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Otezla

Generic Name: Apremilast
Class: Disease-modifying Antirheumatic Drugs
VA Class: 00
Chemical Name: N - [2 - [(1S) - 1 - (3 - Ethoxy - 4 - methoxyphenyl) - 2 - (methylsulfonyl)ethyl] - 2,3 - dihydro - 1,3 - dioxo - 1H - isoindol - 4 - yl] - acetamide
Molecular Formula: C22H24N2O7S
CAS Number: 608141-41-9

Introduction

Disease-modifying antirheumatic drug (DMARD); a selective phosphodiesterase type 4 (PDE4) inhibitor.1 2 3 4 5 6 7 13 19

Uses for Otezla

Psoriatic Arthritis

Management of active psoriatic arthritis in adults.1 2 3 5

Plaque Psoriasis

Management of moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy.1 20

Otezla Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1

Swallow tablets intact.1 Do notcrush, split, or chew.1

Dosage

Adults

Psoriatic Arthritis
Oral

Maintenance dosage: 30 mg twice daily.1

Initiate at low dosage and titrate as follows (over 5 days in increments of 10 mg daily) to reduce the risk of GI symptoms: 10 mg in the morning on day 1, 10 mg in the morning and 10 mg in the evening on day 2, 10 mg in the morning and 20 mg in the evening on day 3, 20 mg in the morning and 20 mg in the evening on day 4, 20 mg in the morning and 30 mg in the evening on day 5, and 30 mg twice daily thereafter.1

Plaque Psoriasis
Oral

Maintenance dosage: 30 mg twice daily.1

Initiate at low dosage and titrate as follows (over 5 days in increments of 10 mg daily) to reduce the risk of GI symptoms: 10 mg in the morning on day 1, 10 mg in the morning and 10 mg in the evening on day 2, 10 mg in the morning and 20 mg in the evening on day 3, 20 mg in the morning and 20 mg in the evening on day 4, 20 mg in the morning and 30 mg in the evening on day 5, and 30 mg twice daily thereafter.1

Special Populations

Hepatic Impairment

No dosage adjustment required.1

Renal Impairment

Severe renal impairment (Clcr <30 mL/minute): Maintenance dosage of 30 mg once daily.1 Initiate at low dosage and titrate as follows to reduce the risk of GI symptoms: 10 mg in the morning for 3 days (days 1, 2, and 3), followed by 20 mg in the morning for 2 days (days 4 and 5), then 30 mg once daily thereafter.1 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1

Cautions for Otezla

Contraindications

  • Known hypersensitivity to apremilast or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Depression and Suicidality

Depression, depressed mood, and suicidal ideation/behaviors reported.1

Carefully weigh the risks and benefits prior to using apremilast in patients with a history of depression and/or suicidal thoughts or behavior.1 Carefully evaluate the risks and benefits of continuing apremilast therapy if such effects occur.1 (See Advice to Patients.)

Weight Loss

Weight loss of 5–10% or more of body weight reported.1

Regularly monitor patient’s weight.1 If unexplained or clinically important weight loss occurs, evaluate weight loss and consider discontinuing apremilast.1

Interactions

Concomitant use of potent CYP inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) is not recommended.1 (See Interactions.)

Specific Populations

Pregnancy

Category C.1

Pregnancy registry at 877-311-8972.1 Increases in spontaneous abortion and embryofetal death reported in animal reproduction studies.1

Lactation

Distributed into milk in mice; not known whether distributed into human milk.1 Use with caution in nursing women.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No overall differences in safety observed between geriatric and younger adults with psoriatic arthritis.1

No overall differences in efficacy and safety observed between geriatric and younger adults with psoriasis.1

Renal Impairment

Systemic exposure increased in patients with severe renal impairment (Clcr <30 mL/minute).1 (See Special Populations under Pharmacokinetics.) Reduced dosage recommended.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Patients with psoriatic arthritis: Diarrhea,1 2 nausea,1 2 headache,1 2 upper respiratory tract infection,1 vomiting,1 nasopharyngitis,1 upper abdominal pain.1

