| Active Ingredient | CABOZANTINIB S-MALATE (Capsule) |
|---|
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| COMETRIQ | (NDA) 203756 | EXELIXIS | CAPSULE;ORAL | EQ 20MG BASE, EQ 80MG BASE | EQ 80MG BASE (RS) | November 29, 2012 | November 29, 2017 | November 29, 2019 | 1 New molecular entity (NME) | P Priority review drug O Orphan drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
/Structural_Formula.jpg) |
| Chemical Name | N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate |
| CAS No | 849217-68-1 |
| Molecular Formula | C28H24FN3O5.C4H6O5 |
| Molecular Weight | 635.6 Daltons as malatesalt |
| Appearance | a white to off-white crystalline substance |
| Solubility | It is practically insoluble in water above pH 4. Cometriq contains the malate salt of cabozantinib because the freebase is insoluble in water. |
| Water Solubility | - |
| Polymorphism | Polymorphism has been observed for cabozantinib (S)-malate. It is known to exist in two crystalline solid forms (N-1 and N-2) that have similar properties and one amorphous form. The N-2 form was selected for commercial development. |
| pKa (Strongest Acidic) | - |
| pKa (Strongest Basic) | - |
| Log P | - |
| Identification | HPLC, FTIR |
| Degradation | No degradation was observed under acidic and light-stressed conditions. Degradation was observed under heat and oxidative conditions, and significant degradation was observed under the basic hydrolysis. |
| Hygroscopic | not hygroscopic |
| Photostability study | Photostable |
| Melting Point | - |
| BCS Class | II |
| Manufacture of API | It is synthesised in five main steps (with four product isolations), using well defined starting materials. Adequate specifications and control methods have been presented for the starting materials, intermediate products and reagents. Adequate in-process controls applied during the synthesis. |
| Parameters | Details |
|---|---|
| Indications and Usage | COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). |
| Dosage and Administration |
The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruitjuice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. |
| Mechanism of action |
In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. |
| Absorption |
A population pharmacokinetic analysis of cabozantinib was performed using data collected from 289 patients with solid tumors including MTC following oral administration of 140 mg daily doses. The predicted effective half-life is approximately 55 hours, the oralvolume of distribution (V/F) is approximately 349 L, and the clearance (CL/F) at steady-state is estimated to be 4.4 L/hr. Following oral administration of COMETRIQ, median time to peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 5 hours post-dose. |
| Food Effect | A high-fat meal increased Cmaxand AUC values by 41% and 57%, respectively relative to fasted conditions in healthy subjects administered a single 140 mg oral COMETRIQ dose. |
| Distribution | Repeat daily dosing of COMETRIQ at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15. Cabozantinib is highly protein bound inhuman plasma (≥99.7%). |
| Metabolism |
Cabozantinib is a substrate of CYP3A4 in vitro. Inhibition ofCYP3A4 reduced the formation of the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20%reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1had no effect on cabozantinib metabolite formation. |
| Elimination | Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy subjects, approximately 81% of the total administered radioactivity was recovered with 54% in feces and 27% in urine. |
| Peak plasma time (Tmax) | 2 to 5 hours |
| Half life | 55 hours |
| Bioavailability | - |
| Age, gender | A population PK analysis did not identify clinically relevant differences in clearance of cabozantinib between females and males or between Whites (89%) and non-Whites (11%). Cabozantinib pharmacokinetics was not affected by age (20-86 years). |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 31522 | A | II | March 30, 2017 | MSN LABORATORIES PRIVATE LTD |
| Parameters | Details | ||
|---|---|---|---|
| Strength | 20MG | 80MG | |
| Excipients used | silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid | ||
| Composition of coating material | - | ||
| Composition of caspule shell | The grey gelatin capsule shells contain black iron oxide and titanium dioxide and the Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide. The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide. | - | |
| Pharmaceutical Development |
Based on criteria such as crystallinity, solubility and stability, five salts were selected for further evaluation: chloride, maleate, phosphate, L-tartarate, and L-malate. Of these, the malate salt exhibited an acceptable combination of crystallinity, solubility, and stability during initial scale up and was selected for development of immediate release formulation. During the pharmaceutical development it became clear though that cabozantinib (S)-malate exists as two closely related crystalline solid forms (N-1 and N-2) that have similar properties. An amorphous form has also been identified and characterized. Both crystalline forms, N-1 and N-2, have been thoroughly characterized. Cometriq contains standard excipients: silicified microcrystalline cellulose (filler) which consists of microcrystalline cellulose and silicon dioxide, croscarmellose sodium (disintegrant), sodium starch glycolate (disintegrant), silica colloidal anhydrous (glidant), stearic acid (lubricant). The empty gelatine capsule consists of gelatin (capsule matrix), black iron oxide, red iron oxide (colourants), titanium dioxide (opacifier) and printing ink. The two strengths comprise the same excipients except for the iron oxide colourant. The excipient concentrations have been optimized by studying the effect of various excipient concentrations on the content of uniformity and dissolution. |
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| Manufacture of the product | Cometriq hard gelatine capsules are manufactured by a standard manufacturing process, the main manufacturing steps are: i) delumping of the active substance and excipients, ii) direct blending of components in a diffusion blender, iii) capsule filling and iv) weight sorting. | ||
| Tablet / Capsule Image |
/20MG.jpg)
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/80MG.jpg)
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| Appearance | Hard gelatin capsules are grey with “XL184 20mg” printed in black on the body of the capsule | Hard gelatin capsules are Swedish orange with “XL184 80mg” printed in black on the body of the capsule | |
| Imprint code / Engraving / Debossment | “XL184 20mg” printed in black on the body of the capsule | “XL184 80mg” printed in black on the body of the capsule | |
| Score | no score | no score | |
| Color | Grey | Swedish Orange | |
| Shape | Capsule | Capsule | |
| Dimension | 19mm | 19mm | |
| Mfg by | Exelixis, Inc (US), TMC Pharma Services Ltd. (EU) | ||
| Mfg for | - | ||
| Marketed by | TMC Pharma Services Ltd. (EU) | ||
| Distributed by | Exelixis, Inc (US) | ||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N203756 | 1 | 7579473 | Aug 14, 2026 | Y | Y | - | - | Download |
| N203756 | 1 | 8877776 | October 8, 2030 | Y | Y | U - 1617 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) with sinker | 75 | 0.01 N HCl with 0.5% Triton X-100 (degassed) | 900 | 5, 10, 15, 20 and 30 | June 2, 2016 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | |
| European Public Assessment Report | Download |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | COMETRIQ | Download |
| UK | COMETRIQ | Download |
| US | COMETRIQ | Download |
| - |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
