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Psoriatic Arthritis

Mechanism of Action

Otezla® (apremilast) inhibits PDE4 intracellularly and has anti-inflammatory properties1-4
 
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LEARN MORE ABOUT THE INTRACELLULAR MECHANISM OF ACTION OF OTEZLA IN THE VIDEO BELOW

The specific mechanism(s) by which Otezla exerts its therapeutic action in psoriasis is not well defined.1

PDE4, phosphodiesterase 4.

Next: Mechanism of Action Diagram – PDE4

THE ROLE OF PDE4 AND cAMP IN CONTROLLING INFLAMMATION1-3

The interior of an inflammatory cell showing how phosphodiesterase 4 (PDE4) breaks down cyclic AMP into AMP

Inflammatory cella

  • Cyclic adenosine monophosphate (cAMP) is a second messenger for a variety of inflammatory mediators1
  • Phosphodiesterase 4 (PDE4) is a cAMP-specific PDE that has been shown to degrade cAMP to AMP in inflammatory cells1,4,5
  • The balance between cAMP and AMP within a cell may modulate the expression of pro-inflammatory and anti-inflammatory mediators3
a

Visual representation based on preclinical evidence.

Next: Mechanism of Action Diagram – Otezla

Otezla is a non-biologic oral PDE4 inhibitor with a distinct mechanism of action4

The interior of an inflammatory cell showing how apremilast binds to phosphodiesterase 4 (PDE4) to inhibit the hydrolyzation of cyclic AMP in to AMP

Inflammatory cella

Otezla inhibits PDE4 intracellularly4

  • The specific mechanism(s) by which apremilast exerts its therapeutic action in patients with psoriatic arthritis is not well defined4
  • By elevating cAMP levels, Otezla is thought to indirectly modulate production of inflammatory mediators2,3
  • An exploratory PALACE 1 substudy evaluating 47 biomarkers, some of which are relevant in the pathophysiology of psoriatic disease, observed6-9,b,c:
    • An increase in anti-inflammatory mediators, such as IL-10
    • A decrease in pro-inflammatory mediators, such as TNF-α, IL-17A, and IL-23
a

Visual representation based on preclinical evidence.

b

Based on an exploratory PALACE 1 biomarker substudy of patients with active psoriatic arthritis (n = 150 peripheral blood plasma samples at baseline, weeks 4, 16, 24, and 40) for a total of 47 biomarkers using a validated, multiplexed immunoassay.

c

Prior exposure to a biologic was higher in the biomarker subset compared to the full patient population (48.8% vs 23.6%).

 

IL, interleukin; PALACE, Psoriatic Arthritis Long-Term Assessment of Clinical Efficacy; PDE4, phosphodiesterase 4; TNF, tumor necrosis factor.

Next: Study Design

References: 1. Moore AR, Willoughby DA. Clin Exp Immunol. 1995;101(3):387-389. 2. Schafer PH, Parton A, Gandhi AK, et al. Br J Pharm. 2010;159(4):842-855. 3. Schafer P. Biochem Pharmacol. 2012;83(12):1583-1590. 4. Otezla [package insert]. Thousand Oaks, CA: Amgen Inc. 5. Soto FJ, Hanania NA. Curr Opin Pulm Med. 2005;11(2):129-134. 6. Schafer PH, Chen P, Fang L, Wang A, Chopra R. J Immun Res. 2015. doi:10.1155/2015/906349. 7. van Kujik AW, Reinders-Blankert P, Smeets TJ, Dijkmans BA, Tak PP. Ann Rheum Dis. 2006;65(12):1551-1557. 8. Ritchlin CT, Haas-Smith DH, Cappuccio J, Osterland CK, Looney RK. J Rheumatol. 1998;25(8):1544-1552. 9. Barnas JL, Ritlin CT. Rheum Dis Clin North Am. 2015;41(4):643-663.

INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

Otezla® (apremitast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

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

Otezla is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s Disease.