Patients with psoriasis: Diarrhea,1 20 nausea,1 20 upper respiratory tract infection,1 20 tension headache,1 20 headache,1 20 abdominal pain,1 vomiting,1 20 fatigue,1 dyspepsia,1 20 decreased appetite,1 insomnia,1 back pain,1 migraine,1 frequent bowel movements.1

Interactions for Otezla

Undergoes oxidative metabolism (mediated mainly by CYP3A4, with minor contributions from CYP1A2 and CYP2A6) with subsequent glucuronidation; also undergoes non-CYP-mediated hydrolysis.1 21

Does not inhibit CYP isoenzyme 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro; does not induce CYP isoenzyme 1A2, 2B6, 2C9, 2C19, or 3A4 in vitro.1

A substrate but not an inhibitor of P-glycoprotein (P-gp) in vitro; neither a substrate nor inhibitor of organic anion transporters (OAT) 1 and 3, organic anion transporting polypeptides (OATP) 1B1 and 1B3, organic cation transporter (OCT) 2, or breast cancer resistance protein (BCRP) in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP inducers: Reduced systemic exposure and possible loss of efficacy of apremilast; concomitant use not recommended.1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Systemic exposure and efficacy of apremilast may be reduced1

Concomitant use not recommended1

Estrogens/progestins

Contraceptive containing ethinyl estradiol and norgestimate: No substantial pharmacokinetic interaction1 21

Ketoconazole

No clinically important effects on apremilast exposure1 21

Methotrexate

No substantial effects on pharmacokinetics of either drug1 21

Rifampin

Reduced apremilast AUC and peak plasma concentration; possible loss of apremilast efficacy1 21

Concomitant use not recommended1

Otezla Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of about 73%.1 Peak plasma concentrations achieved about 2.5 hours after oral administration.1

Food

Food does not alter extent of absorption.1

Special Populations

Moderate or severe hepatic impairment does not alter apremilast pharmacokinetics.1

In patients with severe renal impairment, AUC and peak plasma concentrations increased by approximately 88 and 42%, respectively.1 Effect of mild to moderate renal impairment on apremilast exposure not elucidated.1

In healthy geriatric individuals (65–85 years of age), AUC and peak plasma concentrations increased by about 13 and 6%, respectively, compared with younger adults (18–55 years of age).1

In healthy women, extent of exposure and peak plasma concentrations increased by about 31 and 8%, respectively, compared with men.1 21

Apremilast exposure is similar among Hispanic Caucasians, non-Hispanic Caucasians, and African Americans; pharmacokinetics in healthy Chinese and Japanese men similar to that in healthy Caucasian men.1 21

Distribution

Plasma Protein Binding

Approximately 68%.1

Elimination

Metabolism

Undergoes oxidative metabolism (mediated mainly by CYP3A4, with minor contributions from CYP1A2 and CYP2A6) with subsequent glucuronidation; also undergoes non-CYP-mediated hydrolysis.1 21

Elimination Route

Following oral administration of radiolabeled apremilast, radioactivity recovered in urine (58%) and feces (39%), with about 3 or 7% of dose recovered as unchanged drug in urine or feces, respectively.1

Half-life

Approximately 6–9 hours.1

Stability

Storage

Oral

Tablets

Store at <30°C.1

Actions

  • Selectively inhibits PDE4, the dominant phosphodiesterase expressed in immune cells and a major enzyme involved in metabolism of cyclic adenosine-3',5'-monophosphate (cAMP).1 2 3 4 5 6 7 13

  • Selective inhibition of PDE4 results in accumulation of intracellular cAMP, a modulator of inflammatory responses, which can down-regulate inflammatory responses by increasing expression of anti-inflammatory mediators and partially inhibiting expression of inflammatory cytokines that are thought to play a role in the pathogenesis of psoriasis and active psoriatic arthritis.2 4 5 6

