| Active Ingredient | TACROLIMUS (CAPSULE, EXTENDED RELEASE) |
|---|
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ASTAGRAF XL | (NDA) 204096 | ASTELLAS | CAPSULE, EXTENDED RELEASE;ORAL | EQ 0.5MG BASE , EQ 1 G BASE, EQ 5MG BASE | EQ 5MG BASE | July 19, 2013 | _ | _ | 3 New dosage form | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
/Structural_Formula.jpg) |
| Chemical Name | [3S-[3R*[E(1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26ahexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclo-hexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. |
| CAS No | 104987-11-3 |
| Molecular Formula | C44H69NO12•H2O |
| Molecular Weight | 822.03 |
| Appearance | White crystals or crystalline powder |
| Solubility | Freely soluble in ethanol, and very soluble in methanol and chloroform |
| Water Solubility | Practically insoluble in water |
| Polymorphism | - |
| pKa (Strongest Acidic) | 9.96 (Predicted) |
| pKa (Strongest Basic) | -2.9 (predicted) |
| Log P | 3.3 |
| Identification | IR, HPLC |
| Degradation | - |
| Hygroscopic | - |
| Photostability study | - |
| Melting Point | 126 °C |
| BCS Class | II |
| Manufacture of API | Tacrolimus contains one water molecule as a water of crystallization, and does not intakeor release any water under atmospheric conditions. Tacrolimus is obtained by fermentation in line with Ph.Eur.’s General Monograph on "Products of Fermentation”. Since 1988, three methods have been developed and used, i.e. Process I and Methods I and II, in order to improve productivity. The clinical and stability batches were manufactured by the original manufacturing method, Process I, as well as by the current manufacturing method, method I. Commercial batches have been manufactured by the current method, method I. While Method I was used originally, Method II was introduced in response to the need for larger batch sizes (approx. 15 kg versus 58 kg). Batch analyses confirmed that and the impurity profiles and physical properties of tacrolimus drug substance produced by Method II are equivalent to those of tacrolimus drug substance manufactured by Method I. The manufacturing route is divided into two parts: a) Fermentation process and b) Extraction and purification process. There is no intermediate compound involved in the manufacturing process of tacrolimus drug substance. a) Fermentation process: b) Extraction and purification |
| Parameters | Details |
|---|---|
| Indications and Usage | ASTAGRAF XL is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants Limitation of Use: Not interchangeable or substitutable with other tacrolimus products |
| Dosage and Administration | Refer PIL |
| Mechanism of action | Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression). |
| Absorption |
In healthy subjects, the administration of escalating ASTAGRAF XL doses ranging from 1.5 mg to 10 mg resulted in dose-proportional increases in tacrolimus AUC and C24h, and no change in elimination half-life. Chronopharmacokinetic Effect In 23 healthy subjects, a diurnal effect on the absorption of tacrolimus was observed. Evening dosing of ASTAGRAF XL reduced AUCinf by 35% relative to morning dosing. ASTAGRAF XL capsules should be taken consistently at the same time every morning. |
| Food Effect | The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions. In 24 healthy subjects, administration of ASTAGRAF XL immediately following a high-fat meal (150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories) reduced the Cmax, AUCt, and AUCinf of tacrolimus by approximately 25% compared with fasting values. Food delayed the median Tmax from 2 hours in the fasted state to 4 hours in the fed state; however, the terminal half-life remained 36 hours regardless of dosing conditions. The time when a meal is consumed also affected tacrolimus bioavailability. In 24 healthy subjects, when ASTAGRAF XL was administered 1.5 hours after consumption of a high-fat breakfast, tacrolimus exposure was decreased approximately 35%. Administration of ASTAGRAF XL 1 hour prior to a high-fat breakfast reduced tacrolimus exposure by 10%. ASTAGRAF XL capsules should be taken preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal. |
| Distribution | The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial in which tacrolimus was administered as tacrolimus immediate-release, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67) |
| Metabolism |
The desired pharmacological activity of tacrolimus is primarily due to the parent drug. Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. |
