| Active Ingredient | CANAGLIFLOZIN; METFORMIN HCl (XR 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| INVOKAMET XR | NDA#205879 | JANSSEN PHARMS | TABLET, EXTENDED RELEASE;ORAL | 50MG;500MG, 50MG;1GM, 150MG;500MG, 150MG;1GM | 50MG;500MG, 50MG;1GM, 150MG;500MG, 150MG;1GM (RS) | September 20, 2016 | March 29, 2018 | - | Type 4 - New Combination | STANDARD | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
/Structural_Formula.jpg) |
| Chemical Name | (1) Canagliflozin: (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4methylphenyl]-D-glucitol hemihydrate (2) Metformin hydrochloride:1,1Dimethylbiguanide hydrochloride |
| CAS No | (1) Canagliflozin: 842133-18-0 (2) Metformin hydrochloride: 657-24-9 |
| Molecular Formula | (1) Canagliflozin: C24H25FO5S•1/2 H2O (2) Metformin hydrochloride:C4H11N5 ● HCl |
| Molecular Weight | (1) Canagliflozin: 453.53 (2) Metformin hydrochloride:165.62 |
| Appearance | (1) Canagliflozin: a white to off-white powder (2) Metformin hydrochloride: a white, solid, crystalline powder |
| Solubility | (1) Canagliflozin: It is practically insoluble in water and aqueous media from pH 1.1 to 12.9 and freely soluble in ethanol. (2) Metformin hydrochloride:It is soluble in water and practically insoluble in acetone. |
| Water Solubility | (1) Canagliflozin: 0.0045 mg/mL (Predicted) (2) Metformin hydrochloride: Freely soluble as HCl salt |
| Polymorphism | (1) Canagliflozin: Polymorphism has been observed for canagliflozin: the manufactured form I, which is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process. |
| pKa (Strongest Acidic) | (1) Canagliflozin: 12.57 (Predicted) (2) Metformin hydrochloride: 12.4 |
| pKa (Strongest Basic) | (1) Canagliflozin:-3 (Predicted) (2) Metformin hydrochloride: 12.33 (Predicted) |
| Log P | (1) Canagliflozin: 3.09 (Predicted) (2) Metformin hydrochloride:-0.5 |
| Identification | (1) Canagliflozin: IR |
| Degradation | (1) Canagliflozin: The active substance is stable at high temperature and humidity and degrades moderately under basic and peroxide conditions. Canagliflozin is unstable under photolytic and radical oxidation conditions. |
| Hygroscopic | (1) Canagliflozin: non-hygroscopic (2) Metformin hydrochloride: slighly hygroscopic |
| Photostability study | - |
| Melting Point | (1) Metformin hydrochloride: 223-226 °C |
| BCS Class | (1) Canagliflozin: IV (2) Metformin hydrochloride:III |
| Manufacture of API | (1) Canagliflozin: Canagliflozin is manufactured by one source and is synthesized in five main synthetic steps plus two purification steps using well defined starting materials with acceptable specifications. (2) Metformin hydrochloride:The steps, description of manufacturing process and in- process controls, characterisation and additional test on residual solvents, control of material, control of critical steps and intermediates, process validation and manufacturing process development are descibed well. |
| Parameters | Details |
|---|---|
| Indications and Usage | INVOKAMET XR (canagliflozin and metformin hydrochloride extended release) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both canagliflozin and metformin is appropriate. INVOKAMET XR is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. |
| Dosage and Administration | Individualize the starting dose of INVOKAMET XR (canagliflozin and metformin hydrochloride extended-release), taken once-daily with the morning meal, based on the effectiveness and tolerability of the patient’s current regimen:Refer FDA Label. |
| Mechanism of action |
