| Active Ingredient | EVEROLIMUS (Tablet, Oral) |
|---|
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AFINITOR | (NDA) 022334 | NOVARTIS | TABLET;ORAL | 2.5MG, 5MG, 7.5MG, 10MG | 2.5MG, 5MG, 7.5MG, 10MG (RS) | March 30, 2009 | - | Oct 29, 2017 May 5, 2018 Apr 26, 2019 Feb 26, 2023 | 1 New molecular entity (NME) | PRIORITY | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
/Structural_Formula.jpg) |
| Chemical Name | (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20pentaone |
| CAS No | 159351-69-6 |
| Molecular Formula | C53H83NO14 |
| Molecular Weight | 958.2 |
| Appearance | a white to faintly yellow amorphous powder |
| Solubility | It is almost insoluble in water. The reported everolimus solubility is < 0.01% (0.1 mg/mL) in water, 0.1 N HCl, and citrate buffer (pH 2.0 - 10.0). |
| Water Solubility | 0.00163 mg/mL (Predicted) |
| Polymorphism | - |
| pKa (Strongest Acidic) | 9.96 (Predicted) |
| pKa (Strongest Basic) | (Predicted) -2.7 |
| Log P | 5.01 (Predicted) |
| Identification | IR, X-ray, HPLC |
| Degradation | It is unstable at temperatures above 25 °C and is sensitive to light. No significant alteration of the active substance could be observed when stored in the deep freezer in a very tight packaging (aluminium bags) under protective gas. When increasing temperature, a clear correlation could be observed between the increase of degradation products and a decrease of the antioxidant BHT. The comparison of the stability of samples with BHT (0.2 %) or without BHT demonstrated the protective effect of the antioxidant. |
| Hygroscopic | - |
| Photostability study | Light sensitive |
| Melting Point | - |
| BCS Class | III/IV |
| Manufacture of API | The manufacturing process consists of four main steps, (1) fermentation, (2) extraction of rapamycin from the fermentation broth, (3) chemical modification of rapamycin starting material, (4) purification of crude everolimus and stabilisation with BHT. The choice of the stabilizer has been sufficiently explained and justified by experimental results. Rapamycin, obtained by a fermentation process, was used as the starting material. |
| Parameters | Details |
|---|---|
| Indications and Usage | AFINITOR is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. AFINITOR is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. AFINITOR is indicated for the treatment of adult patients with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lungorigin with unresectable, locally advanced or metastatic disease. AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors. AFINITOR is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. AFINITOR is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. AFINITOR Tablets and AFINITOR DISPERZ are indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. |
| Dosage and Administration |
The recommended dose in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced NET, Advanced RCC, and Renal Angiomyolipoma with TSC of AFINITOR Tablets is 10 mg, to be taken once daily at the same time every day. Administer either consistently with food or consistently without food. AFINITOR Tablets should be swallowed whole with a glass of water. Do not break or crush tablets. Continue treatment until disease progression or unacceptable toxicity occurs. |
| Mechanism of action |
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake inin vitroand/orin vivo studies. Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1or TSC2leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1or the TSC2gene lead to hamartoma formation throughout the body. |
| Absorption |
After administration of AFINITOR tablets in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing. Dose Proportionality in Patients with SEGA and TSC: In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2. |
| Food Effect | In healthy subjects, high-fat meals reduced systemic exposure to AFINITOR 10 mg tablet (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and Cmax by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and Cmax by 50%. |
| Distribution | The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given AFINITOR 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. |
| Metabolism |
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself. In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. |
| Elimination | No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours. |
| Peak plasma time (Tmax) | 1 to 2 hours |
| Half life | 30 hours |
| Bioavailability | - |
| Age, gender |
In a population pharmacokinetic evaluation in cancer patients,no relationship was apparent between oral clearance and patient age or gender. In patients with SEGA, the geometric mean Cminvalues normalized to mg/m2 dose in patients aged < 10 years and 10 to 18 years were lower by 54% and 40%, respectively, than those observed in adults (> 18 years of age), suggesting that everolimus clearance normalized to body surface area was higher in pediatric patients as compared to adults. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 26350 | A | II | June 14, 2013 | CONCORD BIOTECH LTD |
| 26738 | A | II | December 17, 2012 | HANGZHOU HUADONG MEDICINE GROUP KANGRUN PHARMACEUTICAL CO LTD |
| 26819 | A | II | February 8, 2013 | CHUNGHWA CHEMICAL SYNTHESIS AND BIOTECH CO LTD |
| 29405 | A | II | June 5, 2015 | CHENGDU YACHT BIO-TECHNOLOGY CO LTD |
