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The active ingredient in OTEZLA/OTEZLA XR tablets is apremilast. Apremilast drug substance is non-hygroscopic. Apremilast drug substance is practically insoluble in water and slightly soluble in alcohol.
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:
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OTEZLA (apremilast) tablets are supplied in 10 mg, 20 mg, and 30 mg strengths for oral administration. Each tablet contains apremilast as the active ingredient and the following inactive ingredients: croscarmellose sodium, iron oxide red, iron oxide yellow (20 and 30 mg only), iron oxide black (30 mg only), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide.
OTEZLA XR (apremilast) extend-ed-release tablets are supplied in a 75 mg strength for oral administration. Each tablet contains apremilast as the active ingredient and the following inactive ingredients: cellulose acetate, colloidal silicon dioxide, ferrosoferric oxide, hydroxypropyl methylcellulose acetate succinate, hypromellose, iron oxide red, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, sodium chloride, titanium dioxide.
Otezla is indicated for the treatment of adult patients and pediatric patients 6 years of age and older and weighing at least 20 kg with active psoriatic arthritis.
Otezla XR is indicated for the treatment of adult patients and pediatric patients 6 years of age and older and weighing at least 50 kg with active psoriatic arthritis.
Otezla/Otezla XR is indicated for the treatment of adult patients with plaque psoriasis who are candidates for phototherapy or systemic therapy.
Otezla is indicated for the treatment of pediatric patients 6 years of age and older and weighing at least 20 kg with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Otezla XR is indicated for the treatment of pediatric patients 6 years of age and older and weighing at least 50 kg with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Otezla/Otezla XR is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s Disease.
The recommended initial dosage titration from Day 1 to Day 5 is shown in Table 1. Following the 5-day titration with Otezla, the recommended maintenance dosage is Otezla 30 mg twice daily or Otezla XR 75 mg once daily taken orally starting on Day 6. This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.
Table 1. Dosage Titration Schedule for Adult Patients with Psoriatic Arthritis, Plaque Psoriasis, or Behçet’s Disease
| Otezla Dosage Titrationa | Otezla/Otezla XR Maintenance Dosage | ||||||||
| Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 & thereafter | ||||
| AM | AM | PM | AM | PM | AM | PM | AM | PM | |
| 10 mg | 10 mg | 10 mg | 10 mg | 20 mg | 20 mg | 20 mg | 20 mg | 30 mg | Otezla 30 mg BID OR Otezla XR 75 mg QD |
BID = twice daily; QD = once daily
a Otezla tablets should be used for the initial titration regardless of whether Otezla or Otezla XR will be used for the maintenance dosage.
Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis Moderate to Severe Plaque PsoriasisThe recommended dosage for pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis or moderate to severe plaque psoriasis is based on body weight. Following the appropriate initial titration schedule shown in Table 2, the recommended maintenance dosage is:
The initial titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.
Table 2. Dosage Titration Schedule for Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis or Moderate to Severe Plaque Psoriasis
| Otezla Dosage Titrationa | Otezla/Otezla XR Maintenance Dosage | |||||||||
| Body Weight | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 & thereafter | ||||
| AM | AM | PM | AM | PM | AM | PM | AM | PM | ||
| 50 kg or more | 10 mg | 10 mg | 10 mg | 10 mg | 20 mg | 20 mg | 20 mg | 20 mg | 30 mg | Otezla 30 mg BID OR Otezla XR 75 mg QD |
| 20 kg to less than 50 kg | 10 mg | 10 mg | 10 mg | 10 mg | 20 mg | 20 mg | 20 mg | 20 mg | 20 mg | Otezla 20 mg BID |
BID = twice daily; QD = once daily
a Otezla tablets should be used for the initial titration regardless of whether Otezla or Otezla XR will be used for the maintenance dosage.
Patients treated with Otezla 30 mg twice daily may be switched to Otezla XR 75 mg once daily the day following the last dose of Otezla 30 mg.
Patients treated with Otezla XR 75 mg once daily may be switched to Otezla 30 mg twice daily the day following the last dose of Otezla XR 75 mg.
For initial dosage titration in adult patients with severe renal impairment (creatinine clearance [CLcr] of less than 30 mL per minute estimated by the Cockcroft–Gault equation), titrate Otezla using only the AM schedule listed in Table 1 and skip the PM doses. The recommended maintenance dosage in this group is Otezla 30 mg once daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Otezla XR is not recommended for adult patients with severe renal impairment; the appropriate dosage for these patients has not been determined [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Pediatric Patients 6 Years of Age and Older and Weighing at Least 20 kg with Psoriatic Arthritis or Moderate to Severe Plaque PsoriasisFor initial dosage titration in pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis or moderate to severe plaque psoriasis and severe renal impairment (CLcr of less than 30 mL per minute estimated by the Cockcroft–Gault equation), titrate Otezla using only the AM schedule listed in Table 2 for the appropriate body weight category and skip the PM doses. The recommended maintenance dosage is:
Otezla XR is not recommended for pediatric patients with severe renal impairment; the appropriate dosage for these patients has not been determined [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Otezla is available as diamond-shaped, film-coated tablets in the following dosage strengths:
Otezla XR is available as 75 mg round, biconvex, pink, film-coated extended-release tablets with “APR 75” printed in black on one side and a hole or indentation on either side of the tablet, which may or may not be visible.