INVOKAMET XR (canagliflozin and metformin hydrochloride) combines two oral antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a member of the biguanide class. Canagliflozin is an inhibitor of Sodium-glucose co-transporter 2 (SGLT2). By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE). Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. |
| Absorption |
After administration of INVOKAMET XR tablets with a high-fat breakfast, the peak (Cmax) and total (AUC) exposure of canagliflozin were not altered relative to dosing in the fasted state. However, the AUC of metformin increased by approximately 61% and Cmax increased by approximately 13%. Following single-dose oral administration of 100 mg and 300 mg of canagliflozin, peak plasma concentrations (median Tmax) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. In both single and multiple-dose studies in healthy subjects, once daily 1,000 mg (two 500 mg tablets) dosing results in up to 35% higher Cmax, of metformin relative to the immediate-release given as 500 mg twice daily without any change in overall systemic exposure, as measured by AUC. |
| Food Effect | Following a single oral dose of 1,000 mg (two 500 mg tablets) metformin extended-release after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. |
| Distribution |
The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 83.5 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride 850 mg immediate-release tablets averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin tablets, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than 1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. |
| Metabolism |
O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans. Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted. |
| Elimination |
Following administration of a single oral [14C] canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible. Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O−glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min. Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. |
| Peak plasma time (Tmax) | (1) Canagliflozin: 1-2 Hours (2) Metformin hydrochloride:7-8 hours |
| Half life | (1) Canagliflozin: 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses (2) Metformin hydrochloride:17.6 hours |
| Bioavailability | (1) Canagliflozin: 65% |
| Age, gender |
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Studies characterizing the pharmacokinetics of canagliflozin and metformin after administration of INVOKAMET XR in geriatric patients have not been performed. Age had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on a population pharmacokinetic analysis. Studies characterizing the pharmacokinetics of canagliflozin and metformin after administration of INVOKAMET XR in pediatric patients have not been performed. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 11924 | I | II | April 17, 1996 | GROUPE LIPHA (METFORMIN HCL) |
| 12647 | A | II | August 9, 1997 | USV LIMITED (METFORMIN HCL) |
| 12670 | A | II | September 30, 1997 | MERCK SANTE SAS (METFORMIN HCL) |
| 13827 | I | II | September 11, 1998 | TAPI PUERTO RICO INC (METFORMIN HCL) |
| 13869 | A | II | November 24, 1998 | FARMHISPANIA SA (METFORMIN HCL) |
| 14055 | A | II | March 19, 1999 | WANBURY LTD (METFORMIN HCL) |
| 14776 | A | II | March 14, 2000 | SHANGHAI MEDICINAL LTD (METFORMIN HCL) |
| 15143 | I | II | November 20, 2000 | VIBRANTIS SA DE CV (METFORMIN HCL) |
| 15148 | A | II | November 16, 2000 | OLON SPA (METFORMIN HCL) |
| 15217 | A | II | February 1, 2001 | HARMAN FINOCHEM LTD (METFORMIN HCL) |
| 15557 | A | II | January 8, 2001 | USV LIMITED (BLENDED METFORMIN HCL) |
| 15612 | A | II | August 25, 2001 | SUN PHARMACEUTICAL INDUSTRIES LTD (METFORMIN HCL) |
| 16047 | A | II | November 7, 2002 | UQUIFA MEXICO SA DE CV (METFORMIN HCL) |
