Formulations Of Levetiracetam Research Articles

Shortages of antiseizure medications in Australia and the association with patient switching, and adherence in a community setting

PurposeTo quantify sponsor-reported shortages of oral antiseizure medications in Australia, estimate the number of patients impacted, and the association between shortages and brand or formulation switching, and changes in adherence. MethodsA retrospective cohort study of sponsor-reported shortages (defined as where the supply of a medicine will not or will not be likely to meet the demand over a 6-month period) of antiseizure medications reported to the Medicine Shortages Reports Database (Therapeutic Goods Administration, Australia); cross-referencing shortages to the IQVIA-NostraData Dispensing Data (LRx) database, a deidentified, population-level dataset collecting longitudinal dispensation data on individual patients from ∼75% of Australian community pharmacy scripts. ResultsNinety-seven sponsor-reported ASM shortages were identified between 2019 and 2020; of those, 90 (93%) were shortages of generic ASM brands. Of 1,247,787 patients dispensed ≥1 ASMs, 242,947 (19.5%) were impacted by shortages. Sponsor-reported shortages occurred more frequently before the COVID-19 pandemic versus during the pandemic, however, shortages were estimated to affect more patients during the pandemic than before the pandemic. An estimated 330,872 patient-level shortage events were observed, and 98.5% were associated with shortages of generic ASM brands. Shortages occurred at a rate of 41.06 shortages per 100 person-years in patients on generic ASM brands versus 0.83 shortages per 100 person-years in patients on originator ASM brands. In patients taking a formulation of levetiracetam affected by a shortage, 67.6% switched to a different levetiracetam brand or formulation during shortages compared with 46.6% in non-shortage periods. ConclusionsApproximately 20% of patients on ASMs were estimated to have been impacted by an ASM shortage in Australia. The rate of patient-level shortages was approximately 50 times higher for patients on generic ASM brands versus originator brands. Shortages of levetiracetam were associated with formulation and brand switching. Improved supply chain management amongst sponsors of generic ASMs is needed to maintain the continuity of supply in Australia.

A randomized, double-blind, double-dummy, multicenter trial comparing the efficacy and safety of extended- and immediate-release levetiracetam in people with partial epilepsy

PurposeThe aim of this trial was to compare the efficacy and safety of two formulations of levetiracetam in people with partial epilepsy over a 12-week treatment period. MethodsWe performed a randomized, paralleled, and multicenter trial that consisted of a 4-week single-blind placebo run-in, followed by a 12-week double-blind, double-dummy treatment phase to compare the efficacy and safety of levetiracetam extended-release (LEV-ER) and immediate-release (LEV-IR) tablets as an adjunctive treatment in adult patients with uncontrolled epilepsy. ResultsThe median partial-onset seizure (POS) frequency per week (min-max) was 0.3 (0.0, 17.4; 95% confidence interval [95% CI] 1.3, 4.8) in the LEV-ER group and 0.3 (0.0, 31.4; 95% CI − 0.1, 4.3) in the LEV-IR group. No serious adverse events occurred during the trial period. Both groups had the same responder rate (58.6%), while a higher rate of seizure freedom over the treatment period was noted in the LEV-ER group compared with the LEV-IR group (27.6% vs. 13.8%, respectively). The European Quality of Life–5 Dimensions scores significantly increased in the LEV-ER–treated group, in contrast to the scores in the LEV-IR group, which decreased (7.2 vs. − 1.5, p = 0.03). ConclusionThese results suggest that LEV-ER is equivalent to LEV-IR in reducing the frequency of POS and has a similar tolerability as LEV-IR as an add-on therapy. In addition, LEV-ER treatment improved the health-related quality of life of people with uncontrolled partial epilepsy.

Bioequivalence and Safety Profiles of a Novel, Extended-Release, High-Dosage Formulation of Levetiracetam in Healthy Adult Subjects (P5.238)

Bioequivalence and Safety Profiles of a Novel, Extended-Release, High-Dosage Formulation of Levetiracetam in Healthy Adult Subjects (P5.238)

Pharmacokinetic evaluation of immediate- and extended-release formulations of levetiracetam in dogs.

