| Active Ingredient | APREMILAST |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OTEZLA | (NDA) 205437 | CELGENE CORP | TABLET;ORAL | 10MG, 20MG, 30MG | 30MG | March 21, 2014 | March 21, 2019 | - | 1 New molecular entity (NME) | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide |
| CAS No | 1258597-46-4 |
| Molecular Formula | C22H24N2O7S |
| Molecular Weight | 460.5 |
| Appearance | a white to pale-yellow powder |
| Solubility | It is practically insoluble in aqueous buffers irrespective of pH range, soluble in acetone, acetonitrile, methylethylketone, methylene chloride and tetrahydrofuran. |
| Water Solubility | 0.0503 mg/mL (Predicted) |
| Polymorphism | Polymorphism has been observed for apremilast and seven polymorphic forms (designated A-G) of the active substance were identified. The desired form B was found to be the most thermodynamically stable anhydrous form of apremilast. The manufacturing process consistently yields active substance of single crystal form B. |
| pKa (Strongest Acidic) | 4.83 (Predicted) |
| pKa (Strongest Basic) | (Predicted) -0.25 |
| Log P | 1.79 (Predicted) |
| Identification | FT-IR, HPLC |
| Degradation | - |
| Hygroscopic | non hygroscopic |
| Photostability study | - |
| Melting Point | 156.1°C |
| BCS Class | IV |
| Manufacture of API | Apremilast active substance is obtained from two manufacturers. The synthesis of apremilast is well described. Two manufacturing processes have been proposed for the synthesis of the active substance. Both processes use the same synthetic route, but differ primarily in the solvents that are used in the isolation of crude active substance. Apremilast is synthesized in either 4 main steps or 3 main steps, using commercially available, well defined starting materials with acceptable specifications. The proposed manufacturing processes differ in the initial stages of synthesis with different isolated intermediates in which chiral purity is controlled. The manufacture of apremilast active substance includes the following steps common to both processes: i) coupling (chemical transformation) of the starting materials and intermediates to yield apremilast crude and ii) recrystallisation and drying of apremilast crude to yield the desired polymorph, Form B. The synthetic route used in the manufacturing process of the active substance is designed to manufacture (S)-enantiomer (i.e. pharmacologically active moiety), with enantiomeric purity routinely controlled by chiral HPLC. It was demonstrated that there is no inter-conversion between the two enantiomers during the manufacturing process and that the final level of the (R)-enantiomer in the active substance reflects that present in the intermediates. |
| Parameters | Details |
|---|---|
| Indications and Usage | OTEZLA is indicated for the treatment of adult patients with active psoriatic arthritis. OTEZLA is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. |
| Dosage and Administration |
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. |
| Mechanism of action | Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action in psoriatic arthritis patients and psoriasis patients is not well defined. |
| Absorption | Apremilast when taken orally is absorbed with an absolute bioavailability of 73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of 2.5 hours. |
| Food Effect | Co-administration with food does not alter the extent of absorption of apremilast. |
| Distribution | Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L. |
| Metabolism | Following oral administration in humans, apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. |
| Elimination | The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively. |
| Peak plasma time (Tmax) | 2.5 hours |
| Half life | 6-9 hours |
| Bioavailability | 73% |
| Age, gender |
A single oral dose of 30-mg apremilast was studied in young adults and elderly healthy subjects. The apremilast exposure in elderly subjects (65 to 85 years of age) was about 13% higher in AUC and about 6% higher in Cmax than in young subjects (18 to 55 years of age). In pharmacokinetic studies in healthy volunteers, the extent of exposure in females was about 31% higher and Cmax was about 8% higher than that in male subjects. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 30248 | A | II | April 6, 2016 | LUPIN LTD |
| 30332 | A | II | March 29, 2016 | MSN LIFE SCIENCES PRIVATE LTD [ROUTE CODE LI] |
| 30732 | A | II | September 30, 2016 | DR REDDYS LABORATORIES LTD (FORM B) |
| 30866 | A | II | August 31, 2016 | MSN LIFE SCIENCES PRIVATE LTD (Form M) |
| 31141 | A | II | November 9, 2016 | ZAKLADY FARMACEUTYCZNE POLPHARMA SA |
| 31159 | A | II | December 23, 2016 | MSN LIFE SCIENCES PRIVATE LTD (Amorphous) |
| 31180 | A | II | December 29, 2016 | RAKS PHARMA PVT LTD |
| 31266 | A | II | March 22, 2017 | LUPIN LTD (Form M) |
| 31360 | A | II | February 28, 2017 | MSN LIFE SCIENCES PRIVATE LTD |
| 31490 | A | II | March 31, 2017 | GLENMARK PHARMACEUTICALS LTD |
