| Active Ingredient | LEVETIRACETAM (TABLET, 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| KEPPRA XR | (NDA) 022285 | UCB INC | TABLET, EXTENDED RELEASE;ORAL | 500 MG, 750 MG | 750 MG | September 12, 2008 | _ | _ | 3 New dosage form | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
/Structural_Formula.jpg) |
| Chemical Name | (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide |
| CAS No | 102767-28-2 |
| Molecular Formula | C8H14N2O2 |
| Molecular Weight | 170.21 |
| Appearance | White to off-white crystalline powder with a faint odor and a bitter taste |
| Solubility | Freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent). |
| Water Solubility | Very soluble in water (104.0 g/100 mL) |
| Polymorphism | - |
| pKa (Strongest Acidic) | 16.09 (Predicted) |
| pKa (Strongest Basic) | -1.6 (Predicted) |
| Log P | -0.6 |
| Identification | - |
| Degradation | - |
| Hygroscopic | Non-hygroscopic |
| Photostability study | - |
| Melting Point | 112 - 115 |
| BCS Class | I |
| Manufacture of API | - |
| Parameters | Details |
|---|---|
| Indications and Usage | KEPPRA XR is indicated for adjunctive therapy in the treatment of partial onset seizures in patients 12 years of age and older with epilepsy |
| Dosage and Administration |
Initiate treatment with a dose of 1000 mg once daily; increase by 1000 mg every 2 weeks to a maximum recommended dose of 3000 mg once daily See full prescribing information for use in patients with impaired renal function |
| Mechanism of action |
The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures. Levetiracetam did not inhibit single seizures inducedby maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests. Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain. In vitroand in vivorecordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity. Levetiracetam at concentrations of up to 10 μM did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gammaaminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second messenger systems. Furthermore, in vitrostudies have failed to find aneffect of levetiracetam on neuronal voltage-gated sodium or T- type calcium currents and levetiracetam does not appear to directly facilitate GABAergicneurotransmission. However, in vitrostudies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-typecalcium currents in neuronal cells. A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated withthe potency of their antiseizure activity in audiogenic seizure-prone mice. These findingssuggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug. |
| Absorption |
Extended-release levetiracetam peak plasma concentrations occur in about 4 hours. The time to peak plasma concentrations is about 3 hours longer with extended-release levetiracetam than with immediate-release tablets. Single administration of two 500 mg extended-release levetiracetam tablets once daily produced comparable maximal plasma concentrations and area under the plasma concentration versus time as did the administration of one 500 mg immediate-release tablet twice daily in fasting conditions. After multiple dose extended-release levetiracetam tablets intake, extent of exposure (AUC0-24) was similar to extent of exposure after multiple dose immediate-release tablets intake. Two 750 mg extended-release levetiracetam tablets were bioequivalent to a single administration of three 500 mg extended-release levetiracetam tablets. |
| Food Effect | Cmaxand Cminwere lower by 17% and 26% after multiple dose extended-release levetiracetam tablets intake in comparisonto multiple dose immediate-release tablets intake. Intake of a high fat, high calorie breakfast before the administration ofextended-release levetiracetam tablets resulted in a higher peak concentration, and longer median time topeak. The median time to peak (Tmax) was 2 hours longer in the fed state. |
| Distribution | - |
| Metabolism | Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion oflevetiracetam or its major metabolite. |
| Elimination | Levetiracetam plasma half-life in adults is 7 1 hour and is unaffected by either dose orrepeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtrationwith subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted byglomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance isreduced in patients with impaired renal function |
| Peak plasma time (Tmax) | 4 hours,The median time to peak (Tmax) was 2 hours longer in the fed state. |
| Half life | 7 1 hour |
| Bioavailability | 100% |
| Age, gender | Extended-release levetiracetam Cmaxwas 21-30% higher and AUC was 8-18% higher in women (N=12) compared to men (N=12). However, clearances adjusted for body weight were comparable. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 16894 | A | II | October 5, 2003 | DIVIS LABORATORIES LTD |
