`-----------------------------CONTRAINDICATIONS------------------------------
`
`Known hypersensitivity to apremilast or any excipients in formulation (4)
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
`
`
` Diarrhea, Nausea, and Vomiting: Consider OTEZLA dose reduction or
`
`
`suspension if patients develop severe diarrhea, nausea, or vomiting (5.1)
`
`
`
`
`
` 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 (5.2)
`
`
`
`
`
`
` Weight Decrease: Monitor weight regularly. If unexplained or clinically
`
`
`
`
`significant weight
`loss occurs, evaluate weight
`loss and consider
`
`
`discontinuation of OTEZLA (5.3)
`
`
`
`
` Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g.,
`
`
`
`
`rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended
`
`because loss of efficacy may occur (5.4, 7.1)
`
`
`-------------------------------ADVERSE REACTIONS----------------------------
`
`
` Psoriatic Arthritis: The most common adverse reactions (≥5%) are
`
`diarrhea, nausea, and headache (6.1)
`
` Psoriasis: The most common adverse reactions (≥5%) are diarrhea, nausea,
`
`
`
`
`upper respiratory tract infection, and headache, including tension headache
`
`
`
`
`
`
`
`(6.1)
`
` Behçet’s Disease: The most common adverse reactions (≥10%) are diarrhea,
`
`nausea, headache, and upper respiratory tract infection (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: 07/2019
`
`
`
`10
`11
`12
`
`13
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`
`8.7 Hepatic Impairment
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`
`14.1 Psoriatic Arthritis
`14.2 Psoriasis
`14.3 Oral Ulcers Associated with Behçet’s Disease
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PATIENT COUNSELING INFORMATION
`
`
`
`
`14
`
`
`
`16
`17
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
`
`
`
`
`
`
`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
`
`
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`
`07/2019
`Indications and Usage (1.3)
`
`
`
`
`Dosage and Administration (2.1)
`07/2019
`
`
`
`
`Warnings and Precautions (5.2, 5.3)
`07/2019
`
`---------------------------INDICATIONS AND USAGE---------------------------
`OTEZLA, an inhibitor of phosphodiesterase 4 (PDE4), is indicated for the
`
`
`
`
`
`
`
`treatment of:
`
`
`
`Adult patients with active psoriatic arthritis (1.1)
`
`
`
`Patients with moderate to severe plaque psoriasis who are candidates for
`
`
`
`
`phototherapy or systemic therapy (1.2)
`
`
`
`Adult patients with oral ulcers associated with Behçet’s Disease (1.3)
`
`
`-----------------------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 (2.2)
`
`
`
`
` 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)
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Psoriatic Arthritis
`
`
`1.2 Psoriasis
`
`1.3 Oral Ulcers Associated with Behçet’s Disease
`
`
`DOSAGE AND ADMINISTRATION
`2.1 Dosage in Psoriatic Arthritis, Psoriasis, and Behçet’s Disease
`
`2.2 Dosage Adjustment in Patients with Severe Renal Impairment
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`5.1 Diarrhea, Nausea, and Vomiting
`
`
`5.2 Depression
`
`5.3 Weight Decrease
`
`5.4 Drug Interactions
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`DRUG INTERACTIONS
`
`
`7.1 Strong CYP450 Inducers
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.2 Lactation
`
`
`
`2
`
`
`
`3
`
`4
`
`5
`
`
`6
`
`
`7
`
`8
`
`
`
`
`
`
`
` 
`
`Reference ID: 4464834
`
`1 
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`
`1
`
`
`
`INDICATIONS AND USAGE
`
`Psoriatic Arthritis
`
`Psoriasis
`
`Oral Ulcers Associated with Behçet’s Disease
`
`
`
`2
`
`1.1
`
`
`OTEZLA is indicated for the treatment of adult patients with active psoriatic arthritis.
`
`1.2
`
`
`OTEZLA is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic
`
`
`
`
`therapy.
`
`1.3
`
`OTEZLA is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s Disease.
`
`
`DOSAGE AND ADMINISTRATION
`
`
`Dosage in Psoriatic Arthritis, Psoriasis, and Behçet’s Disease
`
`
`
`2.1
`
`
`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 4
`
`PM
`AM
`
`20 mg
`20 mg
`
`Day 5
`
`PM
`AM
`
`20 mg
`30 mg
`
`Day 6
`
`& thereafter
`
`PM
`AM
`
`30 mg
`30 mg
`
`
`
`Day 2
`
`PM
`AM
`
`10 mg
`10 mg
`
`Day 3
`
`PM
`AM
`
`10 mg
`20 mg
`
`Day 1
`
`AM
`
`10 mg
`
`Dosage Adjustment in Patients with Severe Renal Impairment
`
`
`2.2
`
`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.
`
`
`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.
`
`
`
`
`
`
`
`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)].
`
`
`
`
`
`
`
` 
`
`Reference ID: 4464834
`
`2 
`
`
`