| Elimination | In a mass balance study of orally-administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered. The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg. The elimination half-life of tacrolimus after oral administration of 4 mg ASTAGRAF XL daily for 10 days was 38 ± 3 hours in 24 healthy subjects. |
| Peak plasma time (Tmax) | 2 hours |
| Half life | Based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations |
| Bioavailability | - |
| Age, gender | A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted; however, there was no difference in total mg daily dosages between male and female patients receiving ASTAGRAF XL in the kidney transplant trials. A retrospective comparison of pharmacokinetics in healthy subjects, and in kidney transplant patients indicated no gender-based differences. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 18442 | A | II | June 21, 2005 | BIOCON LTD |
| 18908 | A | II | October 24, 2005 | CONCORD BIOTECH LTD |
| 18985 | A | II | November 28, 2005 | CHUNGHWA CHEMICAL SYNTHESIS AND BIOTECH CO LTD |
| 19072 | I | II | December 22, 2005 | ZHEJIANG HISUN PHARMACEUTICAL CO LTD |
| 19979 | A | II | November 20, 2006 | LEK PHARMACEUTICALS DD |
| 20390 | I | II | March 26, 2007 | HANGZHOU HUADONG MEDICINE GROUP BIOTECHNOLOGY INSTITUTE CO LTD |
| 21332 | A | II | February 12, 2008 | DR REDDYS LABORATORIES LTD |
| 21808 | A | II | July 16, 2008 | CHEMWERTH INC |
| 22254 | I | - | November 20, 2008 | ANTIBIOTICOS SPA |
| 23213 | A | II | October 26, 2009 | CHUNGHWA CHEMICAL SYNTHESIS AND BIOTECH CO LTD |
| 23365 | A | II | December 8, 2009 | BIOCON LTD |
| 27202 | A | II | June 27, 2013 | HISUN PHARMACEUTICAL HANGZHOU CO LTD |
| 27626 | A | II | September 23, 2013 | MURLI KRISHNA PHARMA PVT LT |
| 28065 | A | II | March 17, 2014 | APOTEX FERMENTATION INC |
| 28524 | A | II | August 24, 2014 | TEVA PHARMACEUTICAL INDUSTRIES LTD |
| 29786 | A | II | September 24, 2015 | BIOCON LTD |
| Parameters | Details | |||
|---|---|---|---|---|
| Strength | 1 MG | 5 MG | 0.5 MG | |
| Excipients used | Ethylcellulose NF, hypromellose USP, magnesium stearate NF and lactose monohydrate NF (102.17 mg). The ingredients are directly proportional across all capsule strengths | Ethylcellulose NF, hypromellose USP, magnesium stearate NF and lactose monohydrate NF (510.9 mg). The ingredients are directly proportional across all capsule strengths | Ethylcellulose NF, hypromellose USP, magnesium stearate NF and lactose monohydrate NF (51.09 mg). The ingredients are directly proportional across all capsule strengths | |
| Composition of coating material | - | |||
| Composition of caspule shell |
Gelatin NF, titanium dioxide USP, ferric oxide NF, and sodium lauryl sulfate. The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total printing ink composition). |
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| Pharmaceutical Development |
Advagraf capsules have been developed to provideonce a day dosing with similar safety and efficacy profiles to the current twice a day formulation ofPrograf(t) capsules. Based on the composition of Prograf(t) capsules, a granule formulation has been developed to prolong the drug release profile of tacrolimus. Initial investigations led to two possibilities, i.e.the hypromellose system, which modifies the drug release profile by forming a polymer gel layer, and the ethylcellulose diffusion matrix system, which modifies the release profile by controlling water penetration and thus drug release. The objective was to achieve 90% drug release at 6 to 12 hours. Two formulations that showed the best dissolution characteristics (Prototype 3 and 4) were promoted for further development. Hypromellose is known to increase oral absorption in the GIT of poorly soluble drugs so it was decided a small amount to be added and investigate its effect on the drug release (Prototype 5). Formulations with hypromellose displayed better overall dissolution characteristics, and therefore, hypromellose became part of the granule formulation. Five further prototype formulations were investigated with varying ethylscellulose, hypromellose and lactose monohydrate concentrations. Formulations designated MR4 and MR3 respectively were selected for a single-dose biopharmaceutics study (99-0-060), while it had been demonstrated that the release profiles of these two formulations were not affected by the dissolution conditions. The biopharmaceutics study showed that MR4 exhibits similar AUC and equal or reduced Cmax compared to immediate release