSAGE FORMS AND STRENGTHS

    Tablets: 10 mg, 20 mg, 30 mg (3)

    CONTRAINDICATIONS

    Known hypersensitivity to apremilast or any excipients in formulation (4)

    WARNINGS AND PRECAUTIONS

    • Depression: Advise patients, their caregivers, and families 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. Carefully weigh risks and benefits of treatment with OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior. (5.1)
    • Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of OTEZLA (5.2)
    • Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended because loss of efficacy may occur (5.3, 7.1)

    ADVERSE REACTIONS

    The most common adverse reactions (≥ 5%) are diarrhea, nausea, and headache (6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact Celgene Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

    USE IN SPECIFIC POPULATIONS

    Severe Renal Impairment: Increased systemic exposure of OTEZLA has been observed, reduction in dose to 30 mg once daily is recommended (2.2, 8.6)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 3/2014

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • 1 INDICATIONS AND USAGE

    1.1 Psoriatic Arthritis

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

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  • 2 DOSAGE AND ADMINISTRATION

    2.1 Dosage in Psoriatic Arthritis

    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.

    Table 1: Dosage Titration Schedule
    Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
    & thereafter
    AM AM PM AM PM AM PM AM PM AM PM
    10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg 30 mg 30 mg

    2.2 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 Cockroft–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.

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  • 3 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.

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  • 4 CONTRAINDICATIONS

    OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Adverse Reactions (6.1)].

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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Depression

    Treatment with OTEZLA is associated with an increase in adverse reactions of depression. During the 0 to 16 weeks placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of patients 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 patients treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated patients (0/495). Depression was reported as serious in 0.2% (3/1441) of patients exposed to OTEZLA, compared to none in placebo treated patients (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of patients while receiving OTEZLA, compared to none in placebo treated patients (0/495). In the clinical trials, two patients who received placebo committed suicide compared to none in OTEZLA treated patients.

    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.

    5.2 Weight Decrease

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

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

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  • 6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience in Psoriatic Arthritis

    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.

    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 two 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.

    Table 2: Adverse Reactions Reported in ≥ 2% of Patients on OTEZLA 30 mg Twice Daily and ≥ 1% Than That Observed in Patients on Placebo For Up To Day 112 (Week 16)
    a Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache.
    b Of the reported adverse drug reactions none were serious.
    cn (%) indicates number of patients and percent.
    Placebo OTEZLA 30 mg BID
    Preferred Term Day 1 to 5
    (N=495)
    n (%)c
    Day 6 to Day 112
    (N=490)
    n (%)
    Day 1 to 5
    (N=497)
    n (%)
    Day 6 to Day 112
    (N=493)
    n (%)
    Diarrhea a 6 ( 1.2) 8 ( 1.6) 46 ( 9.3) 38 ( 7.7)
    Nauseaa 7 ( 1.4) 15 ( 3.1) 37 ( 7.4) 44 ( 8.9)
    Headachea 9 ( 1.8) 11 ( 2.2) 24 ( 4.8) 29 ( 5.9)
    Upper respiratory tract
    infectionb
    3 ( 0.6) 9 ( 1.8) 3 ( 0.6) 19 ( 3.9)
    Vomitinga 2 ( 0.4) 2 ( 0.4) 4 ( 0.8) 16 ( 3.2)
    Nasopharyngitisb 1 ( 0.2) 8 ( 1.6) 1 ( 0.2) 13 ( 2.6)
    Abdominal pain upperb 0 ( 0.0) 1 ( 0.2) 3 ( 0.6) 10 ( 2.0)

    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.

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  • 7 DRUG INTERACTIONS

    7.1 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 (12.3)].

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category 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 maximal 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 dosages 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 dosages 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).

    8.3 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.

    8.4 Pediatric Use

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

    8.5 Geriatric Use

    Of the 1493 patients who enrolled in Studies 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 elderly patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical studies.