| 16272 | I | II | November 25, 2002 | KUNSHAN DOUBLE CRANE PHARMACEUTICAL CO LTD (METFORMIN HCL) |
| 16474 | I | II | March 18, 2003 | WOCKHARDT LTD (METFORMIN HCL) |
| 16625 | A | II | June 6, 2003 | GRANULES INDIA LTD (METFORMIN HCL) |
| 16827 | I | II | August 9, 2003 | NOVUS FINE CHEMICALS LLC (METFORMIN HCL) |
| 16993 | A | II | January 12, 2003 | AUROBINDO PHARMA LTD (METFORMIN HCL) |
| 17743 | A | II | October 14, 2004 | USV LIMITED (METFORMIN HCL DC GRANULES) |
| 17744 | A | II | October 14, 2004 | USV LIMITED (METFORMIN HCl COARSE) |
| 18150 | A | II | February 3, 2005 | WANBURY LTD (METFORMIN HCl) |
| 18323 | A | II | May 26, 2005 | IPCA LABORATORIES LTD (METFORMIN HCl) |
| 18330 | A | II | May 5, 2005 | SMRUTHI ORGANICS LTD (METFORMIN HCl) |
| 18887 | A | II | October 14, 2005 | WANBURY LTD (METFORMIN HCl DC GRADE - 90%) |
| 18888 | A | II | October 14, 2005 | WANBURY LTD (METFORMIN HCl DC GRADE - 95%) |
| 19190 | A | II | February 17, 2006 | VISTIN PHARMA AS (METFORMIN HCl) |
| 19228 | I | II | February 25, 2006 | IONS PHARMA (METFORMIN HCl) |
| 19910 | I | II | October 28, 2006 | AURO LABORATORIES LTD (METFORMIN HCl) |
| 19925 | A | II | November 20, 2006 | IPCA LABORATORIES LTD (METFORMIN HCl) |
| 19985 | I | II | October 19, 2006 | MS MARKSANS PHARMA LTD (METFORMIN HCl) |
| 21097 | I | II | May 12, 2007 | INDOCO REMEDIES LTD (METFORMIN HCl) |
| 21294 | I | II | January 2, 2008 | AARTI DRUGS LTD (METFORMIN HCl) |
| 21695 | A | II | September 4, 2008 | SOHAN HEALTHCARE PVT LTD (METFORMIN HCl) |
| 21891 | I | II | December 8, 2008 | TIANJIN PACIFIC CHEMICAL AND PHARMACEUTICAL CO LTD (METFORMIN HCl) |
| 23273 | A | II | October 27, 2009 | SHOUGUANG FUKANG PHARMACEUTICAL CO LTD (METFORMIN HCl) |
| 24604 | I | II | January 17, 2011 | SHANDONG KEYUAN PHARMACEUTICAL CO LTD (METFORMIN HCl) |
| 25467 | A | II | March 11, 2011 | EXEMED PHARMACEUTICALS (METFORMIN HCl) |
| 25564 | A | II | November 24, 2011 | KOTHARI PHYTOCHEMICALS INTERNATIONAL (METFORMIN HCl) |
| 27139 | A | II | June 5, 2013 | IOL CHEMICALS AND PHARMACEUTICALS LTD (METFORMIN HCl) |
| 29434 | A | II | October 6, 2015 | BEIJING HUIKANG BOYUAN CHEMICAL TECH CO LTD (CANAGLIFLOZIN HEMIHYDRATE) |
| 29496 | A | II | June 30, 2015 | MSN LIFE SCIENCES PRIVATE LTD (CANAGLIFLOZIN HEMIHYDRATE) |
| 30067 | A | II | January 12, 2015 | VISTIN PHARMA (AS METFORMIN DC 92.6% LUBRICATED GRANULES) |
| 30366 | A | II | December 31, 2015 | SHANGHAI DESANO CHEMICAL PHARMACEUTICAL CO LTD (CANAGLIFLOZIN) |
| 30449 | A | II | April 15, 2016 | LUPIN LTD (CANAGLIFLOZIN) |
| 30753 | A | II | September 9, 2016 | MACLEODS PHARMACEUTICALS LTD (CANAGLIFLOZIN) |
| 30771 | A | II | August 30, 2016 | MYLAN LABORATORIES LTD (CANAGLIFLOZIN) |
| 30853 | A | II | August 19, 2016 | CHONGQING PHARMACEUTICAL RESEARCH INSTITUTE CO LTD (CANAGLIFLOZIN) |
| 30879 | A | II | September 20, 2016 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD (CANAGLIFLOZIN) |
| 30941 | A | II | September 16, 2016 | ALKEM LABORATORIES LTD (CANAGLIFLOZIN) |
| 30951 | A | II | October 18, 2016 | INDOCO REMEDIES LTD (CANAGLIFLOZIN) |
| 30964 | A | II | September 28, 2016 | AUROBINDO PHARMA LTD (CANAGLIFLOZIN) |
| 30972 | A | II | November 18, 2016 | DASAMI LAB PRIVATE LTD (CANAGLIFLOZIN) |
| 31025 | A | II | September 30, 2016 | DR REDDYS LABORATORIES LTD (CANAGLIFLOZIN) |
| 31161 | A | II | December 2, 2016 | ALEMBIC PHARMACEUTICALS LTD (CANAGLIFLOZIN) |
| 31231 | A | II | March 16, 2017 | DASAMI LAB PRIVATE LTD (CANAGLIFLOZIN) |
| 31233 | A | II | January 22, 2017 | LAURUS LABS LTD (CANAGLIFLOZIN) |
| 31290 | A | II | March 18, 2017 | SUN PHARMACEUTICAL INDUSTRIES LTD (CANAGLIFLOZIN) |
