| Active Ingredient | ARIPIPRAZOLE |
|---|
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ABILIFY | (NDA) 021436 | OTSUKA | TABLET;ORAL | 2 MG, 5 MG, 10 MG, 15 MG, 20 MG, 30 MG | 5 MG and 10 MG | November 15, 2002 | _ | December 12, 2017 | 1 New molecular entity (NME) | S Standard review drug | Prescription | AB |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril |
| CAS No | 129722-12-9 |
| Molecular Formula | C23H27Cl2N3O2 |
| Molecular Weight | 448.38 |
| Appearance | White crystalline powder |
| Solubility | Solubility is pH dependent |
| Water Solubility | Practically insoluble in water |
| Polymorphism | Aripiprazole can exist in several crystalline forms. |
| pKa (Strongest Acidic) | 13.51 (Predicted) |
| pKa (Strongest Basic) | 7.46 (Predicted) |
| Log P | 4.5 |
| Identification | IR, HPLC, and Power X ray diffraction |
| Degradation | - |
| Hygroscopic | Hygroscopic |
| Photostability study | - |
| Melting Point | 139℃ |
| BCS Class | II |
| Manufacture of API | Aripiprazole is synthesised by a 2-step process. In the first step, 7-hydroxy-3,4-dihydro-2(H)-quinolinone is transformed into an intermediate, which is reacted with 1-(2,3-dichlorophenyl) piperazine hydrochloride to obtain aripiprazole. |
| Parameters | Details |
|---|---|
| Indications and Usage | ABILIFY is an atypical antipsychotic. The oral formulations are indicated for: Schizophrenia Acute Treatment of Manic and Mixed Episodes associated with Bipolar Adjunctive Treatment of Major Depressive Disorder Irritability Associated with Autistic Disorder Treatment of Tourette’s disorder The injection is indicated for: Agitation associated with schizophrenia or bipolar mania |
| Dosage and Administration | Oral formulations: Administer once daily without regard to meals (Refer PIL) |
| Mechanism of action | The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unknown. However, the efficacy of aripiprazole could be mediated through a combination of partial agonist activity at D2 and 5-HT1Areceptors and antagonist activity at 5-HT2Areceptors. Actions at receptors other than D2, 5-HT1A, and 5-HT2Amay explain some of the other clinical effects of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors). |
| Absorption | Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurringwithin 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. |
| Food Effect | ABILIFY can beadministered with or without food. Administration of a 15 mg ABILIFY Tabletwith a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed Tmax by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. |
| Distribution | The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 to 30 mg/day aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans. |
| Metabolism | Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. |
| Elimination | Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. |
| Peak plasma time (Tmax) | 3 hours to 5 hours |
| Half life | 146 hours |
| Bioavailability | 87% |
| Age, gender | - |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 15651 | I | II | October 5, 2001 | BRISTOL-MYERS SQUIBB CO |
| 18471 | I | II | June 30, 2005 | DR REDDYS LABORATORIES LTD |
| 18706 | A | II | August 15, 2005 | ERREGIERRE SPA |
| 18774 | A | II | September 13, 2005 | CAMBREX CHARLES CITY INC |
| 19203 | A | II | February 14, 2006 | IND SWIFT LABORATORIES LTD |
| 19554 | A | II | June 28, 2006 | MYLAN LABORATORIES LTD |
| 19682 | I | II | August 11, 2006 | SYNTHON BV |
| 19739 | A | II | August 31, 2006 | JUBILANT GENERICS LTD |
| 19841 | A | II | October 9, 2006 | CADILA HEALTHCARE LTD |
| 19920 | A | II | November 2, 2006 | SANDOZ PRIVATE LTD |
| 19926 | A | II | November 2, 2006 | TEVA PHARMACEUTICAL INDUSTRIES LTD |
| 19949 | A | II | November 6, 2006 | SUN PHARMACEUTICAL INDUSTRIES LTD |
| 19957 | A | II | November 13, 2006 | APOTEX PHARMACHEM INC |
| 19982 | A | II | October 10, 2006 | TAI HENG INDUSTRY CO LTD |
| 20189 | A | II | July 16, 2007 | CIPLA LTD |
| 20464 | I | II | April 12, 2007 | CADILA PHARMACEUTICALS LTD |
| 21937 | A | II | September 20, 2008 | ORCHID CHEMICALS AND PHARMACEUTICALS LTD |
| 22339 | I | II | December 23, 2008 | SMS PHARMACEUTICALS LIMITED |
| 22563 | A | II | February 23, 2009 | HETERO CORPORATE |
| 22825 | A | II | June 1, 2009 | SUVEN LIFE SCIENCES LTD |