IMPORTANT SAFETY INFORMATION

Contraindications

  • Otezla® (apremilast) is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients In the formulation

Warnings and Precautions

  • Diarrhea, Nausea, and Vomiting: Cases of severe diarrhea, nausea, and vomiting were 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; advise patients to contact their healthcare provider. Consider Otezla dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting
  • Depression: Carefully weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, or in patients who develop such symptoms while on Otezla. Patients, 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 they should contact their healthcare provider if such changes occur
    • Psoriasis: Treatment with Otezla is associated with an increase in depression. During clinical trials, 1.3% (12/920) of patients reported depression compared to 0.4% (2/506) on placebo. Depression was reported as serious in 0.1% (1/1 308) of patients exposed to Otezla, compared to none in placebo-treated patients (0/506). Suicidal behavior was observed in 0.1%(1/1 308) of patients on Otezla, compared to 0.2% (1/506) on placebo. One patient treated with Otezia attempted suicide; one patient on placebo committed suicide
    • Psoriatic Arthritis: Treatment with Otezla is associated with an increase in depression. During clinical trials, 1.0% (10/998) reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. Suicidal ideation and behavior was observed in 0.2% (3/1 441) of patients on Otezla, compared to none in placebo-treated patients. Depression was reported as serious in 0.2% (3/1 441) of patients exposed to Otezla, compared to none in placebo-treated patients (0/495). Two patients who received placebo committed suicide compared to none on Otezla
    • Behcet’s Disease: Treatment with Otezla is associated with an increase in depression. During the clinical trial, 1% (1/104) reported depression or depressed mood compared to 1%(1/103) treated with placebo. No instances of suicidal ideation or behavior were reported in patients treated with Otezla or treated with placebo
  • Weight Decrease: Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla
    • Psoriasis: Body weight loss of 5-10% occurred in 12% (96/784) of patients treated with Otezla and in 5% (1 9/382) of patients treated with placebo. Body weight loss of 10% occurred in 2% (16/784) of patients treated with Otezla compared to 1% (3/382) of patients treated with placebo
    • Psoriatic Arthritis: Body weight loss of 5-10% was reported in 10% (49/497) of patients taking Otezla and in 3.3% (16/495) of patients taking placebo
    • Behçet’s Disease: Body weight loss of >5% was reported in 4.9% (5/103) of patients taking Otezla and ¡n 3.9% (4/102) of patients taking placebo
  • Drug Interactions: Apremilast exposure was decreased when Otezla was co-administered with rilampin, a strong CYP4SO enzyme inducer; loss of Otezla efficacy may occur. Concomitant use of Otezla with CYP45O enzyme inducers (e.g., rifampin. phenobarbital, carbamazepine, phenytoin) is not recommended

Adverse Reactions

  • Psoriasis: Adverse reactions reported in ≥5% of patients were (Otezla%, ptacebo%): diarrhea (17, 6), nausea (17, 7), upper respiratory tract infection (9, 6), tension headache (8, 4), and headache (6, 4)
  • Psoriatic Arthritis: Adverse reactions reported in at (east 2% of patients taking OtezLa, that occurred at a frequency at least 1% higher than that observed in patients taking placebo, for up to 16 weeks (after the initial 5-day titration), were (Otezla%, placebo%): diarrhea (7.7, 1.6); nausea (8.9, 3.1); headache (5.9, 2.2); upper respiratory tract infection (3.9, 1.8); vomiting (3.2, 0.4); nasopharyngitis (2.6, 1.6); upper abdominal pain (2M, 0.2)
  • Behçet’s Disease: Adverse reactions reported in 5% of patients taking Otezta, that occurred at a frequency at least 1% higher than that observed in patients taking placebo, for up to 12 weeks, were (Otezla%, placebo%): diarrhea (41.3, 20.4); nausea (19.2, 10.7); headache (14.4, 10.7); upper respiratory tract infection (11.5, 4.9); upper abdominal pain (8.7, 1.9); vomiting (8.7, 1.9); back pain (7.7, 5.8); viral upper respiratory tract infection (6.7, 4.9); arthralgia (5.8, 2.9)

Use in Specific Populations

  • Pregnancy: Otezla has not been studied in pregnant women. Advise pregnant women of the potential risk of fetal loss. Consider pregnancy planning and prevention for females of reproductive potential 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://mothertoaby.org/ongoing-study/otezla/
  • Lactation: There are no data on the presence of apremilast or its metabolites in human milk, the effects of apremilast on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastleeding should be considered along with the mother’s clinical need for Otezla and any potential adverse effects on the breastled child from Otezla or from the underlying maternal condition
  • Renal Impairment: Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 ml/mm); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information

Please click here for Full Prescribing Information.

INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

Otezla® (apremitast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

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

Otezla is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s Disease.

