| Active Ingredient | TOFACITINIB CITRATE (IR, Tablet) |
|---|
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| XELJANZ | (NDA) 203214 | PF PRISM CV | TABLET;ORAL | EQ 5MG BASE | EQ 5MG BASE (RS) | November 6, 2012 | November 6, 2017 | - | 1 New molecular entity (NME) | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
/Structural_Formula.jpg) |
| Chemical Name | (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino)-ß-oxo-1-piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) |
| CAS No | 477600-75-2 |
| Molecular Formula | C16H20N6O•C6H8O7 |
| Molecular Weight | 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) |
| Appearance | a white to off-white powder |
| Solubility | The solubilityof tofacitinib citrate in water is 2.9 mg/mL and solubility is >28 mg/mL at pH 1.0, and decreases with the increase in pH (0.20 mg/mL at pH >8). |
| Water Solubility | 0.299 mg/mL |
| Polymorphism | An extensive screening study to identify different potential polymorphic forms has demonstrated that only polymorph A can be consistently obtained in different circumstances studied. Therefore polymorphism has not been considered a critical quality attribute. |
| pKa (Strongest Acidic) | 8.46 (Predicted) |
| pKa (Strongest Basic) | 7.13 (Predicted) |
| Log P | 1.808 |
| Identification | FTIR |
| Degradation | Tofacitinb citrate is found to be sensitive to oxidative, acidic and alkaline conditions. |
| Hygroscopic | non hygroscopic |
| Photostability study | Photo stable |
| Melting Point | - |
| BCS Class | III |
| Manufacture of API | The synthesis of tofacitinib citrate consists of four chemical transformations in three steps. A design space was applied for the manufacturing process of the active substance. The drug substance CQAs and the control strategy have been adequately described. The design space was established with lab scale batches. The conclusions of these design of experiments (DoEs) generally support the ranges of critical process parameters (CPPs) and non (CPPs) described. The manufacturing process is well described and adequate in-process controls are applied during the synthesis. |
| Parameters | Details |
|---|---|
| Indications and Usage | Rheumatoid Arthritis: XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It maybe used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). Limitations of Use: Use of XELJANZ in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. |
| Dosage and Administration | Dosage in Rheumatoid Arthritis:XELJANZ maybe used as monotherapyor in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). The recommended dose of XELJANZ is 5 mg twice daily. XELJANZ is given orallywith or without food. |
| Mechanism of action | Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activityincluding gene expression. Tofacitinib modulates the signaling pathwayat the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known. |
| Absorption |
Following oral administration of XELJANZ, peak plasma concentrations are reached within 0.5-1 hour, elimination half-life is 3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration. The absolute oral bioavailabilityof tofacitinib is 74%. |
| Food Effect | Coadministration of XELJANZ with a high-fat meal resulted in no changes in AUC while Cmax was reduced by32%. In clinical trials, XELJANZ was administered without regard to meals. |
| Distribution | After intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is ~40%. Tofacitinib binds predominantlyto albumin and does not appear to bind to 1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. |
| Metabolism | Clearance mechanisms for tofacitinib are approximately70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. |
| Elimination | In a human radiolabeled study, more than 65% of the total circulating radioactivitywas accounted for byunchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activityof tofacitinib is attributed to the parent molecule. |
| Peak plasma time (Tmax) | 0.5-1 hour |
| Half life | 3 hours |
| Bioavailability | 74% |
| Age, gender | No dose adjustent is required based on age and gender. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 27721 | A | II | November 30, 2013 | MSN LABORATORIES PRIVATE LTD |
| 29002 | A | II | March 11, 2015 | GLENMARK PHARMACEUTICALS LTD |
| 30531 | A | II | June 4, 2016 | CADILA HEALTHCARE LTD |
