| Active Ingredient | DEFERASIROX (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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| JADENU | (NDA) 206910 | NOVARTIS PHARMS CORP | TABLET;ORAL | 90MG, 180MG, 360MG | 90MG, 180MG, 360MG (RS) | March 30, 2015 | _ | January 23, 2020 | Type 5 - New Formulation or New Manufacturer | STANDARD | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
/Structural_Formula.jpg) |
| Chemical Name | 4-[3,5-Bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]-benzoic acid |
| CAS No | 201530-41-8 |
| Molecular Formula | C21H15N3O4 |
| Molecular Weight | 373.4 |
| Appearance | White to slightly yellow powder |
| Solubility | Ppractically in soluble in acid medium, the solubility increasing with pH |
| Water Solubility | Practically insoluble in water , 0.038 mg/mL at 37 °C |
| Polymorphism | Two polymorphic forms have been identified. The active is the thermodynamically stable polymorph A. The other polymorph cannot be formed under recommended storage conditions for the active substance/finished product and under conditions used to manufacture the finished product. |
| pKa (Strongest Acidic) | 4.55 (Predicted) |
| pKa (Strongest Basic) | 0.19 (Predicted) |
| Log P | 3.52 |
| Identification | IR and XRPD |
| Degradation | Very stable drug substance in the solid state |
| Hygroscopic | Not hygroscopic |
| Photostability study | Not light sensitive |
| Melting Point | 116-117 °C |
| BCS Class | II |
| Manufacture of API | Deferasirox is produced by two different manufacturers from commercially available starting materials in a two-step synthesis followed by purification by crystallisation and micronisation. Deferasirox contains very low levels of process-related impurities and detectable amounts were only found in early development batches. The only impurityrelevant at low levels is 4-hydrazinobenzoic acid (starting material), which has a genotoxic and carcinogenic potential. Catalysts are not used in the synthesis. However the active being a complexing agent for several metal ions, their level in the active has been controlled and results showed that no heavy metals are extracted from the production equipment. |
| Parameters | Details |
|---|---|
| Indications and Usage | JADENU is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. This indication is approved under accelerated approval based on a reduction of liver iron concentrations and serum ferritin levels. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. JADENU is indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5 milligrams of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L. This indication is approved under accelerated approval based on a reduction of liver iron concentrations (to less than 5 mg Fe/g dw) and serum ferritin levels. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. |
| Dosage and Administration |
JADENU therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1000 mcg/L. Refer FDA Label for more details. |
| Mechanism of action | JADENU (deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain. |
| Absorption |
Based on studies in patients with the tablet for oral suspension, deferasirox is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5 to 4 hours. In healthy subjects, JADENU showed comparable tmax. The Cmax and AUC of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3 to 2.3 after multiple doses with the tablet for oral suspension formulation. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of JADENU was 36% greater than with deferasirox tablets for oral suspension. After strength-adjustment, JADENU (i.e., 360 mg strength) was equivalent to deferasirox tablets for oral suspension (i.e., 500 mg strength) with respect to the mean AUC under fasting conditions, however the mean Cmax was increased by 30%. The exposure-response analysis for safety indicated that 30% increase in JADENU Cmax is not clinically meaningful. |
| Food Effect | A food-effect study involving administration of JADENU to healthy subjects under fasting conditions and with a low-fat (fat content <7% of total calories) or high-fat (fat content >50% of total calories) meal indicated that the AUC and Cmax were slightly decreased after a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and Cmax were increased by 18% and 29%, respectively. The increases in Cmax due to the change in formulation and due to the effect of a high-fat meal may be additive and therefore, it is recommended that JADENU should be taken on an empty stomach or with a light meal (contains less than 7% fat content and approximately 250 calories). |
