| Active Ingredient | LINAGLIPTIN |
|---|
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| TRADJENTA | (NDA) 201280 | BOEHRINGER INGELHEIM | TABLET;ORAL | 5MG | 5MG (RS) | May 2, 2011 | - | - | 1 New molecular entity (NME) | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione |
| CAS No | 668270-12-0 |
| Molecular Formula | C25H28N8O2 |
| Molecular Weight | 472.54 g/mol |
| Appearance | a white to yellowish crystalline solid substance |
| Solubility | It is very slightly soluble in water (0.9 mg/mL). Linagliptin is very soluble in aqueous media (> 1 mg/ml) over the entire physiological pH range, soluble in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1 mg/mL), and very slightly soluble in isopropanol and acetone (ca. 1 mg/mL) |
| Water Solubility | 0.0502 mg/mL (Predicted) |
| Polymorphism | The active substance simultaneously exists in two polymorphic forms, which are enantiotropically related and which reversibly convert into each other approximately at room temperature. The two polymorphic forms do not differ with regard to biopharmaceutical properties. |
| pKa (Strongest Acidic) | - |
| pKa (Strongest Basic) | 9.86 (Predicted) |
| Log P | 2.62 (Predicted) |
| Identification | (IR spectrum, Chiral HPLC, Melting point |
| Degradation | The result of stress studies demostrated that in solid form, the active substance is very stable at elevated temperatures, high humidity and the combined effect of both conditions. During photostability testing, only a slighly change in color was observed, but no change in impurity profile leading to the conclusion that the active substance is not sensitive to light. |
| Hygroscopic | slightly hygroscopic, but water uptake does not change the crystal modification. |
| Photostability study | Photo stable |
| Melting Point | - |
| BCS Class | III |
| Manufacture of API | The synthetic process for linagliptin consists of three steps and then a milling step follows. The manufacturing process has been described in sufficient detail including suitable reaction schemes. The synthetic process does not involve Class 1 solvents or metal catalysts. The Class 2 and the Class 3 solvents used in the synthesis have been shown to be efficiently removed during the process. |
| Parameters | Details |
|---|---|
| Indications and Usage | TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. TRADJENTA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using TRADJENTA. |
| Dosage and Administration | The recommended dose of TRADJENTA is 5 mg once daily. TRADJENTA tablets can be taken with or without food. |
| Mechanism of action | Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta-cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction in hepatic glucose output. |
| Absorption |
The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmol*h/L and maximum concentration (Cmax) was 8.9 nmol/L.Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady state compared with the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in a less than dose-proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes. The absolute bioavailability of linagliptin is approximately 30%. |
| Food Effect | High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. TRADJENTA may be administered with or without food. |
| Distribution | The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75%-89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment. |
| Metabolism | Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin. |
| Elimination | Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min. |
| Peak plasma time (Tmax) | 1.5 hours |
| Half life | >100 hours (terminal half-life) |
| Bioavailability | 30% |
| Age, gender | No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. Studies characterizing the pharmacokinetics of linagliptin in pediatric patients have not yet been performed. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 27907 | A | II | March 24, 2014 | GLENMARK PHARMACEUTICALS LTD |
| 28098 | A | II | March 28, 2014 | MSN PHARMACHEM PRIVATE LTD |
| 28404 | A | II | June 26, 2014 | BEIJING HUIKANG BOYUAN CHEMICAL TECH CO LTD |
| 28748 | A | II | October 31, 2014 | MYLAN LABORATORIES LTD |
| 28766 | A | II | November 19, 2014 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD |
| 28767 | A | II | January 30, 2015 | DR REDDYS LABORATORIES LTD |
| 28769 | A | II | November 11, 2014 | TEVA PHARMACEUTICAL INDUSTRIES LTD |