    8.6 Renal Impairment

    OTEZLA pharmacokinetics were not characterized in subjects with mild (creatinine clearance of 60-89 mL per minute estimated by the Cockroft–Gault equation) or moderate (creatinine clearance of 30-59 mL per minute estimated by the Cockroft–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 Cockroft–Gault equation) [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 dose adjustment is necessary in these patients.

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  • 10 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.

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  • 11 DESCRIPTION

    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:

    Otezla Chemical Structure

    OTEZLA tablets are supplied in 10, 20, and 30 mg strengths for oral administration. Each tablet contains apremilast as the active ingredient and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red, iron oxide yellow (20 and 30 mg only) and iron oxide black (30 mg only).

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  • 12 CLINICAL PHARMACOLOGY

    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 in psoriatic arthritis patients is not well defined.

    12.3 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 30mg 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), CYP 450 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 [see Warnings and Precautions (5.3) and Drug Interactions (7.1)].

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  • 13 NONCLINICAL TOXICOLOGY

    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 the 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 dosages up to approximately 3-times the MRHD based 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 dosages of 10, 20, 40, or 80 mg/kg/day. At dosages ≥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 dosages 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).

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  • 14 CLINICAL STUDIES

    14.1 Psoriatic Arthritis

    The safety and efficacy of OTEZLA was evaluated in 3 multi-center, randomized, double-blind, placebo-controlled trials (Studies PsA-1, PsA-2, and PsA-3) of similar design. A total of 1493 adult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior or current treatment with disease-modifying antirheumatic drug (DMARD) therapy were randomized. Patients enrolled in these studies 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 Study PsA-3. Previous treatment with a biologic, including TNF-blockers was allowed (up to 10% could be TNF-blocker therapeutic failures). Across the 3 studies, patients were randomly assigned to placebo (n = 496), OTEZLA 20 mg (n = 500), or OTEZLA 30 mg (n = 497) given orally twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1)]. Patients 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 Studies PsA-1, PsA-2 and PsA-3. There was an additional stratification of BSA > 3% with psoriasis in study PsA-3. The patients 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 patients achieving American College of Rheumatology (ACR) 20 response at Week 16. Placebo-controlled efficacy data were collected and analyzed through Week 24. Patients 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 OTEZLA 20 mg twice daily or 30 mg twice daily following the titration schema [see Dosage and Administration (2.1)]. OTEZLA patients remained on their initial treatment. At Week 24, all remaining placebo patients were re-randomized to either 20 mg twice daily or 30 mg twice daily.

    Patients with subtypes of PsA were enrolled across the 3 studies, including symmetric polyarthritis (62.0%), 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. Patients 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 patients and prior treatment with biologic DMARDs was reported in 22.0% of patients, which includes 9.0% who had failed prior biologic DMARD treatment.

    Clinical Response in Patients with Psoriatic Arthritis

    The percent of patients achieving ACR 20, 50 and 70 responses in Studies PsA-1, PsA-2, and PsA-3 are presented in Table 3 below. OTEZLA ± DMARDs, compared with Placebo ± DMARDs resulted in a greater improvement in signs and symptoms of psoriatic arthritis as demonstrated by the proportion of patients with an ACR 20 response at Week 16.

    Table 3: Proportion of Patients with ACR Responses in Studies PsA-1, PsA-2 and PsA-3
    aN is number of randomized and treated patients
    b Statistically significantly different from placebo (p>0.05)
    PsA-1 PsA-2 PsA-3
    Na Placebo
    ±
    DMARDs

    N = 168
    Otezla
    30 mg
    twice daily
    ±
    DMARDs

    N = 168
    Placebo
    ±
    DMARDs

    N = 159
    Otezla
    30 mg
    twice daily
    ±
    DMARDs

    N = 162
    Placebo
    ±
    DMARDs

    N = 169
    Otezla
    30 mg
    twice daily
    ±
    DMARDs

    N = 167
    ACR 20
          Week 16
    19% 38% b 19% 32% b 18% 41% b
    ACR 50
          Week 16
    6% 16% 5% 11% 8% 15%
    ACR 70
          Week 16
    1% 4% 1% 1% 2% 4%

    OTEZLA 30 mg twice daily resulted in improvement for each ACR component, compared to placebo at Week 16 in Study PsA-1 (Table 4). Consistent results were observed in Studies PsA-2 and PsA-3.