| Distribution | Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 ± 2.69 L in adults. |
| Metabolism | Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy subjects study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC) by interfering with the enterohepatic recycling of deferasirox. |
| Elimination | Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean elimination half-life (t1/2) ranged from 8 to 16 hours following oral administration. |
| Peak plasma time (Tmax) | 1.5 to 4 hours |
| Half life | 8 to 16 hours |
| Bioavailability | - |
| Age, gender |
Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children <6 years of age, systemic exposure was about 50% lower than in adults. The pharmacokinetics of deferasirox have not been studied in elderly patients (65 years of age or older). Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 22369 | A | II | December 20, 2008 | MYLAN LABORATORIES LTD |
| 24209 | A | II | October 28, 2010 | GLENMARK PHARMACEUTICALS LTD |
| 25733 | A | II | January 26, 2012 | NEULAND LABORATORIES LTD |
| 25837 | A | II | February 21, 2012 | MSN LABORATORIES PRIVATE LTD |
| 25888 | A | II | March 30, 2012 | JUBILANT GENERICS LTD |
| 25964 | A | II | March 27, 2012 | PARABOLIC DRUGS LTD |
| 26003 | A | II | April 19, 2012 | BACHEM SA |
| 26468 | A | II | September 20, 2012 | ERREGIERRE SPA |
| 26833 | A | II | February 27, 2013 | ALEMBIC PHARMACEUTICALS LTD |
| 27648 | A | II | January 8, 2014 | TEVA PHARMACEUTICALS INDUSTRIES LTD |
| 28379 | A | II | June 30, 2014 | APOTEX PHARMACHEM INDIA PVT LTD |
| 28626 | A | II | January 2, 2015 | BIOCON LTD |
| 28805 | A | II | October 15, 2014 | WATERSTONE PHARMACEUTICALS HUBEI CO LTD |
| 29320 | A | II | August 21, 2015 | SUN PHARMACEUTICAL INDUSTRIES LTD |
| 29548 | A | II | July 27, 2015 | WATSON PHARMA PRIVATE LTD |
| 30213 | A | II | January 27, 2016 | CTX LIFE SCIENCES PVT LTD |
| Parameters | Details | |||
|---|---|---|---|---|
| Strength | 90 MG | 180 MG | 360 MG | |
| Excipients used | microcrystalline cellulose, crospovidone, povidone (K30), magnesium stearate, colloidal silicon dioxide, and poloxamer (188) | |||
| Composition of coating material | opadry blue | |||
| Composition of caspule shell | - | |||
| Pharmaceutical Development | - | |||
| Manufacture of the product | - | |||
| Tablet / Capsule Image |
/90 MG.jpg)
|
/180 MG.jpg)
|
/360 MG.jpg)
|
|
| Appearance | Light blue oval biconvex film-coated tablet with beveled edges, debossed with ‘NVR’ on one side and ‘90’ on a slight upward slope in between two debossed curved lines on the other side. | Medium blue oval biconvex film-coated tablet with beveled edges, debossed with ‘NVR’ on one side and ‘180’ on a slight upward slope in between two debossed curved lines on the other side. | Dark blue oval biconvex film-coated tablet with beveled edges, debossed with ‘NVR’ on one side and ‘360’ on a slight upward slope in between two debossed curved lines on the other side. | |
| Imprint code / Engraving / Debossment | debossed with ‘NVR’ on one side and ‘90’ on a slight upward slope in between two debossed curved lines on the other side. | debossed with ‘NVR’ on one side and ‘180’ on a slight upward slope in between two debossed curved lines on the other side. | debossed with ‘NVR’ on one side and ‘360’ on a slight upward slope in between two debossed curved lines on the other side. | |
| Score | No score | No score | No score | |
| Color | Light blue | Medium blue | Dark blue | |
| Shape | OVAL | OVAL | OVAL | |
| Dimension | 11mm | 14mm | 17mm | |
| Mfg by | - | |||
| Mfg for | - | |||
| Marketed by | Novartis Pharmaceuticals Corporation (US) | |||
| Distributed by | Novartis Pharmaceuticals Corporation (US) | |||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N206910 | 1 | 6465504 | April 5, 2019 | DS | DP | - | - | Download |
| N206910 | 1 | 6596750 | June 24, 2017 | DS | - | U-735 | - | Download |
| N206910 | 1 | 9283209 | November 21, 2034 | DS | DP | - | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 75 | 0.5% Tween 20 in Phosphate Buffer, pH 6.8 | 900 | 5, 10, 15, 20 and 30 | March 17, 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 | Download |
| European Public Assessment Report |
| Deferasirox belongs to a novel class of tridentate iron chelators. Two molecules of deferasirox are needed to form a soluble complex with one Fe3+ion. Particle size is likely to be important to the rate and possibly to the extent of absorption. |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