| Parameters | Details | |||
|---|---|---|---|---|
| Strength | 10MG | 20MG | 30MG | |
| Excipients used | lactose monohydrate (60 mg), microcrystalline cellulose (26.25 mg), croscarmellose sodium (3 mg), magnesium stearate (0.75 mg) | lactose monohydrate (120 mg), microcrystalline cellulose (52.5 mg), croscarmellose sodium (6 mg), magnesium stearate (1.5 mg) | lactose monohydrate (180 mg), microcrystalline cellulose (78.75 mg), croscarmellose sodium (9 mg), magnesium stearate (2.25 mg) | |
| Composition of coating material | Opadry II pink (polyvinyl alcohol - 40% titanium dioxide - 24.6%, macrogol - 20.2% talc - 14.8% iron oxide red dye (E172) - 0 , 4%) - 4 mg | Opadry II brown (polyvinyl alcohol - 40% titanium dioxide - 12.13%, macrogol - 20.2% talc - 14.8% iron oxide red dye (E172) - 1 22% iron oxide yellow dye (E172) - 11.65) - 8 mg | Opadry II beige (polyvinyl alcohol - 40% titanium dioxide - 22.99% Macrogol - 20.2% talc - 14.8% iron oxide red dye (E172) - 1 18% colorant ferric oxide yellow (E 172) - 0.43%, the dye black iron oxide (E172) - 0.4) - 12 mg | |
| Composition of caspule shell | - | |||
| Pharmaceutical Development |
The aim of the pharmaceutical development was to develop an immediate release solid dosage form for oral use providing high bioavailability of the active substance that is practically insoluble in water (7 μg/mL at room temperature). In order to allow for flexibility in posology requirements, film-coated tablets containing 10 mg, 20 mg or 30 mg of apremilast as active substance were developed. Physico chemical properties of active substance that could affect critical quality attributes (assay, content uniformity, and dissolution), were assessed. During formulation development, different formulations were developed. During formulation development, different formulations were developed. The proposed commercial formulation contains qualitatively the same core formulation composition as the formulation used in phase III clinical studies. These formulations were manufactured by the essentially the same manufacturing process. Changes in formulation have been supported by dissolution studies and f2 comparisons showing adequate product development. In particular dissolution comparison was carried out at three pH values, between formulation tablets used in clinical studies and commercial formulation tablets. Certain bioequivalence and bioavailability data in support of formulations during development has been provided. |
|||
| Manufacture of the product | The manufacturing process consists of three main steps: i) blending and lubrication process, ii) compression process and iii) coating process. The process is considered to be a standard manufacturing process. | |||
| Tablet / Capsule Image |
|
|||
| Appearance | Pink, diamond shaped film-coated tablet with “APR” engraved on one side and “10” on the opposite side | Brown, diamond shaped film-coated tablet with “APR” engraved on one side and “20” on the opposite side | Beige, diamond shaped film-coated tablet with “APR” engraved on one side and “30” on the opposite side | |
| Imprint code / Engraving / Debossment | “APR” engraved on one side and “10” on the opposite side | “APR” engraved on one side and “20” on the opposite side | “APR” engraved on one side and “30” on the opposite side | |
| Score | no score | no score | no score | |
| Color | Pink | Brown | Beige | |
| Shape | Diamond | Diamond | Diamond | |
| Dimension | 8mm | 10mm | 12mm | |
| Mfg by | - | |||
| Mfg for | - | |||
| Marketed by | Celgene Corporation (US, EU) | |||
| Distributed by | - | |||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N205437 | 1 | 6020358 | October 30, 2018 | Y | Y | U - 1504 | - | Download |
| N205437 | 1 | 6962940 | March 19, 2023 | - | - | U - 1504 | - | Download |
| N205437 | 1 | 7208516 | March 19, 2023 | - | - | U - 1505 | - | Download |
| N205437 | 1 | 7427638 | November 17, 2024 | Y | Y | - | - | Download |
| N205437 | 1 | 7659302 | March 19, 2023 | - | - | U - 1505 | - | Download |
| N205437 | 1 | 7659302 | March 19, 2023 | - | - | U - 1505 | - | Download |
| N205437 | 1 | 7893101 | December 9, 2023 | Y | Y | - | - | Download |
| N205437 | 1 | 8455536 | March 19, 2023 | - | - | U - 1595 | - | Download |
| N205437 | 1 | 8455536 | March 19, 2023 | - | - | U - 1595 | - | Download |
| N205437 | 1 | 8802717 | March 19, 2023 | - | - | U - 1561 | - | Download |
| N205437 | 1 | 9018243 | March 19, 2023 | - | - | U - 1505 | - | Download |
| N205437 | 1 | 9018243 | March 19, 2023 | - | - | U - 1505 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 60 | 0.15% SLS in 25 mM Sodium Phosphate Buffer, pH 6.8 | 900 | 10, 15, 20, 30, and 45 | May 18, 2017 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | Download |
| European Public Assessment Report | Download |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | OTEZLA | Download |
| UK | OTEZLA | Download |
| US | OTEZLA | Download |
| - |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov, www.drug.com |