    Table 4: ACR Components Mean Change from Baseline at Week 16 in Study PsA-1
    Mean changes from baseline are least square means from analyses of covariance.
    a Scale 0-78
    b Scale 0-76
    c VAS = Visual Analog Scale; 0 = best, 100 = worst
    d HAQ-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 0-0.5 mg/dL
    * N reflects randomized patients; actual number of patients evaluable for each endpoint may vary by timepoint.
    Placebo
    (N=168)
    OTEZLA 30 mg
    twice daily
    (N=168)
    Number of tender jointsa
        Sample Size
        Baseline
        Mean Change at Week 16
    166
    23
    -2
    164
    23
    -7
    Number of swollen jointsb
        Sample Size
        Baseline
        Mean Change at Week 16
    166
    13
    -2
    164
    13
    -5
    Patient’s assessment of painc
        Sample Size
        Baseline
        Mean Change at Week 16
    165
    61
    -6
    159
    58
    -14
    Patient’s global assessment of disease
    activityc
        Sample Size
        Baseline
        Mean Change at Week 16
    165
    59
    -3
    159
    56
    -10
    Physician’s global assessment of disease
    activityc
        Sample Size
        Baseline
        Mean Change at Week 16
    158
    55
    -8
    159
    56
    -19
    HAQ-DId score
        Sample Size
        Baseline
        Mean Change at Week 16
    165
    1.2
    -0.09
    159
    1.2
    -0.2
    CRPe
        Sample Size
        Baseline
        Mean Change at Week 16
    166
    1.1
    0.1
    167
    0.8
    -0.1

    Treatment with OTEZLA resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis.

    Physical Function Response

    OTEZLA 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 Study PsA-1. The proportions of HAQ-DI responders (≥ 0.3 improvement from baseline) at Week 16 for the OTEZLA 30 mg twice daily group were 38%, compared to 27%, for the placebo group in Study PsA-1. Consistent results were observed in Studies PsA-2 and PsA-3.

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    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.

    Tablets are supplied in the following strengths and package configurations

    Package configuration Tablet strength NDC code
    Bottles of 60 30 mg 59572-631-06
    Two week starter pack 13-tablet blister titration pack
    containing: 10 mg, 20 mg, and 30
    mg tablets with an additional (14) 30
    mg tablets
    59572-630-27
    28 count carton 2-30mg blister cards containing (14)
    30 mg tablets
    59572-631-28

    Storage and Handling
    Store tablets below 30 °C (86°F).

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  • 17 PATIENT COUNSELING INFORMATION

    • 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 [see Warnings and Precautions (5.1)].
    • Weight Decrease
      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 [see Warnings and Precautions (5.2)].

    • Drug Interactions
      The use of strong cytochrome P450 enzyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended [see Warnings and Precautions (5.3), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].
    • Instruct patients to take OTEZLA only as prescribed.
    • Advise patients OTEZLA can be taken with or without food.
    • Advise patients that the tablets should not be crushed, split, or chewed.
    • Advise patients about the side effects associated with OTEZLA [See Adverse Reactions (6.1)].

    Manufactured for: Celgene Corporation
                                  Summit, NJ 07901

    OTEZLA® is a registered trademarks of Celgene Corporation.

    Pat. www.celgene.com

    ©2014 Celgene Corporation, All Rights Reserved.

