Apremilast

L04A - Immunosuppressants ATC L04AA32 Small molecule approved 2014 Oral First-in-class Natural product

JFDA label: Apriva

Mechanism of Action

Inhibitor of Phosphodiesterase 4 — Phosphodiesterase 4 inhibitor

Target	Action	Gene / class
Phosphodiesterase 4 efficacy	INHIBITOR

Indications

Approved

Psoriasis
Psoriatic arthritis

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Pregnancy Absolute
Hypersensitivity to apremilast or any component of the formulation Absolute
breast-feeding Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (7)

Not Known depression · fatigue · headache · insomnia · migraine · paresthesia · Tension headache

Gastrointestinal disorders (10)

Not Known abdominal distention, arthralgia, nasopharyngitis, sinusitis, bronchitis ( · abdominal distress · abdominal pain · decreased appetite · Diarrhea · dyspepsia · frequent bowel movements · nausea · upper abdominal pain · vomiting

Dosing

Source: Lexicomp

Active psoriatic arthritis or plaque psoriasis (moderate to severe): Oral: Initial: 10 mg in the morning. Titrate upward by additional 10 mg per day on days 2 to 5 as follows: Day 2: 10 mg twice daily; Day 3: 10 mg in the morning and 20 mg in the evening; Day 4: 20 mg twice daily; Day 5: 20 mg in the morning and 30 mg in the evening. Maintenance dose: 30 mg twice daily starting on day 6

Refer to adult dosing.

No dosage adjustment necessary.

Warnings & Precautions

Source: Lexicomp

GI effects

Severe diarrhea, nausea, and vomiting have been reported, usually observed within the first few weeks of initiating therapy. Monitor patients who are more susceptible to complications of diarrhea or vomiting; use with caution in elderly patients (≥65 years) and patients taking medications that may lead to volume depletion or hypotension. Symptom improvement observed with dose reduction or discontinuation of therapy; consider dose reduction or suspension of therapy if severe symptoms occur.

Neuropsychiatric effects

Neuropsychiatric effects (eg, depression, suicidal ideation, mood changes) have been reported. Use with caution in patients with a history of depression and/or suicidal thoughts /behavior. Instruct patients/caregivers to report worsening psychiatric symptoms and consider risks/benefits of continuation of therapy in such patients.

Weight loss

May cause weight loss; monitor weight regularly. Discontinuation of therapy should be considered with unexplained or significant weight loss. Disease-related concerns:

Renal impairment

Use with caution in renal impairment. Systemic exposure is increased in patients with severe renal impairment (CrCl Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events were observed in some animal reproduction studies. A registry is available for women exposed to apremilast during pregnancy (877-311-8972).

Lactation

It is not known if apremilast is present in breast milk. The manufacturer recommends that caution be exercised when administering apremilast to breastfeeding women.

Monitoring

Clinical pearl	Monitor weight regularly during therapy; renal function; signs or symptoms of mood changes, depression, or suicidal thoughts

Chemistry & Properties

Formula	C22H24N2O7S
Molecular weight	460.51 g/mol
IUPAC name	N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindol-4-yl]acetamide
CAS	608141-41-9
PubChem CID	11561674
InChIKey	`IMOZEMNVLZVGJZ-QGZVFWFLSA-N`
logP	2.43 (XLogP 1.8)
Polar surface area	119.08 Å²
H-bond acceptors / donors	7 / 1
Drug-likeness (QED)	0.60
Lipinski violations	0

SMILES

CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.115 h
Volume of distribution	1.87 L/kg
Protein binding	71.2%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 3)

Target	Action	Affinity
phosphodiesterase 4A (PDE4A)	Inhibitor	pIC50 7.8
phosphodiesterase 4D (PDE4D)	Inhibitor	pIC50 7.5
phosphodiesterase 4C (PDE4C)	Inhibitor	pIC50 6.9

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)OAT1 (Substrate)OAT3 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)OCT2 (Substrate)P-gp (Substrate)

Drug–drug interactions (71, DDInter)

Interacting drug	Severity	Management
Apalutamide	major
Carbamazepine	major
Enzalutamide	major
Fosphenytoin	major
Lumacaftor	major
Mitotane	major
Phenobarbital	major
Phenytoin	major
Primidone	major
Rifampicin	major
St. John's Wort	major
Abametapir (topical)	moderate
Aminoglutethimide	moderate
Amobarbital	moderate
Betrixaban	moderate
Bexarotene	moderate
Binimetinib	moderate
Bosentan	moderate
Brigatinib	moderate
Butabarbital	moderate
Butalbital	moderate
Cenobamate	moderate
Dabrafenib	moderate
Deferasirox	moderate
Dexamethasone	moderate
Echinacea	moderate
Efavirenz	moderate
Elagolix	moderate
Encorafenib	moderate
Erdafitinib	moderate
Eslicarbazepine	moderate
Etravirine	moderate
Felbamate	moderate
Fostamatinib	moderate
Gilteritinib	moderate
Glasdegib	moderate
Griseofulvin	moderate
Isavuconazonium	moderate
Ivosidenib	moderate
Lasmiditan	moderate

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Registered Products (4)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Apinza	Tablet 30 mg	56 tab	/ Pharma International Company/Jordan / General	—
Apinza	Tablet 10, 20 & 30 mg	20 tab	/ Pharma International Company/Jordan / General	—
Apriva	Tablet 30 mg	60 tab	شركة أدوية الحكمة / Hikma Pharmaceuticals / Not Determined	—
Apriva Starter Pack	Tablet 10, 20, 30 mg	21 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	—