| 28785 | A | II | December 22, 2014 | HEC PHARM CO LTD |
| 28877 | A | II | July 1, 2015 | HONOUR LAB LTD |
| 28878 | A | II | July 1, 2015 | HONOUR LAB LTD (LINAGLIPTIN PREMIX) |
| 28940 | A | II | June 1, 2015 | AUROBINDO PHARMA LTD |
| 28971 | A | II | February 19, 2015 | SUN PHARMACEUTICAL INDUSTRIES LTD |
| 29017 | A | II | January 31, 2015 | CADILA HEALTHCARE LTD |
| 29692 | A | II | December 8, 2015 | VIWIT PHARMACEUTICAL CO LTD |
| 29844 | A | II | September 25, 2015 | ZAKLADY FARMACEUTYCZNE POLPHARMA SA |
| 31294 | A | II | December 30, 2016 | WISDOM PHARMACEUTICAL CO LTD |
| 31452 | A | II | March 30, 2017 | ALEMBIC PHARMACEUTICALS LTD |
| Parameters | Details |
|---|---|
| Strength | 5MG |
| Excipients used | mannitol, pregelatinized starch, corn starch, copovidone, and magnesium stearate |
| Composition of coating material | hypromellose, titanium dioxide, talc, polyethylene glycol, and red ferric oxide |
| Composition of caspule shell | - |
| Pharmaceutical Development |
The objective of the product development was to obtain an immediate release oral dosage form with rapid disintegration and dissolution, preferably as a film-coated tablet formulation. Linagliptin is a highly soluble active substance. It is considered to be a class 3 drug substance (high solubility, poor permeability) according to the Biopharmaceutical Classification System (BCS) due to its incomplete oral systemic bioavailability (about 30% compared to intravenous administration) and the moderate permeability observed in Caco-2 cells. Due to the low active substance content in the final formulation, the active substance is milled to ensure an adequate content uniformity. Several particle size ranges were investigated and a change in the active substance particle size distribution within the investigated range has no relevant influence on in-vitro dissolution while the content uniformity of the tablets is acceptable. All components are inert showing no interactions with drug release. A standard aqueous wet granulation process was chosen to manufacture the product. All critical process parameters have been identified and controlled by appropriate in process controls. |
| Manufacture of the product | The manufacturing process is a standard process for these kinds of formulations such as: blending, wet granulation, compression and coating. |
| Tablet / Capsule Image |
|
| Appearance | light red, round, biconvex, bevel-edged, film-coated tablets with “D5” debossed on one side and the Boehringer Ingelheim logo debossed on the other side |
| Imprint code / Engraving / Debossment | “D5” debossed on one side and the Boehringer Ingelheim logo debossed on the other side |
| Score | no score |
| Color | RED |
| Shape | ROUND |
| Dimension | 8mm |
| Mfg by | Boehringer Ingelheim Pharmaceuticals, Inc. (EU) |
| Mfg for | - |
| Marketed by | Boehringer Ingelheim Pharmaceuticals, Inc. (US, EU), Eli Lilly and Company (US) |
| Distributed by | Boehringer Ingelheim Pharmaceuticals, Inc. (US, EU) |
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N201280 | 1 | 6303661 | April 24, 2017 | - | - | U - 1270 | - | Download |
| N201280 | 1 | 7459428 | February 2, 2019 | - | - | U - 1270 | - | Download |
| N201280 | 1 | 7407955 | May 2, 2025 | Y | Y | - | - | Download |
| N201280 | 1 | 8178541 | August 12, 2023 | - | - | U - 1244 | - | Download |
| N201280 | 1 | 9173859 | May 4, 2027 | - | Y | U - 1503 | - | Download |
| N201280 | 1 | 8846695 | June 4, 2030 | - | - | U - 1503 | - | Download |
| N201280 | 1 | 8853156 | March 5, 2031 | - | - | U - 1642 | - | Download |
| N201280 | 1 | 8883805 | November 26, 2025 | - | Y | - | - | Download |
| N201280 | 1 | 6890898 | February 2, 2019 | - | - | U-493 U-1270 | - | Download |
| N201280 | 1 | 7078381 | February 2, 2019 | - | - | U-493 U-1270 | - | Download |
| N201280 | 1 | 8119648 | August 12, 2023 | - | - | U-774 U-1270 | - | Download |
| N201280 | 1 | 8673927 | May 4, 2027 | - | - | U-1503 | - | Download |
| N201280 | 1 | 9173859 | May 4, 2027 | - | Y | U - 1503 | - | Download |
| N201280 | 1 | 9486526 | August 5, 2029 | - | - | U-1915 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| I (Basket) | 50 | 0.1 N HCl | 900 | 5, 10, 15, 20, 30 and 45 | August 15, 2013 |
| 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 | TRAJENTA | Download |
| UK | TRAJENTA | Download |
| US | AUROBINDO PHARMA LTD (ANDA # 208415) Tentative Approval | |
| US | TRADJENTA | Download |
| - |
| - |