| 29651 | A | II | September 30, 2015 | BIOCON LTD |
| 29696 | A | II | September 30, 2015 | NATCO PHARMA LTD |
| 29854 | A | II | October 19, 2015 | SCINOPHARM TAIWAN LTD |
| 31073 | A | II | October 27, 2016 | APOTEX FERMENTATION INC |
| Parameters | Details | ||||
|---|---|---|---|---|---|
| Strength | 2.5MG | 5MG | 7.5MG | 10MG | |
| Excipients used | anhydrous lactose (71.88MG), butylated hydroxy toluene (0.05MG), crospovidone (25MG), hypromellose (22.5MG), lactose monohydrate (2.45MG), and magnesium stearate (0.63MG) | anhydrous lactose (143.78MG), butylated hydroxy toluene (0.10MG), crospovidone (50MG), hypromellose (45MG), lactose monohydrate (4.90MG), and magnesium stearate (1.25MG) | anhydrous lactose, butylated hydroxy toluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate | anhydrous lactose (287.50MG), butylated hydroxy toluene (0.20MG), crospovidone (100MG), hypromellose (90MG), lactose monohydrate (9.80MG), and magnesium stearate (2.50MG) | |
| Composition of coating material | - | ||||
| Composition of caspule shell | - | ||||
| Pharmaceutical Development |
The objective was to develop an oral dosage form for a hydrophobic, poorly soluble and chemically unstable active substance. During the early stages of development of everolimus tablets, stress tests of active substance with a number of excipients commonly used for oral formulations were stored and tested for compatibility. Based on those experiments, the following excipients were chosen: butylhydroxytoluene (antioxidant), lactose monohydrate (filing agent), hypromellose (carrier), magnesium stearate (lubricant), lactose anhydrous (filling agent). |
||||
| Manufacture of the product |
The manufacture is a two step process: preparation of the solid dispersion and preparation of the tablets. The solid dispersion is tested for identity everolimus (XRPD, detection of crystalline Everolimus in the solid dispersion), residual solvents, water (Karl Fischer), identification and assay of BHT (GC), identification everolimus (HPLC), Assay everolimus (HPLC), degradation products (HPLC) and Microbial limit tests. Everolimus solid dispersion was stored in triple laminated foil bags or stainless steel containers to protect it from water uptake by storing it in tightly closed containers. The solid dispersion is subsequently processed with the other excipients by direct compression to obtain the medicinal product. The equipment used consists of a diffusion mixer, a sieve and a powder assisted tablet press. The tabletting mixture is prepared with conventional mixing and sieving procedures and final direct compression. |
||||
| Tablet / Capsule Image |
/2.5MG.jpg)
|
/5MG.jpg)
|
/10MG.jpg)
|
||
| Appearance | White to slightly yellow, elongated tablets with a bevelled edge and engraved with “LCL” on one side and “NVR” on the other. | White to slightly yellow, elongated tablets with a bevelled edge and engraved with “5” on one side and “NVR” on the other. | White to slightly yellow, elongated tablets with a bevelled edge and engraved with “7P5” on one side and “NVR” on the other. | White to slightly yellow, elongated tablets with a bevelled edge and engraved with “UHE” on one side and “NVR” on the other. | |
| Imprint code / Engraving / Debossment | engraved with “LCL” on one side and “NVR” on the other | engraved with “5” on one side and “NVR” on the other | engraved with “7P5” on one side and “NVR” on the other | engraved with “UHE” on one side and “NVR” on the other | |
| Score | no score | no score | no score | no score | |
| Color | White to slightly yellow | White to slightly yellow | White to slightly yellow | White to slightly yellow | |
| Shape | OVAL | OVAL | OVAL | OVAL | |
| Dimension | 12mm | 15mm | 10mm | 15mm | |
| Mfg by | Novartis Pharma (US, EU) | ||||
| Mfg for | - | ||||
| Marketed by | Novartis Pharma (EU) | ||||
| Distributed by | Novartis Pharma (US) | ||||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N022334 | 1 | 5665772 | September 9, 2019 | Y | Y | - | - | Download |
| N022334 | 1 | 5665772*PED | March 9, 2020 | - | - | - | - | |
| N022334 | 1 | 6004973 | July 12, 2016 | - | Y | - | - | Download |
| N022334 | 1 | 6004973*PED | January 12, 2017 | - | - | - | - | |
| N022334 | 1 | 7297703*PED | June 6, 2020 | - | - | - | - | |
| N022334 | 1 | 7741338 | December 6, 2019 | - | Y | - | - | Download |
| N022334 | 1 | 8410131 | November 1, 2025 | - | - | U - 1368 | - | Download |
| N022334 | 1 | 8410131*PED | May 1, 2026 | - | - | - | - | |
| N022334 | 1 | 8436010 | February 22, 2022 | - | - | U - 1396 | - | Download |
| N022334 | 1 | 8436010*PED | August 22, 2022 | - | - | - | - | |
| N022334 | 1 | 8778962 | February 18, 2022 | - | - | U - 1541 | - | Download |
| N022334 | 1 | 8778962*PED | August 18, 2022 | - | - | - | - | |
| N022334 | 1 | 9006224 | July 1, 2028 | - | - | U - 1681 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 50 | Water with 0.4% sodium dodecylsulfate | 500 | 10, 20, 30 and 45 | July 1, 2010 |
| 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 | AFINITOR | Download |
| UK | AFINITOR | Download |
| US | AFINITOR | Download |
| US | PAR PHARM INC (ANDA #207934)* | |
| US | WEST-WARD PHARMS INT (ANDA #207486)* |
| 7.5MG strength of Afinitor is not approved in EU and UK. Exclusivity Code: Exclusivity Expiration; I-724: Feb 26, 2019 and PED: Apr 29, 2018 |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov, www.drug.com |