The following adverse reactions are described elsewhere in the labeling:
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.
OTEZLA was evaluated in three 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 three trials, there were 1493 subjects 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 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 OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA 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 3 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 OTEZLA 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 OTEZLA 30 mg twice daily and 1.2% for placebo-treated subjects.
Table 3. Adverse Reactions Reported in ≥ 2% of Adult Subjects with Active Psoriatic Arthritis
on OTEZLA 30 mg Twice Daily and ≥ 1% than That Observed in Subjects on Placebo up to Day 112 (Week 16)
| Placebo | OTEZLA 30 mg BIDd | |||
| Adverse Reactions | 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 (%) |
| Diarrheaa | 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) |
| Nasopharyngiti sb | 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) |
| 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 subject 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 subjects and percent. d BID = twice daily. |
||||
The safety of OTEZLA was assessed in 1426 subjects in three 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 (see Table 4). 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 plaque 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 4. Adverse Reactions Reported in ≥ 1% of Adult Subjects with Moderate to Severe Plaque
Psoriasis on OTEZLA and With Greater Frequency Than in Subjects on Placebo up to Day 112 (Week 16)
| Adverse Reactions | Placebo (N = 506) n (%) |
OTEZLA 30 mg BIDb (N = 920) n (%) |
| Diarrhea | 32 (6) | 160 (17) |
| Nausea | 35 (7) | 155 (17) |
| Upper respiratory tract infection | 31 (6) | 84 (9) |
| Tension headache | 21 (4) | 75 (8) |
| Headache | 19 (4) | 55 (6) |
| Abdominal paina | 11 (2) | 39 (4) |
| Vomiting | 8 (2) | 35 (4) |
| Fatigue | 9 (2) | 29 (3) |
| Dyspepsia | 6 (1) | 29 (3) |
| Decreased appetite | 5 (1) | 26 (3) |
| Insomnia | 4 (1) | 21 (2) |
| Back pain | 4 (1) | 20 (2) |
| Migraine | 5 (1) | 19 (2) |
| Frequent bowel movements | 1 (0) | 17 (2) |
| Depression | 2 (0) | 12 (1) |
| Bronchitis | 2 (0) | 12 (1) |
| Tooth abscess | 0 (0) | 10 (1) |
| Folliculitis | 0 (0) | 9 (1) |
| Sinus headache | 0 (0) | 9 (1) |
| a Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. b BID = twice daily. |
||
Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.
OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-3) in adults with moderate to severe plaque psoriasis of the scalp [see Clinical Studies (14.2)]. A total of 302 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. The most commonly reported adverse reactions that occurred at a higher rate in the OTEZLA group than in the placebo group were: diarrhea (31% vs. 11%), nausea (22% vs. 6%), headache (12% vs. 5%), and vomiting (6% vs. 2%). The proportion of subjects who discontinued treatment because of any adverse reaction during the 16-week placebo-controlled period of the trial was 6% for subjects who received OTEZLA 30 mg twice daily and 3% for subjects who received placebo. Gastrointestinal adverse reactions that led to discontinuation of treatment were diarrhea (3% vs. 0%), nausea (1.5% vs. 1%), and vomiting (1.5% vs. 0%) in the OTEZLA group compared to placebo.
OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-5) in adults with moderate to severe plaque psoriasis of the genital area [see Clinical Studies (14.2)]. A total of 289 subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Overall, the safety profile observed in the OTEZLA group during the placebo-controlled phase was consistent with the safety profile previously established in adult subjects with moderate to severe plaque psoriasis.
Adverse Reactions from Clinical Trials in Pediatric Subjects 6 to 17 Years of AgeOTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-6) in pediatric subjects 6 to 17 years of age with moderate to severe plaque psoriasis [see Clinical Studies (14.3)]. A total of 245 subjects were randomized to receive OTEZLA (163 subjects, at a dosage of 20 mg twice daily or 30 mg twice daily, based on body weight) or placebo (82 subjects) twice daily during the 16-week placebo-controlled phase of the trial. The trial also included a 36-week extension phase during which all subjects received OTEZLA 20 mg or 30 mg twice daily. Overall, the safety profile observed in pediatric subjects treated with OTEZLA during the study was consistent with the safety profile established in adult subjects with moderate to severe plaque psoriasis.
OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (PSOR-4) in adult subjects with mild to moderate plaque psoriasis [see Clinical Studies (14.4)]. A total of 595 subjects were randomized to receive OTEZLA 30 mg twice daily (297 subjects) or placebo twice daily (298 subjects) during the placebo-controlled phase of the trial. The trial also included an open label extension phase during which all subjects received OTEZLA 30 mg twice daily. Overall, the safety profile observed in the OTEZLA group during the placebo-controlled phase was consistent with the safety profile previously established in adult subjects with moderate to severe plaque psoriasis.
OTEZLA was evaluated in a Phase 3, multicenter, randomized, placebo-controlled trial (BCT-002) in adult subjects with Behçet’s Disease (BD) with active oral ulcers [see Clinical Studies (14.5)]. A total of 207 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)]. After Week 12, all subjects received treatment with OTEZLA 30 mg twice daily. Subjects 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 (see Table 5). The proportion of subjects with BD who discontinued treatment due to any adverse reaction during the placebo-controlled period of the trial, was 2.9% for subjects treated with OTEZLA 30 mg twice daily and 4.9% for placebo-treated subjects.
Table 5. Adverse Reactions Reported in ≥ 5% of Adult Subjects with BD with Active Oral Ulcers
on OTEZLA and with at Least 1% Greater Frequency than Subjects on Placebo up to Week 12
| Adverse Reactions | Placebo (N = 103) n (%) |
OTEZLA 30 mg twice daily (N = 104) n (%) |
| Diarrheaa | 21 (20.4) | 43 (41.3) |
| Nauseaa | 11 (10.7) | 20 (19.2) |
| Headache | 11 (10.7) | 15 (14.4) |
| Upper respiratory tract infection | 5 (4.9) | 12 (11.5) |
| Abdominal pain upper | 2 (1.9) | 9 (8.7) |
| Vomitinga | 2 (1.9) | 9 (8.7) |
| Back pain | 6 (5.8) | 8 (7.7) |
| Viral upper respiratory tract infection | 5 (4.9) | 7 (6.7) |
| Arthralgia | 3 (2.9) | 6 (5.8) |
| a There were no serious adverse reactions of diarrhea, nausea or vomiting. | ||
* 1 subject treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.
Co-administration with strong CYP450 inducers (such as rifampin) decreases apremilast exposure and may result in loss of efficacy of OTEZLA/OTEZLA XR [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].
Included as part of the PRECAUTIONS section.
Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported during post marketing surveillance. Avoid the use of OTEZLA/OTEZLA XR 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 OTEZLA/OTEZLA XR and institute appropriate therapy.
There have been 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/OTEZLA XR dosage reduction or suspension if patients develop severe diarrhea, nausea, or vomiting.
Treatment with apremilast is associated with an increased incidence of depression. Before using OTEZLA/OTEZLA XR in patients with a history of depression and/or suicidal thoughts or behavior, carefully weigh the risks and benefits of treatment with OTEZLA/OTEZLA XR. Advise patients, their caregivers, and families 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. Carefully evaluate the risks and benefits of continuing treatment with OTEZLA/OTEZLA XR if such events occur.
Psoriatic Arthritis: During the 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.
Plaque Psoriasis: During the 16-week placebo-controlled period of the 3 controlled clinical trials in adult subjects with moderate to severe plaque psoriasis, 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.
During the 16-week placebo-controlled period of the clinical trial in adults with mild to moderate plaque psoriasis, the incidence of subjects reporting depression was similar to what was observed in the adult moderate to severe plaque psoriasis trials.
Behçet’s Disease: During the placebo-controlled period of the phase 3 trial, 1% (1/104) of subjects 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 discontinuation from the trial. No instances of suicidal ideation or behavior were reported during the placebo-controlled period of the phase 3 trial in subjects treated with OTEZLA (0/104) or treated with placebo (0/103).
Weight loss may occur in adult or pediatric patients treated with OTEZLA/OTEZLA XR.
Regularly monitor the weight of patients treated with OTEZLA/OTEZLA XR. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of OTEZLA/OTEZLA XR [see Adverse Reactions (6.1)].
During the placebo-controlled period of the trials 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 placebo-controlled period of the trials in adults with moderate to severe plaque 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 placebo-controlled period of the clinical trial in adults with mild to moderate plaque psoriasis, weight decrease was similar to what was observed in the trials of adults with moderate to severe plaque psoriasis.
During the placebo-controlled period of the phase 3 trial 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) subjects treated with placebo.