| 30554 | A | II | May 19, 2016 | SINTENOVO SA DE CV |
| 30578 | A | II | June 13, 2016 | QILU TIANHE PHARMACEUTICAL CO LTD |
| 30617 | A | II | August 2, 2016 | SUN PHARMACEUTICAL INDUSTRIES LTD |
| 30621 | A | II | August 3, 2016 | MICRO LABS LTD |
| 30654 | A | II | July 5, 2016 | UNICHEM LABORATORIES LTD |
| 30686 | A | II | June 22, 2016 | OLON SPA |
| Parameters | Details |
|---|---|
| Strength | 5MG tofacitinib equivalent to 8MG tofacitinib citrate |
| Excipients used | microcrystalline cellulose (122.615MG), lactose monohydrate (61.307MG), croscarmellose sodium (6MG), magnesium stearate (2MG) |
| Composition of coating material | Opadry II white (6MG): HPMC 2910/Hypromellose 6cP, titanium dioxide, macrogol/PEG3350, and triacetin |
| Composition of caspule shell | - |
| Pharmaceutical Development |
After a comprehensive screening of various potential counter ions of tofacitinib, the crystalline citrate salt of tofacitinib was selected for the commercial product of immediate release film coated tablet. It is highly soluble across physiologically relevant pH and has suitable pharmaceutical properties for development. Tofacitinib citrate is classified a BCS class 3 compound (high solubility and low permeability) and the particle size is not expected to have significant effect on dissolution. However, drug substance particle size could influence uniformity of dosage units, because of the low drug load in the tablet formulation. To assess the impact of drug substance particle size on uniformity of dosage units, a QbD approach, that includes mathematical modelling, development scale multivariate experiments, and pilot/production scale manufacturing experience, was followed. The main factors identified as CQAs for drug product were the uniformity of dosage units, the tablet water content and the level of degradants. Excipients used are microcrystalline cellulose (diluent), lactose monohydrate (diluent), croscarmellose sodium (disintegrant), and magnesium stearate (lubricant). These excipients are typically used for dry granulation. The selection of the commercial film-coating system was based on compatibility of the various coating materials with the drug substance. A hydroxypropyl methylcellulose (HPMC) based coating system with luminium lake pigments was selected. The 5mg and 10mg commercial tablets use a common blend and share the same manufacturing process, the equivalence between the 5mg and 10mg registration tablets was demonstrated by the in vitro dissolution test. |
| Manufacture of the product | The Xeljanz tablets are manufactured by a conventional dry granulation process that includes the steps: blending, milling, intragranular lubrication, dry granulation, extragranular lubrication, compression, film coating. |
| Tablet / Capsule Image |
/5MG tofacitinib equivalent to 8MG tofacitinib citrate.jpg)
|
| Appearance | White, round, immediate-release film-coated tablets, debossed with “Pfizer” on one side, and “JKI5” on the other side. |
| Imprint code / Engraving / Debossment | debossed with “Pfizer” on one side, and “JKI5” on the other side. |
| Score | no score |
| Color | WHITE |
| Shape | ROUND |
| Dimension | 8mm |
| Mfg by | Pfizer labs (EU) |
| Mfg for | - |
| Marketed by | Pfizer labs (EU) |
| Distributed by | Pfizer labs (US) |
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N203214 | 1 | 6965027 | March 25, 2023 | Y | - | - | - | Download |
| N203214 | 1 | 7091208 | December 8, 2020 | - | - | U - 247 | - | Download |
| N203214 | 1 | 7301023 | May 23, 2022 | Y | - | - | - | Download |
| N203214 | 1 | RE41783 | December 8, 2025 | Y | - | - | - | Download |
| N203214 | 1 | 7265221 | December 8, 2020 | Y | - | - | - | Download |
| N203214 | 1 | 6956041 | December 8, 2020 | - | Y | - | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| I (Basket) | 100 | 0.1N HCl | 900 | 5, 10, 15, 20 and 30 | June 25, 2015 |
| 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 | XELJANZ | Download |
| UK | XELJANZ | Download |
| US | XELJANZ | Download |
| Exclusivity Code: Exclusivity Expiration is M - 135: Feb 21, 2017. The Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation in EU for the medicinal product Xeljanz, intended for the treatment of rheumatoid arthritis. |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