To compare the pharmacokinetics of various formulations of levetiracetam after oral administration of a single dose to healthy dogs. 6 neurologically normal mixed-breed dogs. A crossover study design was used. Blood samples for serum harvest were collected from each dog before and at various points after oral administration of one 500-mg tablet of each of 2 generic extended-release (ER) formulations, 1 brand-name ER formulation, or 1 brand-name immediate-release (IR) formulation of levetiracetam. Serum samples were analyzed to determine pharmacokinetic properties of each formulation by means of ultra-high-performance liquid chromatography with tandem mass spectrometry. No dogs had clinically important adverse effects for any formulation of levetiracetam. All ER formulations had a significantly lower maximum serum drug concentration and longer time to achieve that concentration than did the IR formulation. Half-lives and elimination rate constants did not differ significantly among formulations. Values for area under the drug concentration-versus-time curve did not differ significantly between ER formulations and the IR formulation; however, 1 generic ER formulation had a significantly lower area under the curve than did other ER formulations. All ER formulations of levetiracetam had similar pharmacokinetic properties in healthy dogs, with some exceptions. Studies will be needed to evaluate the clinical efficacy of the various formulations; however, findings suggested that twice-daily administration of ER formulations may be efficacious in the treatment of seizures in dogs.

Pharmacokinetics of the antiepileptic drug levetiracetam in healthy Japanese and Caucasian volunteers following intravenous administration.

The intravenous (iv) formulation of levetiracetam has been available in clinical practice worldwide for several years, but not in Japan. Two open-label studies were conducted: Study A evaluated the bioequivalence of iv and oral tablet formulations in healthy Japanese volunteers; and Study B subsequently compared the pharmacokinetics of iv levetiracetam in healthy Japanese and Caucasian volunteers. Study A had a randomised, two-way crossover design; a single 1,500mg levetiracetam dose was administered as a 15-min iv infusion and as 3×500mg oral tablets to Japanese volunteers. In Study B, 1,500mg levetiracetam was administered as single and repeated 15-min iv infusions to Japanese and Caucasian volunteers. Overall, 26/27 volunteers completed Study A and 32/32 (16 Japanese; 16 Caucasian) completed Study B. In Study A, the point estimate and 90% confidence interval (CI) for the geometric least squares mean (LSM) ratio (iv vs oral) were fully included within the acceptance range for bioequivalence (0.85-1.25) for the area under plasma concentration-time curve from 0 to last quantifiable observation (AUClast 0.97 [0.95, 0.99]), but not for the maximum plasma concentration (C max 1.64 [1.47, 1.83]). In Study B, after a single iv infusion, the point estimates (90% CI) for the geometric LSM ratio (Japanese vs Caucasian) for body weight-normalised C max and AUClast were 1.21 (1.07, 1.36) and 0.97 (0.90, 1.04), respectively. Corresponding values after repeated iv infusions were C max,ss 1.01 (0.91, 1.12) and AUCτ,ss 0.89 (0.83, 0.96). Levetiracetam was well tolerated in both studies. Study A did not demonstrate the bioequivalence of single doses of levetiracetam 1,500mg administered as an iv infusion and as oral tablets in healthy Japanese adults. Study B, however, showed that pharmacokinetic profiles were generally similar between Japanese and Caucasian adults after single and repeated iv infusions of levetiracetam 1,500mg.

Stability of levetiracetam oral solution repackaged in oral plastic syringes

The long-term stability of levetiracetam solution in oral syringes was investigated in order to define a suitable beyond-use date and demonstrate the feasibility of storing prepared syringes for extended periods as an alternative to commercial levetiracetam unit dose cups. Levetiracetam oral solution (100 mg/mL) was drawn into 1- and 10-mL amber polypropylene oral syringes. Triplicate samples of the syringe preparations were stored at refrigeration (2-8 °C) or room temperature (20-25 °C) and evaluated at monthly intervals for up to six months. At each time point, the samples were visually inspected and levetiracetam stability was assessed via pH measurement and high-performance liquid chromatography (HPLC). A short-term forced degradation study was conducted to confirm that the HPLC assay method was stability indicating. Over the six-month storage period, there was no significant change in either the visual appearance or pH of any of the levetiracetam samples. The results of serial HPLC assessment indicated that at least 97% of the initial levetiracetam concentration was retained in all samples of 1- and 10-mL oral syringes at both refrigeration and room temperature. Although this study was conducted using a generic product, the stability data obtained may be applied in repackaging decisions regarding other generic formulations of levetiracetam with similar excipient compositions. Commercial levetiracetam 100-mg/mL oral solution was stable for up to six months in amber polypropylene oral syringes stored at both refrigeration and room temperature conditions.

