Otezla apremilast Kit, 1 kit

8 USE IN SPECIFIC POPULATIONS Severe Renal Impairment : Increased systemic exposure of OTEZLA has been observed. For adults and for pediatric patients weighing 50 kg or more, reduce dosage to OTEZLA 30 mg once daily. For pediatric patients weighing 20 kg to less than 50 kg, reduce dosage to OTEZLA 20 mg once daily ( 2.3 , 8.6 ).

8.1Pregnancy Risk Summary Available data with OTEZLA use in pregnant women have not identified a drug-associated risk of major birth defects or adverse maternal or fetal outcomes (see Data ) . 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 approximately 2-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD.

When apremilast was administered to pregnant mice during organogenesis, there were no apremilast-induced malformations up to exposures 4-times the MRHD. Based on findings from animal reproduction studies, OTEZLA/OTEZLA XR may increase the risk for fetal loss (see Data ) . Advise pregnant women of the potential risk of fetal loss.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Human Data A pregnancy registry conducted by the Organization of Teratology Information Specialists (OTIS) in the United States and Canada assessed the risk of major birth defects in liveborn infants of women with psoriatic arthritis, psoriasis, or Behçet's Disease exposed to apremilast in the first trimester. The study compared pregnant women treated with apremilast (n = 15) with disease matched pregnant women who were not exposed to apremilast (n = 106). In the apremilast-exposed cohort, there were no reports of liveborn infants with major birth defects nor miscarriages.

One stillbirth was reported in the apremilast exposed cohort. These data are limited by the small sample size of apremilast-exposed pregnancies. 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 [GD] 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-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 (GD 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 GD 15. No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in post-implantation loss at doses corresponding to a systemic exposure of approximately 2-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…

8.1Pregnancy Risk Summary Available data with OTEZLA use in pregnant women have not identified a drug-associated risk of major birth defects or adverse maternal or fetal outcomes (see Data ) . 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 approximately 2-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD.

When apremilast was administered to pregnant mice during organogenesis, there were no apremilast-induced malformations up to exposures 4-times the MRHD. Based on findings from animal reproduction studies, OTEZLA/OTEZLA XR may increase the risk for fetal loss (see Data ) . Advise pregnant women of the potential risk of fetal loss.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Human Data A pregnancy registry conducted by the Organization of Teratology Information Specialists (OTIS) in the United States and Canada assessed the risk of major birth defects in liveborn infants of women with psoriatic arthritis, psoriasis, or Behçet's Disease exposed to apremilast in the first trimester. The study compared pregnant women treated with apremilast (n = 15) with disease matched pregnant women who were not exposed to apremilast (n = 106). In the apremilast-exposed cohort, there were no reports of liveborn infants with major birth defects nor miscarriages.

One stillbirth was reported in the apremilast exposed cohort. These data are limited by the small sample size of apremilast-exposed pregnancies. 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 [GD] 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-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 (GD 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 GD 15. No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in post-implantation loss at doses corresponding to a systemic exposure of approximately 2-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-times the MRHD (on an AUC basis at doses ≥…

8.4Pediatric Use OTEZLA Plaque Psoriasis The safety and effectiveness of OTEZLA have been established in 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. Use of OTEZLA in these patients is supported by evidence from a 52-week adequate and well-controlled clinical trial (PSOR-6) in 245 pediatric subjects 6 years of age and older with moderate to severe plaque psoriasis. Weight loss in OTEZLA-treated pediatric subjects was comparable to weight loss observed in adults [see Warnings and Precautions (5.4) , Adverse Reactions (6.1) and Clinical Studies (14.3) ] .

Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted. The safety and effectiveness of OTEZLA have not been established in pediatric patients below the age of 6 years or weighing less than 20 kg with moderate to severe plaque psoriasis.

Psoriatic Arthritis The safety and effectiveness of OTEZLA have been established for pediatric patients 6 years of age and older and weighing at least 20 kg with psoriatic arthritis. Use of OTEZLA in these patients is supported by evidence from adequate and well controlled trials of OTEZLA in adults with psoriatic arthritis, pharmacokinetic data from adult patients with psoriatic arthritis, adult patients with psoriasis, and pediatric patients with psoriasis, and safety data from a clinical trial in 245 pediatric patients 6 years of age and older with psoriasis.

Steady-state exposure of OTEZLA in pediatric patients with psoriatic arthritis is estimated to be comparable to adults with psoriatic arthritis and pediatric patients with psoriasis [see Clinical Pharmacology (12.3) ] . Closely monitor growth (height and weight) in OTEZLA-treated pediatric patients. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.4) ] .

The safety and effectiveness of OTEZLA have not been established in pediatric patients below the age of 6 years or weighing less than 20 kg with psoriatic arthritis. Behçet's Disease The safety and effectiveness of OTEZLA have not been established in pediatric patients with psoriatic arthritis or oral ulcers associated with Behçet's Disease. OTEZLA XR Plaque Psoriasis and Psoriatic Arthritis The safety and effectiveness of OTEZLA XR have been established for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in pediatric patients 6 years of age and older and weighing at least 50 kg.

Use of OTEZLA XR in these patients is supported by pharmacokinetic data from healthy adults demonstrating comparable PK exposure between OTEZLA XR 75 mg once daily and OTEZLA 30 mg twice daily, which is the recommended OTEZLA dosage for pediatric patients weighing at least 50 kg [see Dosage and Administration (2.1) , Clinical Pharmacology (12.3) ] . Closely monitor growth (height and weight) in pediatric patients treated with OTEZLA XR. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

The safety and effectiveness of OTEZLA XR have not been established in pediatric patients below the age of 6 years or weighing less than 50 kg with moderate to severe plaque psoriasis or psoriatic arthritis. Behçet's Disease The safety and effectiveness of OTEZLA XR have not been established in pediatric patients with oral ulcers associated with Behçet's Disease.

8.5Geriatric Use Of the 1493 patients who enrolled in Trials PsA-1, PsA-2, and PsA-3, a total of 146 (9.8%) psoriatic arthritis patients were 65 years of age and older, including 19 (1.3%) patients 75 years and older. No overall differences were observed in the safety profile of geriatric patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical trials. Of the 1257 subjects who enrolled in two placebo-controlled plaque psoriasis trials (PSOR-1 and PSOR-2), a total of 108 (8.6%) plaque psoriasis patients were 65 years of age and older, including 9 (0.7%) patients who were 75 years of age and older.

No overall differences were observed in the safety or effectiveness in geriatric patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical trials. Because patients 65 years of age or older may be at a higher risk of complications such as volume depletion or hypotension from severe diarrhea, nausea, or vomiting, monitor geriatric patients closely for such complications [see Warnings and Precautions (5.2) ] .