| 16966 | A | II | November 17, 2003 | DR REDDYS LABORATORIES LTD |
| 17327 | A | II | April 26, 2004 | ESTEVE QUIMICA SA |
| 17738 | A | II | October 7, 2004 | HETERO LABS LTD |
| 17799 | A | II | November 2, 2004 | NEULAND LABORATORIES LTD |
| 19033 | A | II | December 15, 2005 | TEVA PHARMACEUTICAL INDUSTRIES LTD |
| 19051 | I | II | December 19, 2005 | RANBAXY LABORATORIES LTD |
| 19080 | A | II | December 30, 2005 | LUPIN LTD |
| 19104 | I | II | January 10, 2006 | HIKAL LTD |
| 19387 | A | II | April 18, 2006 | AUROBINDO PHARMA LTD |
| 19738 | I | II | August 31, 2006 | CAMBREX CHARLES CITY INC |
| 19747 | A | II | September 11, 2006 | ORCHID CHEMICALS AND PHARMACEUTICALS LTD |
| 20412 | A | II | April 4, 2007 | SIGNA SA DE CV |
| 21122 | I | II | November 26, 2007 | ALEMBIC PHARMACEUTICALS LTD |
| 21201 | A | II | December 20, 2007 | MYLAN LABORATORIES LTD |
| 21414 | A | II | March 5, 2008 | SUN PHARMACEUTICAL INDUSTRIES LTD |
| 21743 | I | II | June 27, 2008 | WANBURY LTD |
| 21747 | A | II | June 27, 2008 | ZACH SYSTEM SPA |
| 21837 | A | II | July 28, 2008 | ESTEVE QUIMICA SA |
| 22235 | A | II | November 21, 2008 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD |
| 23585 | I | II | March 2, 2010 | AMOLI ORGANICS PVT LTD |
| 23853 | A | II | June 2, 2010 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD |
| 24200 | A | II | October 28, 2010 | JUBILANT GENERICS LTD |
| 24757 | A | II | March 15, 2011 | SRINI PHARMACEUTICALS LTD |
| 25005 | A | II | May 19, 2011 | ZHEJIANG APELOA JIAYUAN PHARMACEUTICAL CO LTD |
| 25120 | A | II | June 30, 2011 | SECOND PHARMA CO LTD |
| 25762 | A | II | February 8, 2012 | AMOLI ORGANICS PVT LT |
| 26194 | A | II | June 25, 2012 | WATERSTONE PHARMACEUTICALS HUBEI CO LTD |
| 26500 | A | II | September 27, 2012 | STRIDES SHASUN LTD |
| 27458 | A | II | September 6, 2013 | CTX LIFE SCIENCES PVT LTD |
| 28431 | A | II | June 30, 2014 | SMS PHARMACEUTICALS LIMITED |
| 30119 | A | II | December 23, 2015 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD |
| 30185 | A | II | January 8, 2016 | DIVIS LABORATORIES LTD |
| 30626 | A | II | June 27, 2016 | HETERO LABS LTD |
| Parameters | Details | ||
|---|---|---|---|
| Strength | 750 MG | 500 MG | |
| Excipients used |
Colloidal anhydrous silica, hypromellose, magnesium stearate, polyethylene glycol 6000 |
||
| Composition of coating material |
Polyvinyl alcohol-partially hydrolyzed, titanium dioxide (E171), Macrogol/PEG3350, and talc. The imprinting ink contains shellac, FD&C Red #40, n-butyl alcohol, propylene glycol, titanium dioxide, ethanol, and methanol. |
||
| Composition of caspule shell | - | ||
| Pharmaceutical Development | - | ||
| Manufacture of the product | - | ||
| Tablet / Capsule Image |
/750 MG.jpg)
|
/500 MG.jpg)
|
|
| Appearance | White, oblong-shaped, film-coated tablets imprinted with “UCB 750XR” in red on one side | White, oblong-shaped, film-coated tablets imprinted with “UCB 500XR” in red on one side | |
| Imprint code / Engraving / Debossment | Imprinted with “UCB 750XR” in red on one side | Imprinted with “UCB 500XR” in red on one side | |
| Score | No score | No score | |
| Color | White | White | |
| Shape | Oblong-shaped | Oblong-shaped | |
| Dimension | 19 mm | 19 mm | |
| Mfg by | - | ||
| Mfg for | UCB, Inc. (US) | ||
| Marketed by | - | ||
| Distributed by | - | ||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| (NDA) 022285 | 1 | 7858122 | September 17, 2028 | - | DP | - | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| - | - | - | - | - | |
| I (Basket) | 50 | 0.05 M Phosphate Buffer, pH 6.0 | 900 | 1, 2, 4, 6, 8 and 12 hours | April 2, 2009 |
| 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 |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | - | |
| UK | - | |
| US | ACTAVIS ELIZABETH* | |
| US | ACTAVIS LABS FL INC* | |
| US | ANCHEN PHARMS* | |
| US | APOTEX INC* | |
| US | APOTEX INC* (1 mg) | Download |
| US | DEXCEL PHARMA* | |
| US | INTELLIPHARMACEUTICS* | |
| US | KEPPRA XR | Download |
| US | LOTUS PHARM CO LTD* | |
| US | LUPIN LTD* | |
| US | MYLAN PHARMS INC* | |
| US | NOSTRUM LABS INC | |
| US | PAR PHARM* | |
| US | PHARMADAX INC* | |
| US | PRINSTON INC* | |
| US | ROUSES POINT PHARMS* | |
| US | SUN PHARM INDS* | |
| US | SUN PHARMA GLOBAL* | |
| US | TEVA PHARMS* | |
| US | TORRENT PHARMS LTD* | |
| US | VINTAGE PHARMS LLC* |
| The medication is combined with a drug release controlling polymerthat provides a drug release at a controlled rate. The biologically inert components of the tablet may occasionallyremain intact during GI transit and will be eliminatedin the feces as a soft, hydrated mass. |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