Prograf(t) capsules,thus it was selected for further development. Subsequently, the amount of lactose monohydrate and magnesium stearate of the final blend for MR4 prototype capsules was optimized for the three strengths 0.5 mg, 1 mg and 5 mg. The excipient drug substance ratio is identical for all three capsulestrengths, and the only differences being the filling amount into the capsule and the capsule size. One batch of each strength was prepared and used in single dose bioequivalence study and dissolution comparisons. The dissolution curves of the three capsule strengths have been shown to be very similar. The same quantitative composition has been used for all clinical batches, stability batches and proposed commercial production batches. With regard to the drug substance, there were no particle size considerations as it is dissolved in ethanol during the manufacturing process. However, the influence of kneading time and particle size distribution of intermediate granules on the dissolution profile was investigated, and a particle size specification has been established for the intermediate granules. In addition, the influence of drying temperature, thickness of the paste on the drying tray on dissolution characteristics, residual solvent and related substances levels was investigated. Finally, the influence of the rotating speed of the blender and the blending time on content uniformityand dissolution profile was investigated but neither of them was found to affect these parameters. All excipients are well established and commonly usedexcipients in the manufacture of solid oral dose forms and are described in harmacopoeia. The compatibility of the tacrolimus with the excipients has been studied and deemed established. The final dosage form is an oral capsule, which is formulated to achieve prolonged release in order to allow a once daily dosage. |
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| Manufacture of the product | The manufacturing process consists of two distinct processes: i) granule manufacture by wet granulation and ii) capsule filling. Tacrolimus is granulated with dehydrated ethanol, ethylcellulose, hypromellose and lactose monohydrate. The resulting paste undergoes drying and sizing to produce intermediate granules. The granules are then mixed with lactose monohydrate and magnesium stearate and that mixture is filled into capsules. | |||
| Tablet / Capsule Image |
/1 MG.jpg)
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/5 MG.jpg)
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| Appearance | Gelatin capsules imprinted in red with “1 mg” on the white capsule cap and “* 677” on the orange capsule body, containing white powder. | Gelatin capsules imprinted in red with “5 mg” on the greyish red capsule cap and ”* 687” on the orange capsule body, containing white powder. | Gelatin capsules imprinted in red with “0.5 mg” on the light yellow capsule cap and “*647” on the orange capsule body, containing white powder. | |
| Imprint code / Engraving / Debossment | Branded with red “ *677” on capsule body and “1 mg” on capsule cap | Branded with red “ * 687” on capsule body and “5 mg” on capsule cap | Branded with red “ * 647” on capsule body and “0.5 mg” on capsule cap. | |
| Score | No Score | No Score | No Score | |
| Color | White cap and orange body | Grayish-red cap and orange body | Light yellow cap and orange body | |
| Shape | Oblong capsule | Oblong capsule | Oblong capsule | |
| Dimension | 14 mm | 22 mm | 11 mm | |
| Mfg by | Astellas Ireland Co., Limited (US) | |||
| Mfg for | - | |||
| Marketed by |
Astellas Pharma US, Inc. (US) Astellas Pharma Europe B.V (EU) |
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| Distributed by | - | |||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| (NDA) 204096 | 1 | 6440458 | March 25, 2019 | - | DP | - | - | Download |
| (NDA) 204096 | 1 | 6576259 | March 25, 2019 | - | DP | U-1420 | - | Download |
| (NDA) 204096 | 1 | 6884433 | March 25, 2019 | - | DP | U-1420 | - | Download |
| (NDA) 204096 | 1 | 8551522 | March 25, 2019 | - | DP | - | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| Not Available | |||||
| 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 | Advagraf | Download |
| UK | Advagraf | Download |
| US | ASTAGRAF XL | Download |
| Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment used to prepare a suspension of Advagraf capsule contents must not contain PVC. Tacrolimus CAPSULE 3 MG , EXTENDED RELEASE;ORAL is marketed in EU. |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