`

`WARNINGS AND PRECAUTIONS
`
`
`Diarrhea, Nausea, and Vomiting
`
`Depression
`
`
`
`5
`
`5.1
`
`There have been postmarketing reports of severe diarrhea, nausea, and vomiting associated with the use of OTEZLA. 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
`
`
`OTEZLA generally improved quickly. Consider OTEZLA dose reduction or suspension if patients develop severe diarrhea, nausea, or
`
`
`
`vomiting.
`
`5.2
`
`
`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.
`
`
`
`
`
`
`
`Behçet’s disease: During the placebo-controlled period of the phase 3 study, 1% (1/104) of patients treated with OTEZLA reported
`
`
`
`
`
`
`depression/depressed mood compared to 1% (1/103) treated with placebo. None of these reports of depression was serious or led to study
`
`
`
`
`
`
`
`
`
`
`
`
`discontinuation. No instances of suicidal ideation or behavior were reported during the placebo-controlled period of the phase 3 study in
`
`
`patients treated with OTEZLA (0/104) or treated with placebo (0/103).
`
`5.3
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`During the controlled period of the phase 3 study in Behçet’s disease, weight decrease >5% of body weight was reported in 4.9% (5/103)
`of subjects treated with OTEZLA 30 mg twice daily compared to 3.9% (4/102) patients 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 [see Adverse Reactions (6.1)].
`
`
`5.4
`
`
`
`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)].
`
`
`
`Weight Decrease
`
`
`Drug Interactions
`
`
` 
`
`Reference ID: 4464834
`
`3 
`
`
`

`

`ADVERSE REACTIONS
`
`
`
`6
`
`The following adverse reactions are described elsewhere in the labeling:
`
`
`
` Diarrhea, Nausea, and Vomiting [see Warnings and Precautions (5.1)]
`
`
`
` Depression [see Warnings and Precautions (5.2)]
`
`
`
` Weight Decrease [see Warnings and Precautions (5.3)]
`
`
`
`
` Drug Interactions [see Warnings and Precautions (5.4)]
`
`
`
`
`Clinical Trials Experience
`
`
`
`6.1
`
`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
`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.
`
`
`
`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)
`
`
`
`
`
`
`
`
`
`Day 1 to 5
`
`(N=495)
`
`n (%)c
`
` 6 (1.2)
`
`
` 7 (1.4)
`
`
` 9 (1.8)
`
`
`3 (0.6)
`
`Placebo
`
`
` Day 6 to Day 112
`
` (N=490)
`n (%)
`
`
` 8 (1.6)
`
`
` 15 (3.1)
`
` 11 (2.2)
`
`
`
`9 (1.8)
`
`OTEZLA 30 mg BID
`
`
`
` Day 6 to Day 112
`
` Day 1 to 5
`
` (N=493)
`
` (N=497)
`n (%)
`n (%)
`
` 46 (9.3)
`
`
` 38 (7.7)
`
` 37 (7.4)
`
`
` 44 (8.9)
`
` 24 (4.8)
`
` 29 (5.9)
`
`
`
`
` 3 (0.6)
`19 (3.9)
`
`Preferred Term
`Diarrheaa
`
`Nauseaa
`
`Headachea
`
`Upper respiratory tract
`infectionb
`
`Vomitinga
`
`
` 16 (3.2)
`
` 4 (0.8)
`
`
` 2 (0.4)
`
`
` 2 (0.4)
`
`Nasopharyngitisb
`
`
` 13 (2.6)
`
` 1 (0.2)
`
`
` 8 (1.6)
`
`
` 1 (0.2)
`
`Abdominal pain upperb
`
` 10 (2.0)
`
`
` 3 (0.6)
`
` 1 (0.2)
`
`
` 0 (0.0)
`
`
`
`
` 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.
`
`c n (%) indicates number of patients and percent.
`
`
`
`
`
`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*
`
` 
`
`Reference ID: 4464834
`
`4 
`
`

