Formulation Diary

Active Ingredient	CABOZANTINIB S-MALATE (Tablet)

NDA filling and Orange book information

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
CABOMETYX	(NDA) 208692	EXELIXIS	TABLET;ORAL	EQ 20MG BASE, EQ 40MG BASE, EQ 60MG BASE	EQ 20MG BASE, EQ 40MG BASE, EQ 60MG BASE (RS)	April 25, 2016	November 29, 2017	-	Type 3 - New Dosage Form	PRIORITY	Prescription	None

API Information

Parameters	Details
Structural Formula
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.

Label Information

Parameters	Details
Indications and Usage	CABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.
Dosage and Administration	Do not substitute CABOMETYX tablets with cabozantinib capsules. The recommended daily dose of CABOMETYX is 60 mg. Do not administer CABOMETYX with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking CABOMETYX. Continue treatment until patient no longer experiences clinical benefit or experiences unacceptable toxicity. Swallow CABOMETYX tablets whole. Do not crush CABOMETYX tablets. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during CABOMETYX treatment.
Mechanism of action	In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.
Absorption	Repeat daily dosing of cabozantinib 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. Following oral administration of cabozantinib, median time to peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 3 hours post-dose. A 19% increase in the Cmax of the tablet formulation (CABOMETYX) compared to the capsule formulation (COMETRIQ®) was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations.
Food Effect	Cabozantinib Cmax and AUC values increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single 140 mg oral dose of an investigational cabozantinib capsule formulation.
Distribution	The oral volume of distribution (Vz/F) of cabozantinib is approximately 319 L. Cabozantinib is highly protein bound in human plasma (≥ 99.7%).
Metabolism	Cabozantinib is a substrate of CYP3A4 in vitro.
Elimination	The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady-state is estimated to be 2.2 L/hr.
Peak plasma time (Tmax)	2 to 3 hours
Half life	99 hours
Bioavailability	-
Age, gender	The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (32-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease equation)).

API Drug Master File

DMF	Status	Type	Submit Date	Holder
31522	A	II	March 30, 2017	MSN LABORATORIES PRIVATE LTD

Innovator Formulation Information

Parameters	Details
Strength	20MG	40MG	60MG
Excipients used	microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate
Composition of coating material	hypromellose, titanium dioxide, triacetin, and iron oxide yellow
Composition of caspule shell	-
Pharmaceutical Development	CABOMETYX (cabozantinib) tablets are supplied as film-coated tablets containing 20 mg, 40 mg, or 60 mg of cabozantinib, which is equivalent to 25 mg, 51 mg, or 76 mg of cabozantinib (S)-malate, respectively. The formulation has been optimised with regard to the the drug loading and excipients ratio and dissolution performance; the choice of excipients has been justified. The selected film coating system was selected among other following an evaluation with regard to their effect on stability and dissolution.The manufacturing consists of high-shear wet granulation, fluid bed drying, milling, blending, compression, and film coating. All tablet strengths are dose proportional and are prepared from a common final blend. Each tablet strength is differentiated by shape.
Manufacture of the product	Dispensing and excipient de-lumping, pre-mixing, granulation, wet milling, fluid bed drying, dry milling, extra-granular blending, lubrication blending, tablet compression, film coating
Tablet / Capsule Image
Appearance	yellow film-coated, round with no score, and debossed with “XL” on one side and “20” on the other side.	yellow film-coated, triangle shaped with no score, and debossed with “XL” on one side and “40” on the other side.	yellow film-coated, oval shaped with no score, and debossed with “XL” on one side and “60” on the other side.
Imprint code / Engraving / Debossment	debossed with “XL” on one side and “20” on the other side	debossed with “XL” on one side and “40” on the other side	debossed with “XL” on one side and “60” on the other side
Score	no score	no score	no score
Color	YELLOW	YELLOW	YELLOW
Shape	Round	Triangle	Oval
Dimension	6mm	8mm	11mm
Mfg by	Patheon Pharma (EU)
Mfg for	Exelixis, Inc (US)
Marketed by	Ipsen Pharma (EU)
Distributed by	-

Orange Book Listed Patent

Application No.	Prod No	Patent No	Patent Expiration	Drug Substance Claim	Drug Product Claim	Patent Use Code	Delist Requested	Link
N208692	1	7579473	August 14, 2026	DS	DP	-	-	Download
N208692	1	8497284	September 24, 2024	-	-	U-1220	-	Download
N208692	1	8877776	October 8, 2030	DS	DP	-	-	Download

Office of Generic Drug Media

USP Apparatus	Speed (RPMs)	Medium	Volume (mL)	Recommended Sampling Times (minutes)	Date Updated
II (Paddle	75	0.01 N HCl with 0.375% Triton X-100 (degassed)	900	5, 10, 15, 20 and 30	July 28, 2016

Packaging System

Market	EU	US
Strength	Packaging System
20MG	Blister (PVC/PCTFE) with push-through aluminum foil backing containing 7 film-coated tablets. Each carton contains 4 blisters with 28 film-coated tablets Bbottle (HDPE bottle with silica gel desiccant canisters and a polypropylene child-resistant closure) of 30 tablets	bottles of 30 tablets
40MG	Blister (PVC/PCTFE) with push-through aluminum foil backing containing 7 film-coated tablets. Each carton contains 4 blisters with 28 film-coated tablets Bbottle (HDPE bottle with silica gel desiccant canisters and a polypropylene child-resistant closure) of 30 tablets	bottles of 30 tablets
60MG	Blister (PVC/PCTFE) with push-through aluminum foil backing containing 7 film-coated tablets. Each carton contains 4 blisters with 28 film-coated tablets Bbottle (HDPE bottle with silica gel desiccant canisters and a polypropylene child-resistant closure) of 30 tablets	bottles of 30 tablets
Storage	Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the blister, bottle label and carton after EXP. The expiry date refers to the last day of that month. This medicinal product does not require any special storage conditions. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.	Store CABOMETYX at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Innovator Product Information

Label	Link
FDA label	Download
FDA chemistry review
FDA Pharmacology Review(s)
FDA Clinical Pharmacology Biopharmaceutics Review(s)
FDA BE Recommendation
European Public Assessment Report	Download

Product Available

Territory	Brand name / Generic company name	Link
EU	CABOMETYX	Download
UK	CABOMETYX	Download
US	CABOMETYX	Download

Remarks

Exclusivity Code; Exclusivity Expiration: NP (New Product); Apr 25, 2019

References

www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov

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