During the placebo-controlled period of the clinical trial in pediatric subjects 6 years of age and older with moderate to severe plaque psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (19/163) of pediatric subjects treated with OTEZLA compared to 2.5% (2/80) of pediatric subjects treated with placebo. Weight decrease of ≥ 10% of body weight occurred in 1% (1/163) of pediatric subjects treated with OTEZLA twice daily compared to 0% (0/80) of pediatric subjects treated with placebo.
Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA/OTEZLA XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted.
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/OTEZLA XR. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA/OTEZLA XR is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
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 approximately 9- times 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 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 post-implantation losses. There was no effect of apremilast approximately 1.0-times the MRHD (10 mg/kg/day).
No information provided.
OTEZLA/OTEZLA XR is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Warnings and Precautions (5.1), see Adverse Reactions (6.1)].
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.
In clinical studies, apremilast decreased IL-17, IL-22 and TNF-alpha levels circulating in blood and reduced expression of these pro-inflammatory cytokine genes in skin. The clinical implications of these pharmacodynamic responses remain unclear.
OTEZLA 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 OTEZLA.
OTEZLA XR when taken orally is absorbed with peak plasma concentrations (Cmax) occurring at a median time (tmax) of ~6 hours. OTEZLA XR 75 mg administered once daily demonstrates comparable PK exposure (steady-state AUC and Cmax) to OTEZLA 30 mg twice daily. When administered with a high-fat meal, OTEZLA XR tmax was delayed by 3 hours and Cmax and AUC were increased by ~28% compared to fasted conditions. Therefore, OTEZLA XR may be taken without regard to meals.
Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L.
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.
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 radiolabeled 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.
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 adult subjects with severe renal impairment administered a single dose of 30 mg OTEZLA, the AUC and Cmax of apremilast increased by approximately 88% and 42%, respectively [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)] .
The effects of renal impairment have not been studied for OTEZLA XR [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)] .
Geriatric Patients: A single oral dose of 30-mg apremilast was studied in young adults and elderly healthy subjects. The apremilast exposure in elderly subjects (65 to 85 years of age) was about 13% higher in AUC and about 6% higher in Cmax than in young subjects (18 to 55 years of age) [see Use in Specific Populations (8.5)].
Pediatric Patients: The pharmacokinetics of OTEZLA were evaluated in a clinical trial in pediatric subjects 6 to 17 years of age with moderate to severe plaque psoriasis at the recommended pediatric dosage regimen [see Dosage and Administration (2.1) and Clinical Studies (14.3)] . Population pharmacokinetic analysis indicated that steady-state exposure (AUC and Cmax) of OTEZLA in pediatric subjects receiving the pediatric maintenance dosage regimen (20 or 30 mg twice daily, based on body weight) was comparable to steady-state exposure in adult subjects at the 30 mg twice daily dosage.
Male and Female Patients: In pharmacokinetic trials in healthy volunteers, the extent of exposure in females was about 31% higher and Cmax was about 8% higher than that in male subjects.
Racial or Ethnic Groups: The pharmacokinetics of apremilast in Chinese and Japanese healthy male subjects is comparable to that in White healthy male subjects. In addition, apremilast exposure is similar among White subjects (including Hispanic or Latino and not Hispanic or Latino subjects) and Black or African American subjects.
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 inducerrifampin (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 (5.5) and Drug Interactions (7.1)] .
Instruct patients to take OTEZLA/OTEZLA XR only as prescribed [see Dosage and Administration (2.1 and 2.3)]. Advise patients to take OTEZLA/OTEZLA XR with or without food. Instruct patients to swallow tablets whole and not to crush, split, or chew prior to swallowing [see Dosage and Administration (2.4)].
Inform patients that hypersensitivity reactions can occur following administration of OTEZLA/OTEZLA XR. Instruct patients to contact their healthcare provider if they experience symptoms of an allergic reaction [see Warnings and Precautions (5.1)].
Advise patients of the potential complications of severe diarrhea, nausea, or vomiting and instruct them to contact their healthcare provider if they experience these adverse reactions, especially if the patient is 65 years of age or older [see Warnings and Precautions (5.2)].
Inform patients that treatment with OTEZLA/OTEZLA XR is associated with an increased incidence of depression. Advise patients, their caregivers, and families 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 [see Warnings and Precautions (5.3)].
Inform patients that treatment with OTEZLA/OTEZLA XR is associated with potential weight loss. Instruct patients or caregivers to have their or their child’s weight monitored regularly and, if unexplained or clinically significant weight loss occurs, to contact their healthcare provider for evaluation of the weight loss [see Warnings and Precautions (5.4)].
Advise pregnant patients and patients of reproductive potential of the potential risk to a fetus. Advise patients to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)].
Patients receiving OTEZLA XR may notice an inert tablet shell passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert tablet shell.