Formulation and Evaluation of Levetiracetam Extended Release Tablets

Extended release formulation of levetiracetam is approved by the food and drug administration as an add-on to other antiepileptic drugs for adults with partial onset seizures. The main objective of present study was to developed and evaluate matrix tablet of levetiracetam by using various grade of hydroxypropylmethylcellulose (HPMC) polymer. Various trials were taken by using HPMC K4M, K15M, and K100M. Different parameters like Physical properties, FTIR, DSC, in vitro drug release profile and swelling index were determined. In vitro drug release was performed in phosphate buffer pH 6.8. The in vitro release profile was compared with model independent method. Stability studies were performed as per ICH guidelines for 1 month at (40 °C ± 2 °C/75 % ± 5 % RH).Data analysis was performed for determination of drug mechanism and order of drug release. The in vitro drug release profile of optimized formulation was compared with marketed formulation LEVERAXR. The regression value for zero order, first order, Higuchi and Korsmeyer Peppas was found to be 0.9604, 0.9245, 0.9889 and 0.9729, respectively. Similarity factor (f2) and dissimilarity factor (f1) was found to be 88.61 and 1.82, respectively. The FTIR and DSC study shows that there is no chemical interaction between levetiracetam and excipients. From the data analysis, it was concluded that optimized formulation follow Higuchi model having diffusion mechanism. The order of drug release was considered zero order release. Stability study shows that there was no remarkable change in drug release after 1 month. It is concluded that the formulation is stable at accelerated conditions.

Bioequivalence of a Novel Minitablet Formulation of Levetiracetam

To investigate whether rapidly dissolving levetiracetam minitablets are bioequivalent to a single tablet of the same strength. 2 bioequivalence studies were carried out investigating the 1 000 mg and 1 500 mg strength of such novel medicinal products relative to single-unit film-coated originator tablets for reference. In each study, 16 young healthy subjects (8 males, 8 females) were investigated according to a 2,2,2-cross-over design with 1 week between periods for washout purposes. Each time, the plasma pharmacokinetics were profiled for 36 h after dosing.There were no relevant differences between the formulations with regard to tmax, apparent terminal half-life and the mean residence time. For the 1 000 mg strength, the estimated ratios of the true treatment means for test to reference were 1.008 (90% CI: 0.897-1.133), 1.010 (90% CI: 0.964-1.057), and 1.012 (90% CI: 0.965-1.062) for Cmax, AUC(0-tz), and AUC(0-∞), respectively; for the 1 500 mg strength, the respective ratio estimates were 0.960 (90% CI: 0.892-1.034), 1.005 (90% CI: 0.971-1.040), and 1.006 (90% CI: 0.970-1.042).Rapidly dissolving levetiracetam minitablets are bioequivalent with the originator single-unit reference tablets. Such alternative medicinal products make it easier and more convenient to individualise treatment of patients with epilepsy eligible to treatment with levetiracetam, particularly at higher doses when single-unit tablets, by being very large are difficult to swallow.

Levetiracetam Extended Release as Adjuvant Therapy for the Control of Partial-onset Seizures

Extended release (XR) formulation of levetiracetam (LEV) is approved by the Food and Drug Administration as an add-on to other antiepileptic drugs (AEDs) for adults with partial onset seizures. This is based on class-I evidence demonstrating significant seizure reduction in once daily dosing. Keppra-XR is marketed with the brand name of Keppra XR since 2008 (UCB Pharma). Its original immediate release (IR) formulation has been in the market since 2000. LEV has a unique molecular structure which is chemically unrelated to existing AEDs. The precise mechanism of action is unknown. Animal studies showed binding to synaptic vesicle protein SV2A, thought to be involved in modulating synaptic neurotransmitter release. LEV-IR is proven effective as adjunctive therapy for partial-onset seizures, primary generalized tonic-clonic seizures and myoclonic seizures. It was shown to be equivalent to carbamazepine as first-line treatment for partial-onset seizures. The extended release formulation added advantages such as better tolerance and increased compliance.

Seizure risk in brain tumor patients with conversion to generic levetiracetam

Breakthrough seizure activity has been reported with conversion from brand name to generic anticonvulsants. This has prompted several organizations to support physician notification of generic substitution and patient consent. Recently, a generic formulation of levetiracetam has become available. Risk of seizures with generic levetiracetam has yet to be reported. Literature was reviewed regarding risk of generic substitution. Four cases of seizure activity in primary brain tumor patients after conversion from Keppra to generic levetiracetam are reported. In all cases, there was no evidence of tumor growth or concurrent illness that would increase the risk of seizures. In three cases, the patients have remained seizure free with conversion back to Keppra. The final patient required an increased dose of levetiracetam. As has been described with generic substitution of other anticonvulsants, patients switched to generic levetiracetam may be at risk for breakthrough seizure activity.

Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures

Levetiracetam is a second-generation antiepileptic drug (AED) with a unique chemical structure and mechanism of action. The extended release formulation of levetiracetam (Keppra XR(); UCB Pharma) was recently approved by the Food and Drug Administration for adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. This approval is based on a double-blind, randomized, placebo-controlled, multicenter, multinational trial. Levetiracetam XR allows for once-daily dosing, which may increase compliance and, given the relatively constant plasma concentrations, may minimize concentration-related adverse effects. Levetiracetam's mode of action is not fully elucidated, but it has been found to target high-voltage, N-type calcium channels as well as the synaptic vesicle protein 2A (SV2A). Levetiracetam has nearly ideal pharmacokinetics. It is rapidly and almost completely absorbed after oral ingestion, is <10% protein-bound, demonstrates linear kinetics, is minimally metabolized through a pathway independent of the cytochrome P450 system, has no significant drug-drug interactions, and has a wide therapeutic index. The most common reported adverse events with levetiracetam XR were somnolence, irritability, dizziness, nausea, influenza, and nasopharyngitis. Levetiracetam XR provides an efficacious and well-tolerated treatment option for adjunctive therapy in the treatment of partial-onset seizures.