    APRPI.002   03/14

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - NDC: 59572-630-27 - Starter Pack Label (OUTSIDE)
    otezla starter pack label: 4 - 10 mg  4 - 20 mg  19 - 30 mg

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - NDC: 59572-630-27 - Starter Pack Label (INSIDE)
    otezla starter pack label: 4 - 10 mg  4 - 20 mg  19 - 30 mg

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - NDC: 59572-630-99 - Starter Sample Pack Label (OUTSIDE)
    otezla starter sample pack label: 4 - 10 mg  4 - 20 mg  19 - 30 mg

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - NDC: 59572-630-99 - Starter Sample Pack Label (INSIDE)
    otezla starter sample pack label: 4 - 10 mg  4 - 20 mg  19 - 30 mg

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - NDC: 59572-631-28 - Foil
    Foil Label

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - NDC: 59572-631-28 - Carton Label
    30 mg Carton Label

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - NDC: 59572-631-06 - Bottle Label
    30 mg Bottle Label

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  • INGREDIENTS AND APPEARANCE
    OTEZLA 
    apremilast kit
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59572-630
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:59572-630-27 1 in 1 BLISTER PACK
    2 NDC:59572-630-99 1 in 1 BLISTER PACK
    Quantity of Parts
    Part # Package Quantity Total Product Quantity
    Part 1
    Part 2
    Part 3 19 
    Part 1 of 3
    OTEZLA 
    apremilast tablet, film coated
    Product Information
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    APREMILAST (APREMILAST) APREMILAST 10.0 mg
    Inactive Ingredients
    Ingredient Name Strength
    CELLULOSE, MICROCRYSTALLINE  
    LACTOSE MONOHYDRATE  
    CROSCARMELLOSE SODIUM  
    MAGNESIUM STEARATE  
    Product Characteristics
    Color PINK Score no score
    Shape DIAMOND Size 8mm
    Flavor Imprint Code APR;10
    Contains     
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA205437 04/01/2014
    Part 2 of 3
    OTEZLA 
    apremilast tablet, film coated
    Product Information
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    APREMILAST (APREMILAST) APREMILAST 20.0 mg
    Inactive Ingredients
    Ingredient Name Strength
    CELLULOSE, MICROCRYSTALLINE  
    LACTOSE MONOHYDRATE  
    CROSCARMELLOSE SODIUM  
    MAGNESIUM STEARATE  
    Product Characteristics
    Color BROWN Score no score
    Shape DIAMOND Size 10mm
    Flavor Imprint Code 20;APR
    Contains     
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA205437 04/01/2014
    Part 3 of 3
    OTEZLA 
    apremilast tablet, film coated
    Product Information
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    APREMILAST (APREMILAST) APREMILAST 30.0 mg
    Inactive Ingredients
    Ingredient Name Strength
    CELLULOSE, MICROCRYSTALLINE  
    LACTOSE MONOHYDRATE  
    CROSCARMELLOSE SODIUM  
    MAGNESIUM STEARATE  
    Product Characteristics
    Color WHITE (Beige) Score no score
    Shape DIAMOND Size 12mm
    Flavor Imprint Code 30;APR
    Contains     
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA205437 04/01/2014
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA205437 04/01/2014
    OTEZLA 
    apremilast tablet, film coated
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59572-631
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    APREMILAST (APREMILAST) APREMILAST 30.0 mg
    Inactive Ingredients
    Ingredient Name Strength
    CELLULOSE, MICROCRYSTALLINE  
    LACTOSE MONOHYDRATE  
    CROSCARMELLOSE SODIUM  
    MAGNESIUM STEARATE  
    Product Characteristics
    Color WHITE (Beige) Score no score
    Shape DIAMOND Size 12mm
    Flavor Imprint Code 30;APR
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:59572-631-06 60 in 1 BOTTLE, PLASTIC
    2 NDC:59572-631-28 28 in 1 CARTON
    2 1 in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA205437 04/03/2014
    Labeler - Celgene Corporation (174201137)
    Registrant - Celgene Corporation (174201137)
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