| 22889 | A | II | June 24, 2009 | NEULAND LABORATORIES LTD |
| 23300 | A | II | November 18, 2009 | ALEMBIC PHARMACEUTICALS LTD |
| 23314 | A | II | November 27, 2009 | ZAKLADY FARMACEUTYCZNE POLPHARMA SA |
| 24090 | A | II | August 23, 2010 | MSN PHARMACHEM PRIVATE LTD |
| 24098 | A | II | September 2, 2010 | UNICHEM LABORATORIES LTD |
| 24937 | A | II | May 12, 2011 | ULKAR KIMYA SANAYII VE TICARET AS |
| 24997 | A | II | June 7, 2011 | AUROBINDO PHARMA LTD |
| 25347 | A | II | September 16, 2011 | VALDEPHARM STERILE |
| 25472 | A | II | January 10, 2012 | MACLEODS PHARMACEUTICALS LTD |
| 25685 | A | II | December 20, 2011 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD |
| 25996 | A | II | April 24, 2012 | ZHEJIANG JINHUA CONBA BIO PHARM CO LTD |
| 26743 | A | II | February 26, 2013 | WOCKHARDT BIO AG |
| 26921 | A | II | February 26, 2013 | MAPRIMED SA |
| 27909 | A | II | February 13, 2014 | ALKEM LABORATORIES LTDx |
| 28341 | A | II | June 11, 2014 | ZHEJIANG HISUN PHARMACEUTICAL CO LTD |
| 28563 | A | II | September 16, 2014 | TOPHARMAN SHANDONG CO LTD |
| 29135 | A | II | March 31, 2015 | MSN PHARMACHEM PRIVATE LTD |
| 29138 | A | II | March 24, 2015 | AMOLI ORGANICS PVT LTD |
| 29680 | A | II | September 11, 2015 | CADILA PHARMACEUTICALS LTD |
| 29991 | A | II | November 4, 2015 | SMS PHARMACEUTICALS LTD |
| 30120 | A | II | December 14, 2015 | ZCL CHEMICALS LTD |
| CEP/COS ( R0-CEP 2014-011-Rev 00) | - | - | February 17, 2015 | ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. CN 317 024 Linhai |
| CEP/COS (R0-CEP 2013-230-Rev 01) | - | - | April 20, 2016 | PHARMACEUTICAL WORKS POLPHARMA S.A. PL 83-200 Starogard Gdanski |
| CEP/COS (R0-CEP 2013-292-Rev 01) | - | - | February 25, 2016 | ALEMBIC PHARMACEUTICALS LIMITED IN 390 003 Vadodara |
| CEP/COS (R0-CEP 2013-324-Rev 00) | - | - | June 24, 2016 | JUBILANT GENERICS LIMITED IN 571 302 Nanjangud |
| CEP/COS (R0-CEP 2013-330-Rev 00) | - | - | February 18, 2015 | MYLAN LABORATORIES LIMITED IN 502 325 Hyderabad |
| Cep/COS (R0-CEP 2014-188-Rev 00) | - | - | June 21, 2016 | SANDOZ PRIVATE LIMITED IN 402 301 Mahad |
| CEP/COS (R0-CEP 2014-252-Rev 00) | - | - | December 10, 2015 | EGIS Pharmaceuticals PLC HU 1106 Budapest |
| CEP/COS (R0-CEP 2014-285-Rev 00) | - | - | June 27, 2016 | MSN PHARMACHEM PRIVATE LIMITED IN 502 307 Pashamylaram Village |
| Cep/COS(R0-CEP 2013-337-Rev 00) | - | - | September 16, 2015 | AUROBINDO PHARMA LIMITED IN 500 038 Hyderabad |
| CEPCOS (R0-CEP 2015-010-Rev 00) | - | - | April 22, 2016 | Unichem Laboratories Limited IN 400 102 Mumbai |
| JDMF | - | - | Kyongbo Pharmaceutical Co. , Ltd. |
| Parameters | Details | ||||||
|---|---|---|---|---|---|---|---|
| Strength | 5 MG | 10 MG | 30 MG | 20 MG | 15 MG | 2 MG | |
| Excipients used | Cornstarch, hydroxypropyl cellulose, lactose monohydrate (67 mg ), magnesium stearate, and microcrystalline cellulose. | Cornstarch, hydroxypropyl cellulose, lactose monohydrate (62.18 mg), magnesium stearate, and microcrystalline cellulose. | Cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. | Cornstarch, hydroxypropyl cellulose, lactose monohydrate (186.54 mg), magnesium stearate, and microcrystalline cellulose. | Cornstarch, hydroxypropyl cellulose, lactose monohydrate (57 mg), magnesium stearate, and microcrystalline cellulose. | Cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. | |
| Composition of coating material | Indigo carmine aluminium lake | Red iron oxide | - | Yellow iron oxide | - | ||
| Composition of caspule shell | - | ||||||
| Pharmaceutical Development |
Aripiprazole active substance is a white crystalline powder and is practically insoluble in water and its solubility is pH dependent. Therefore, a particle size effect on dissolution of the tablets can be expected. The product development has taken into consideration the physicochemical characteristics of the active drug substance such as poor aqueous solubility, hygroscopic properties, stability, particle size, polymorphism, and biopharmaceutical issues such as dissolution rate. The formulation contains stable, milled crystalline aripiprazole because of the limited solubility in water and the hydrophobic nature of the active substance. Fluid bed wet granulation process was developed as the manufacturing process for the tablets. The excipients included in the formulation were chosen and adjusted in order to achieve a dosage form with an accurate therapeutic onset. The formulation shows a good bioavailability and the results of pharmacokinetic and in vitro studies support the bioequivalence between clinical and commercial tablets. |
