Otezla
(apremilast)Dosage & Administration
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Otezla Prescribing Information
Psoriatic Arthritis
OTEZLA is indicated for the treatment of adult patients with active psoriatic arthritis.
Psoriasis
OTEZLA is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Oral Ulcers Associated with Behçet's Disease
OTEZLA is indicated for the treatment of adult patients with oral ulcers associated with Behçet's Disease.
Dosage in Psoriatic Arthritis, Psoriasis, and Behçet's Disease
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.
Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 | |||||
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 |
Dosage Adjustment in Patients with Severe Renal Impairment
OTEZLA dosage should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance (CLcr) of less than 30 mL per minute estimated by the Cockcroft–Gault equation) [see Use in Specific Populations and Clinical Pharmacology ]. 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.
OTEZLA is available as diamond shaped, film coated tablets in the following dosage strengths:
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- 10-mg pink tablet engraved with "APR" on one side and "10" on the other side
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- 20-mg brown tablet engraved with "APR" on one side and "20" on the other side
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- 30-mg beige tablet engraved with "APR" on one side and "30" on the other side.
Pregnancy
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 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).
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.
Pediatric Use
The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established.
Geriatric Use
Of the 1493 subjects who enrolled in Studies PsA-1, PsA-2, and PsA-3 a total of 146 psoriatic arthritis subjects were 65 years of age and older, including 19 subjects 75 years and older. No overall differences were observed in the safety profile of elderly subjects ≥65 years of age and younger adult subjects <65 years of age in the clinical studies.
Of the 1257 subjects who enrolled in two placebo-controlled psoriasis trials (PSOR 1 and PSOR 2), a total of 108 psoriasis subjects were 65 years of age and older, including 9 subjects who were 75 years of age and older. No overall differences were observed in the efficacy and safety in elderly subjects ≥65 years of age and younger adult subjects <65 years of age in the clinical trials.
Renal Impairment
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 and Clinical Pharmacology ].
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.
OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Adverse Reactions ].
Diarrhea, Nausea, and Vomiting
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.
Depression
Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur.
Psoriatic arthritis: During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects.
Psoriasis: During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects (0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide.
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).
Weight Decrease
During the controlled period of the studies in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo.
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 ].
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 and Clinical Pharmacology ].