`

`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.
`
`
`
`Table 3: Adverse Reactions Reported in ≥1% of Subjects on OTEZLA and With Greater Frequency
`
`
`
`
`Than in Subjects on Placebo; up to Day 112 (Week 16)
`
`
`
`
`
`
`
`
`Placebo (N=506)
`
`
`n (%)
`Preferred Term
`32 (6)
`Diarrhea
`35 (7)
`
` Nausea
`31 (6)
` Upper respiratory tract infection
`
`
`21 (4)
`Tension headache
`
`19 (4)
`Headache
`
`11 (2)
`Abdominal pain*
`
`
` 8 (2)
`
` Vomiting
`
` 9 (2)
`
` Fatigue
`6 (1)
` Dyspepsia
`
`
`5 (1)
`Decreased appetite
`4 (1)
`Insomnia
`4 (1)
`Back pain
`5 (1)
`
` Migraine
`
`1 (0)
`Frequent bowel movements
`
`
`2 (0)
`Depression
`2 (0)
`Bronchitis
`
`0 (0)
`Tooth abscess
`0 (0)
`Folliculitis
`0 (0)
`Sinus headache
`*Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain.
`
`
`
`OTEZLA 30 mg BID (N=920)
`
`n (%)
`160 (17)
`
` 155 (17)
`
` 84 (9)
`
`
`75 (8)
`55 (6)
`
`39 (4)
`
` 35 (4)
`
` 29 (3)
`29 (3)
`
`26 (3)
`
`
`21 (2)
`20 (2)
`
`
` 19 (2)
`
`
`17 (2)
`
`12 (1)
`
`12 (1)
`
`
`10 (1)
`
`9 (1)
`9 (1)
`
`
`
`
`
`Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.
`
`Behçet’s Disease Clinical Trials
`
`
`
`
`
`OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled study (BCT-002) in adult patients with Behçet’s Disease
`
`
`
`
`(BD) with active oral ulcers. A total of 207 patients 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)]. After Week 12, all patients received treatment with OTEZLA 30 mg
`
`
`
`twice daily. Patients ranged in age from 19 to 72, with a mean age of 40 years.
`
`
`
`
`
`
`
`
`
`
`
`
`Diarrhea, nausea, headache, and upper respiratory tract infection were the most commonly reported adverse reactions. The proportion of
`
`
`
`
`
`
`patients with BD who discontinued treatment due to any adverse reaction during the placebo-controlled period of the study, was 2.9% for
`
`
`patients treated with OTEZLA 30 mg twice daily and 4.9% for placebo-treated patients.
`
`
`
`
`
`
`
` 
`
`Reference ID: 4464834
`
`5 
`
`
`

`

`Table 4: Adverse Reactions Reported in ≥5% of Patients on OTEZLA and with at least 1%
`
`
`
`
`
`Greater Frequency than Patients on Placebo; up to Week 12
`
`
`
`
`
`
`Preferred Term
`
`
`
`
`OTEZLA 30 mg twice daily
`
`(N=104)
`n (%)
`
`
` 43 (41.3)
`
`
`
` 20 (19.2)
`
` 15 (14.4)
`
`
` 12 (11.5)
`
` 9 (8.7)
`
`
` 9 (8.7)
`
` 8 (7.7)
`
` 7 (6.7)
`
` 6 (5.8)
`
`Placebo
`
`(N=103)
`n (%)
`
`
` 21 (20.4)
`Diarrheaa
`Nauseaa
`11 (10.7)
` Headache
`
`11 (10.7)
`
` Upper respiratory tract infection
`5 (4.9)
`Abdominal pain upper
` 2 (1.9)
`Vomitinga
`2 (1.9)
`Back pain
`6 (5.8)
`Viral upper respiratory tract infection
`
` 5 (4.9)
`Arthralgia
`
` 3 (2.9)
` a There were no serious adverse reactions of diarrhea, nausea or vomiting.
`
`
`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)].
`
`
`
`8
`
`8.1
`
`
`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 or visiting https://mothertobaby.org/ongoing-study/otezla/.
`
`
`Risk Summary
`
`
`Available pharmacovigilance data with OTEZLA 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, OTEZLA 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 estimated 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 2-4% and 15-20%, respectively.
`
`Data
`
`Animal Data
`
`
`
`
`
`
`
`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 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
`6 
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`Pregnancy
`
`
` 
`
`Reference ID: 4464834
`
`

`

`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 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 OTEZLA and any potential adverse effects on the breastfed infant from OTEZLA 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
`
`
`The safety and effectiveness of OTEZLA in pediatric patients less than18 years of age have not been established.
`
`
`
`
`8.5
`
`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.
`
`
`
`8.6
`
`
`Apremilast pharmacokinetics were characterized in subjects with mild, moderate, and severe renal impairment as defined by a creatinine
`
`
`
`
`
`
`clearance of 60-89, 30-59, and less than 30 mL per minute, respectively, by the Cockcroft–Gault equation. While no dose adjustment is
`
`
`
`
`
`needed in patients with mild or moderate renal impairment, the dose of OTEZLA 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
`
`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.
`
`10
`
`
`In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should
`
`
`
`there be an overdose.
`
`DESCRIPTION
`
`
`11
`
`
`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.
`
`
`
` 
`
`Reference ID: 4464834
`
`7 
`
`
`Pediatric Use
`
`
`
`Geriatric Use
`
`
`Renal Impairment
`
`
`Hepatic Impairment
`
`
`OVERDOSAGE
`
`
`

`

`The chemical structure is:
`
`
`O
`
`O
`
`H
`S
`O
`O
`
`O
`
`N
`
`O
`
`O
`
`NH
`
`
`
`CLINICAL PHARMACOLOGY
`
`
`
`Pharmacokinetics
`
`
`
`
`
`
`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).
`
`12
`
`
`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
`
`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: 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 Cmax of