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| Manufacture of the product |
The finished product is manufactured in 9 steps: weighing, preparation of binding solution, granulation and drying, sizing, dispersion and blending of colour, lubrication, compression, control and packaging. |
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| Tablet / Capsule Image |
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| Appearance | Blue modified rectangle, tablet marking with “A-007” and “5” | Pink modified rectangle, tablet marking with “A-008” and “10” | Pink round, tablet marking with “A-011” and “30” | White round, tablet marking with “A-010” and “20” | Yellow round, tablet marking with “A-009” and “15” | Green modified rectangle, tablet marking with “A-006” and “2” | |
| Imprint code / Engraving / Debossment | Tabletmarking with “A-007” and “5” | Tablet marking with “A-008” and “10” | Tablet marking with “A-011” and “30” | Tablet marking with “A-010” and “20” | Tablet marking with “A-009” and “15” | Tablet marking with “A-006” and “2” | |
| Score | No score | No score | No score | No score | No score | No score | |
| Color | Blue | Pink | Pink | White | Yellow | Grenn | |
| Shape | Modified rectangle | Modified rectangle | Round | Round | Round | Modified rectangle | |
| Dimension | 8 mm | 8 mm | - | 8 mm | 6 mm | - | |
| Mfg by | Bristol-Myers Squibb S.r.l. (EU) | ||||||
| Mfg for | - | ||||||
| Marketed by | Otsuka Pharmaceutical Europe Ltd (EU) | Not markedt in EU | Otsuka Pharmaceutical Europe Ltd (EU) | Not markedt in EU | |||
| Distributed by | Otsuka Pharmaceutical Company | ||||||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N021436 | 1 | 7053092 | January 28, 2022 | - | - | U - 839 | - | Download |
| N021436 | 1 | 8017615 | June 16, 2024 | - | Y | - | - | Download |
| N021436 | 1 | 8017615*PED | December 16, 2024 | - | - | - | - | Download |
| N021436 | 1 | 8580796 | September 25, 2022 | Y | - | - | - | Download |
| N021436 | 1 | 8580796*PED | March 25, 2023 | - | - | - | - | Download |
| N021436 | 1 | 8642600 | January 28, 2022 | - | - | U - 1492 | - | Download |
| N021436 | 1 | 8642600*PED | July 28, 2022 | - | - | - | - | Download |
| N021436 | 1 | 8642760 | September 25, 2022 | Y | - | - | - | Download |
| N021436 | 1 | 8642760*PED | March 25, 2023 | - | - | - | - | Download |
| N021436 | 1 | 8759350 | March 2, 2027 | - | - | U - 1529 | - | Download |
| N021436 | 1 | 9089567 | January 28, 2022 | - | - | U - 543 | - | Download |
| N021436 | 1 | 9125939 | July 28, 2026 | - | - | U - 1749 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 60 | pH 1.2 USP Buffer (Hydrochloric Acid) (Refer USP) | 900 | 10, 20, 30 and 45 | December 20, 2005 |
| 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 |
|---|---|---|
| Australia | Otsuka Australia Pharmaceutical Pty Ltd (ABILIFY) | |
| Canada | BRISTOL-MYERS SQUIBB CANADA (ABILIFY) | |
| Canada | Pharmascience Inc. (Generic Dossiers Under Development For EU) | |
| EU | ABILIFY | Download |
| South Africa | Bristol-Myers Squibb (Pty) Ltd ( Abilify) | |
| Spain (EU) | Laboratorios Lesvi, S.L. (Dossier Available) | |
| UK | ABILIFY | Download |
| United Kingdom | Macleods Pharmaceuticals Limited ( (Dossier Available)) | |
| US | ABILIFY | Download |
| US | ACCORD HLTHCARE | |
| US | AJANTA PHARMA LTD* | |
| US | ALEMBIC PHARMS LTD* | Download |
| US | AMNEAL PHARMS* | |
| US | APOTEX INC* | |
| US | AUROBINDO PHARMA LTD* | |
| US | BARR LABS INC*(Tentative Approval) | |
| US | HETERO LABS LTD V* | |
| US | MACLEODS PHARMS LTD | |
| US | SCIEGEN PHARMS INC | |
| US | SUN PHARMA GLOBAL*(Tentative Approval) | |
| US | TEVA PHARMS USA* | |
| US | TORRENT PHARMS LTD* |
| M - 137 Exclusivity Expiration on: Jun 9, 2017. I - 700 Exclusivity Expiration on: Dec 12, 2017. Date of first authorisation in EU: 04 June 2004. Date of latest renewal in EU: 04 June 2009. 2 mg and 20 mg tablets are not marketd in EU/UK. |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