| 5951 | A | II | September 8, 1985 | MERCK SANTE SAS (METFORMIN HCL) |
| Parameters | Details | ||||
|---|---|---|---|---|---|
| Strength | 50mg/500mg | 50mg/1000mg | 150mg/500mg | 150mg/1000mg | |
| Excipients used | croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose anhydrous, magnesium stearate (vegetable-sourced), microcrystalline cellulose, polyethylene oxide, and silicified microcrystalline cellulose (50 mg/500 mg and 50 mg/1,000 mg tablets only) | ||||
| Composition of coating material | macrogol/PEG3350, polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, iron oxide red, iron oxide yellow, and iron oxide black (50 mg/1,000 mg and 150 mg/1,000 mg tablets only) | ||||
| Composition of caspule shell | - | ||||
| Pharmaceutical Development | Each 50 mg/500 mg tablet and 50 mg/1,000 mg tablet contains 51 mg of canagliflozin equivalent to 50 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin hydrochloride. Each 150 mg/500 mg tablet and 150 mg/1,000 mg tablet contains 153 mg of canagliflozin equivalent to 150 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin hydrochloride. | ||||
| Manufacture of the product | - | ||||
| Tablet / Capsule Image | |||||
| Appearance | oblong, biconvex, almost white to light orange film-coated tablets with “CM1” on one side. A thin line on the tablet side may be visible. | oblong, biconvex, pink, film-coated tablets with “CM3” on one side. A thin line on the tablet side may be visible. | oblong, biconvex, orange, film-coated tablets with “CM2” on one side. A thin line on the tablet side may be visible. | oblong, biconvex, reddish brown, film-coated tablets with “CM4” on one side. A thin line on the tablet side may be visible. | |
| Imprint code / Engraving / Debossment | “CM1” on one side. A thin line on the tablet side may be visible. | “CM3” on one side. A thin line on the tablet side may be visible. | “CM2” on one side. A thin line on the tablet side may be visible. | “CM4” on one side. A thin line on the tablet side may be visible. | |
| Score | no score | no score | no score | no score | |
| Color | WHITE (almost white to light orange) | PINK | ORANGE | BROWN (reddish brown) | |
| Shape | OVAL (OBLONG, Bicovex) | OVAL (OBLONG, Bicovex) | OVAL (OBLONG, Bicovex) | OVAL (OBLONG, Bicovex) | |
| Dimension | 21mm | 22mm | 21mm | 22mm | |
| Mfg by | - | ||||
| Mfg for | Janssen Pharmaceuticals, Inc.(US) | ||||
| Marketed by | - | ||||
| Distributed by | - | ||||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N205879 | 1 | 6723340 | October 25, 2021 | - | DP | - | - | Download |
| N205879 | 1 | 7943582 | February 26, 2029 | DS | DP | U-493 | - | Download |
| N205879 | 1 | 7943788 | July 14, 2027 | DS | DP | - | - | Download |
| N205879 | 1 | 8222219 | July 30, 2024 | - | - | U-493 | - | Download |
| N205879 | 1 | 8513202 | December 3, 2027 | DS | DP | U-493 | - | Download |
| N205879 | 1 | 8785403 | July 30, 2024 | - | DP | - | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| Met: I (Basket, 40 mesh): Can: I (Basket, 10 mesh [with option of tablet holder]) | Met: 100: Can:100 | Met: Simulated Gastric Fluid [SGF] without enzyme, pH 1.2; Can: 0.1% (w/v) polysorbate 20 in 0.05 M sodium phosphate buffer pH 6.8 ( 50 mg); 0.2% (w/v) polysorbate 20 in 0.05 M sodium phosphate buffer pH 6.8 (150 mg) | Met: 900: Can: 900 | Met: 1, 2, 4, 6, 8 10 and 12 hours: Can: 10, 15, 20, 30, 45 and 60 minutes; | December 22, 2016 |
| 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 |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | - | |
| UK | - | |
| US | INVOKAMET XR | Download |
| - |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