Advice to Patients

  • Importance of taking apremilast only as prescribed.1

  • Advise patients to not crush, split, or chew apremilast tablets.1

  • Inform patients that apremilast may be taken without regard to meals.1

  • Risk of emergence or worsening of depression.1 Instruct patients and their caregivers or families to be alert for the emergence or worsening of depression, suicidal thoughts, or other mood changes and to contact a clinician if such changes occur.1

  • Risk of weight loss.1 Importance of regular monitoring for weight loss; advise patients to inform clinician if substantial or unexplained weight loss occurs.1

  • Risk of interactions with potent CYP inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin).1 Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Apremilast

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

4 Tablets, film-coated, Apremilast 10 mg (Otezla)

4 Tablets, film-coated, Apremilast 20 mg (Otezla)

19 Tablets, film-coated, Apremilast 30 mg (Otezla)

Otezla Starter Pack (available as blister pack containing tablets for first 2 weeks of therapy)

Celgene

Tablets, film-coated

30 mg

Otezla

Celgene

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Celgene Corporation. Otezla(apremilast) tablets prescribing information. Summit, NJ; 2014 Sep.

2. Kavanaugh A, Mease PJ, Gomez-Reino JJ et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014; 73:1020-6. [PubMed 24595547]

3. Strand V, Schett G, Hu C et al. Patient-reported Health-related Quality of Life with apremilast for psoriatic arthritis: a phase II, randomized, controlled study. J Rheumatol. 2013; 40:1158-65. [PubMed 23588944]

4. Schafer PH, Day RM. Novel systemic drugs for psoriasis: mechanism of action for apremilast, a specific inhibitor of PDE4. J Am Acad Dermatol. 2013; 68:1041-2. [PubMed 23680197]

5. Schett G, Wollenhaupt J, Papp K et al. Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2012; 64:3156-67. [PubMed 22806399]

6. Mease PJ, Armstrong AW. Managing patients with psoriatic disease: the diagnosis and pharmacologic treatment of psoriatic arthritis in patients with psoriasis. Drugs. 2014; 74:423-41. [PubMed 24566842]

7. Palfreeman AC, McNamee KE, McCann FE. New developments in the management of psoriasis and psoriatic arthritis: a focus on apremilast. Drug Des Devel Ther. 2013; 7:201-10. [PubMed 23569359]

8. Palace-2: Efficacy and safety study of apremilast to treat active psoriatic arthritis (PALACE 2). From ClinicalTrials.gov Registry. Accessed 2014 Oct 2.

9. Celgene Corporation, Summit, NJ: Personal communication.

10. Palace-3: Efficacy and safety study of apremilast to treat active psoriatic arthritis. From ClinicalTrials.gov Registry. Accessed 2014 Oct 2.

12. Efficacy and safety study of apremilast to treat active psoriatic arthritis (PALACE-1). From Clinicaltrials.gov Registry. Accessed 2014 Oct 16.

13. Wittmann M, Helliwell PS. Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases. Dermatol Ther (Heidelb). 2013; 3:1-15. [PubMed 23888251]

14. Boehncke WH, Qureshi A, Merola JF et al. Diagnosing and treating psoriatic arthritis: an update. Br J Dermatol. 2014; 170:772-86. [PubMed 24266754]

15. Mease PJ. Psoriatic arthritis: update on pathophysiology, assessment and management. Ann Rheum Dis. 2011; 70 Suppl 1:i77-84. [PubMed 21339225]

19. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number205437Orig1s000: Summary review. From FDA website.

20. Papp K, Cather JC, Rosoph L et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet. 2012; 380:738-46. [PubMed 22748702]

21. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number205437Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

22. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number205437Orig1s000: Medical review(s). From FDA website.

23. Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 2005; 64 Suppl 2:ii65-8; discussion ii69-73. [PubMed 15708941]

24. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35. [PubMed 7779114]

25. Felson DT, Anderson JJ, Boers M et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum. 1993; 36:729-40. [PubMed 8507213]

26. Felson DT, Anderson JJ, Lange MLM et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent. Arthritis Rheum. 1998; 41:1564-70. [IDIS 411264] [PubMed 9751088]

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