| Active Ingredient | LEVETIRACETAM (TABLET, FOR SUSPENSION) |
|---|
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SPRITAM | (NDA) 207958 | APRECIA PHARMS CO | TABLET, FOR SUSPENSION;ORAL | 250MG , 500 MG, 750 MG, 1 G | 1 G | July 31, 2015 | _ | _ | 3 New dosage form | P Priority 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 | SPRITAM is indicated for adjunctive therapy in the treatment of: Partial onset seizures in patients with epilepsy 4 years of age and older weighing more than 20 kg Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy |
| Dosage and Administration |
SPRITAM is intended to disintegrate inthe mouth when taken with a sip of liquid. Swallow only after the tablet disintegrates. Do not swallow tablet(s) intact. Partial tablet(s) should not be administered Alternately, add whole SPRITAM tablet(s) to a small volume of liquid in a cup (one tablespoon or enough to cover the medicine). Allow the tablet(s) to disperse prior to consuming entire contents immediately Partial Onset Seizures Adults/pediatric patients 4 years and older weighing over 40 kg: 500 mg twice daily; increase as needed/tolerated by 500 mg twice daily every 2 weeks to a maximum recommended dose of 1500 mg twice daily Pediatric patients 4 years and older weighing 20 to 40 kg: 250 mg twice daily; increase by 250 mg twice daily every two weeks to a maximum of 750 mg twice daily Myoclonic Seizures in Adults and Pediatric Patients 12 Years of Age and Older 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily Primary Generalized Tonic-Clonic Seizures in Patients 6 Years of Age and Older Adults/pediatric patients 6 years and older weighing over 40 kg: 500 mg twice daily; increase as needed/tolerated by 500 mg twice daily every 2 weeks to a maximum recommended dose of 1500 mg twice daily (2.4) Pediatric patients 6 years and older weighing 20 to 40 kg: 250 mg twice daily; increase by 250 mg twice daily every 2 weeks to a maximum of 750 mg twice daily Adult Patients with Renal Impairment Dose adjustment is recommended based on creatinine clearance |
| 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 | Peak plasma concentrations of levetiracetam occurred in about an hour following oral administration in fasted subjects. In a crossover study in healthy volunteers, SPRITAM, administered with a sip of water, was shown to have equivalent rate and extent of absorption to levetiracetam immediate release tablets, administered with a glass of water under fasting conditions. The oral bioavailability of levetiracetam tablets is 100% and the tablets and oral solution are bioequivalent in rate and extent of absorption. Food does not affect the extent of absorption of levetiracetam but it decreases Cmaxby 20% and delays tmaxby 1.5 hours. The pharmacokinetics of levetiracetam are linear over the dose rangeof 500-5000 mg. |
| Food Effect | High fat meal does not affect the extent of absorption of SPRITAM but it decreases Cmaxby 36% and delays tmaxby 3.4 hours. |
| Distribution | Steady state is achieved after 2 days of multiple twice-daily dosing. Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely. |
| 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 of levetiracetam or its major metabolite. |
| Elimination | Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose or repeated 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 0.96mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with renal impairment |
| Peak plasma time (Tmax) | 1 hours |
| Half life | 7 ± 1 hour |
| Bioavailability | 100% |
| Age, gender | Levetiracetam Cmaxand AUC were 20% higher in women (N=11) 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 | 250 MG | 750 MG | 500 MG | 1 G | |
| Excipients used | Colloidal silicon dioxide, glycerin, mannitol, microcrystalline cellulose, polysorbate 20, povidone, sucralose, butylated ydroxyanisole, and natural and artificial spearmint flavor | ||||
| Composition of coating material | - | ||||
| Composition of caspule shell | - | ||||
| Pharmaceutical Development |
SPRITAM tablets for oral suspension are unitary porous structuresproduced by a three-dimensional printing process that binds the powders without compression. SPRITAM tablets for oral suspension disintegratein a mean time of 11 seconds (ranging from 2 to 27 seconds) in the mouth, when taken with a sip of liquid, to produce small particles that may be swallowed. |
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| Manufacture of the product | SPRITAM tablets for oral suspension are unitary porous structuresproduced by a three-dimensional printing process that binds the powders without compression | ||||
| Tablet / Capsule Image |
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| Appearance | Round, white to off-white, spearmint-flavoredtablets, marked with “ ô ”on one side | Round, white to off-white, spearmint-flavoredtablets, marked with “E ”on one side | Round, white to off-white, spearmint-flavoredtablets, marked with “Û ”on one side | Round, white to off-white, spearmint-flavoredtablets, marked with “ L”on one side | |
| Imprint code / Engraving / Debossment | Marked with “ ô ”on one side | Marked with “E ”on one side | Marked with “Û ”on one side | Marked with “ L”on one side | |
| Score | No Score | No Score | No Score | No Score | |
| Color | White to off-white | White to off-white | White to off-white | White to off-white | |
| Shape | Round | Round | Round | Round | |
| Dimension | 13 mm | 19 mm | 17 mm | 21 mm | |
| Mfg by | Aprecia Pharmaceuticals Company (US) | ||||
| Mfg for | - | ||||
| 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) 207958 | 1 | 6471992 | February 20, 2018 | - | 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) | |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | |
| European Public Assessment Report |
| SPRITAM is an oral prescription medicine that is approved for the treatment of certain types of epileptic seizures. SPRITAM is an adjunctive therapy, which means it is taken in addition to other epilepsy medications. There are many types of epilepsy treatments. However, SPRITAM is the first and only medicine made using 3D printing. You may find that SPRITAM is surprisingly easy to take. |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