Two years of experience in the treatment of status epilepticus with intravenous levetiracetam

Since its introduction in 2006, 43 patients with various forms of status epilepticus (SE) have been treated with the intravenous formulation of levetiracetam (LEV) in our clinic. After ineffective treatment with benzodiazepines, intravenous LEV was administered as a short infusion (nonconvulsive and subtle SE) at a dose of 1000 or 2000 mg. In cases of convulsive SE, a fractionated injection of 1000 or 2000 mg was used. When the results for both are combined, SE could be terminated in 19 of 43 patients. Intravenous LEV was more effective in simple focal SE (3/5), complex focal SE (11/18) and myoclonic status (2/2) than in nonconvulsive (2/8) and subtle (1/2) SE. In no case was (secondarily) generalized convulsive status epilepticus (0/8) terminated. Intravenous LEV was also well-tolerated when injected in fractionated form. No severe adverse reactions were observed. As a result of this investigation, intravenous LEV in moderate doses may represent an efficacious and well-tolerated alternative for the treatment of focal (simple and complex focal) and myoclonic SE. Further investigations are needed to confirm this assumption as the patient numbers are quite low.

Bioequivalence of two formulations of levetiracetam

This study was conducted in order to compare the bioavailability of two tablet formulations containing 1,000 mg levetiracetam, (S)-a-ethyl-2-oxo-1-pyrrolidine acetamide, 102767-28-2 CAS registry number. 18 healthy subjects were enrolled in a single-center, randomized, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected up to 36.0 hours post-dosing. Levetiracetam levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection, LC-MS/MS method. Pharmacokinetic parameters used for bioequivalence assessment, area under the concentration-time curve from time 0 to time of last non-zero concentration (AUClast) and from time zero to infinitive (AUCinf) and maximum observed concentration (Cmax), were determined from the levetiracetam concentration data using non-compartmental analysis. The 90% confidence intervals obtained by analysis of variance were 88.98 - 108.75% for Cmax, 99.90 - 104.81% for AUClast and 100.11 - 105.23 %for AUCinf this is, within the predefined ranges. Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.

Review: Recent and future advances in the treatment of status epilepticus

Status epilepticus (SE) is one of the most frequent neurological emergencies with an incidence of 20/100,000 per year and a mortality between 3% and 40% depending on etiology, age, SE type and duration. Generalized convulsive forms of SE (GTCSE), in particular, require aggressive treatment. Presently, only 55-80% of cases of GTCSE are controlled by initial therapy. Therefore, there is a need for new options for the treatment of SE. Here we review the current standard treatment including recent advances and provide a summary of preclinical and clinical data regarding treatment options which may become available in the near future. The initial treatment of SE usually consists of a benzodiazepine (preferably lorazepam 0.1 mg/kg) followed by phenytoin or fosphenytoin or valproic acid (where approved for SE therapy). With intravenous formulations of levetiracetam, available since 2006, and lacosamide, which is expected for autumn of 2008, new treatment options have become available, that should be evaluated in prospective controlled trials. If SE remains refractory, the induction of general anaesthesia using propofol, midazolam, thiopental, or pentobarbital is warranted in GTCSE.

Levetiracetam: Past, Present and Future

Levetiracetam is an antiepileptic drug approved for use as an adjunctive agent in partial-onset seizures in adults. This approval was recently extended to children over 4 years of age. Among the currently approved antiepileptic drugs, levetiracetam is unique in its mechanism of action. Its CNS binding site, the synaptic vesicle protein SV2A, was discovered recently. Binding at this site may be important for the antiseizure activity of levetiracetam and the role of this binding site and its modulation by levetiracetam is an area of active research in epilepsy. Levetiracetam is generally safe, has near to ideal pharmacokinetics and does not interact with other medications. The most serious adverse events are behavioral in nature. Recent studies suggest that levetiracetam may be effective in generalized epilepsies, status epilepticus, pain and selected movement disorders. Intriguing studies using the kindling model of epilepsy suggest that levetiracetam may protect against the development of kindling and chronic epilepsy. A parenteral formulation of levetiracetam may soon become available and may lead to larger studies of levetiracetam in status epilepticus.