IMPORTANT SAFETY INFORMATION

Contraindications

  • Otezla® (apremilast) is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients In the formulation

Warnings and Precautions

  • Diarrhea, Nausea, and Vomiting: Cases of severe diarrhea, nausea, and vomiting were 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; advise patients to contact their healthcare provider. Consider Otezla dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting
  • Depression: Carefully weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, or in patients who develop such symptoms while on Otezla. Patients, 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 they should contact their healthcare provider if such changes occur
    • Psoriasis: Treatment with Otezla is associated with an increase in depression. During clinical trials, 1.3% (12/920) of patients reported depression compared to 0.4% (2/506) on placebo. Depression was reported as serious in 0.1% (1/1 308) of patients exposed to Otezla, compared to none in placebo-treated patients (0/506). Suicidal behavior was observed in 0.1%(1/1 308) of patients on Otezla, compared to 0.2% (1/506) on placebo. One patient treated with Otezia attempted suicide; one patient on placebo committed suicide
    • Psoriatic Arthritis: Treatment with Otezla is associated with an increase in depression. During clinical trials, 1.0% (10/998) reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. Suicidal ideation and behavior was observed in 0.2% (3/1 441) oF patients on Otezla, compared to none in placebo-treated patients. Depression was reported as serious in 0.2% (3/1 441) of patients exposed to Otezla, compared to none in placebo-treated patients (0/495). Two patients who received placebo committed suicide compared to none on Otezla
    • Behcet’s Disease: Treatment with Otezla is associated with an increase in depression. During the clinical trial, 1% (1/104) reported depression or depressed mood compared to 1%(1/103) treated with placebo. No instances of suicidal ideation or behavior were reported in patients treated with Otezla or treated with placebo
  • Weight Decrease: Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla
    • Psoriasis: Body weight loss of 5-10% occurred in 12% (96/784) of patients treated with Otezla and in 5% (1 9/382) of patients treated with placebo. Body weight loss of 10% occurred in 2% (16/784) of patients treated with Otezla compared to 1% (3/382) of patients treated with placebo
    • Psoriatic Arthritis: Body weight loss of 5-10% was reported in 10% (49/497) of patients taking Otezla and in 3.3% (16/495) of patients taking placebo
    • Behçet’s Disease: Body weight loss of >5% was reported in 4.9% (5/103) of patients taking Otezla and ¡n 3.9% (4/102) of patients taking placebo
  • Drug Interactions: Apremilast exposure was decreased when Otezla was co-administered with rilampin, a strong CYP4SO enzyme inducer; loss of Otezla efficacy may occur. Concomitant use of Otezla with CYP45O enzyme inducers (e.g., rifampin. phenobarbital, carbamazepine, phenytoin) is not recommended

Adverse Reactions

  • Psoriasis: Adverse reactions reported in ≥5% of patients were (Otezla%, ptacebo%): diarrhea (17, 6), nausea (17, 7), upper respiratory tract infection (9, 6), tension headache (8, 4), and headache (6, 4)
  • Psoriatic Arthritis: Adverse reactions reported in at (east 2% of patients taking Otezla, that occurred at a frequency at least 1% higher than that observed in patients taking placebo, for up to 16 weeks (after the initial 5-day titration), were (Otezla%, placebo%): diarrhea (7.7, 1.6); nausea (8.9, 3.1); headache (5.9, 2.2); upper respiratory tract infection (3.9, 1.8); vomiting (3.2, 0.4); nasopharyngitis (2.6, 1.6); upper abdominal pain (2M, 0.2)
  • Behçet’s Disease: Adverse reactions reported in 5% of patients taking Otezta, that occurred at a frequency at least 1% higher than that observed in patients taking placebo, for up to 12 weeks, were (Otezla%, placebo%): diarrhea (41.3, 20.4); nausea (19.2, 10.7); headache (14.4, 10.7); upper respiratory tract infection (11.5, 4.9); upper abdominal pain (8.7, 1.9); vomiting (8.7, 1.9); back pain (7.7, 5.8); viral upper respiratory tract infection (6.7, 4.9); arthralgia (5.8, 2.9)

Use in Specific Populations

  • Pregnancy: Otezla has not been studied in pregnant women. Advise pregnant women of the potential risk of letal loss. Consider pregnancy planning and prevention for females of reproductive potential 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/
  • Lactation: There are no data on the presence of apremilast or its metabolites in human milk, the effects of apremilast on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastleeding should be considered along with the mother’s clinical need for Otezla and any potential adverse effects on the breastled child from Otezla or from the underlying maternal condition
  • Renal Impairment: Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 ml/mm); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information

Please click here for Full Prescribing Information.