Carbamazepine Form Research Articles

Effect of HPMC on solubility and dissolution of carbamazepine form III in simulated gastrointestinal fluids

The effect of HPMC on solubility and dissolution of carbamazepine form III (CBZ) was investigated in 50% w/w of CBZ form III in HPMC solid dispersion and physical mixture. Powdered samples of CBZ form III, physical mixture, and solid dispersion were characterized for thermal behavior (DSC), crystallinity (PXRD), and compatibility (FT-IR). Solubility and dissolution studies were carried out in different simulated gastrointestinal fluids and de-ionized water. Solubility studies in simulated gastric fluid (SGF) revealed that acidic pH favors formation of CBZ dihydrate.Triton X 100 in blank fast-state simulated gastric fluid (FaSSGF) prevents the formation of CBZ dihydrate in acidic pH. A maximum solubility of 268.77 μg/mL was achieved with fed-state simulated intestinal fluid (FeSSIF). Correlation between solubility and pH could not be established. Both solubility and dissolution studies revealed that HPMC had a profound effect of enhancement of solubility and dissolution of CBZ form III in both physical mixtures and solid dispersions. HPMC prevents the formation of CBZ dihydrate and thereby improves the solubility and dissolution. This was further correlated with results obtained from DSC and XRD. There was no drastic difference in solubility and dissolution of CBZ form III with different media. It was observed that there was no existing relationship between solubility and dissolution of CBZ form III in different media.

Qualitative in situ analysis of multiple solid‐state forms using spectroscopy and partial least squares discriminant modeling

This study used in situ spectroscopy to reveal the multiple solid-state forms that appear during isothermal dehydration. Hydrate forms of piroxicam and carbamazepine (CBZ) were investigated on hot-stage at different temperatures using near-infrared (NIR) and Raman spectroscopy combined with multivariate modeling. Variable temperature X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and Karl Fisher titrimetry were used as reference methods. Partial least squares discriminant analysis (PLS-DA) was performed to qualitatively evaluate the phase transition. It was shown that the constructed PLS-DA models, where spectral differences were directly correlated to solid-state modifications, enabled differentiation between the multiple forms. Qualitative analysis revealed that during dehydration, hydrates, such as CBZ dihydrate, may go through several solid-state forms, which must be considered in quantitative model construction. This study demonstrates that in situ analysis can be used to monitor the dehydration and reveal associated solid-state forms prior to quantification. The utility of the complementary spectroscopic techniques, NIR and Raman, have been shown.

Liquisolid technique for dissolution rate enhancement of a high dose water-insoluble drug (carbamazepine)

Different liquisolid formulations of carbamazepine were accomplished by dissolving the drug in the non-toxic hydrophilic liquids, and adsorbing the solution onto the surface of silica. In order to reduce the amounts of carrier and aerosil in liquisolid formulations, some additives namely polyvinylpyrrolidone (PVP), hydroxypropyle methylcellulose (HPMC) and polyethylene glycol (PEG 35000) were added to liquid medication to increase loading factor. The effects of various ratios of carrier to coating material, PVP concentration, effect of aging and type of the carrier on dissolution rate of liquisolid compacts were studied. X-ray crystallography and differential scanning calorimetery (DSC) were used for evaluation of physicochemical properties of carbamazepine in liquisolid formulations. The results showed that the drug loading factor was increased significantly in the presence of additives. Liquisolid formulations containing PVP as additive, exhibited significantly higher drug dissolution rates compared to the compacts prepared by the direct compression technique. It was shown that microcrystalline cellulose had more liquid retention potential in comparison with lactose, and the formulations containing microcrystalline cellulose as carrier, showed higher dissolution rate. By decreasing the ratio of microcrystalline cellulose to silica from 20 to 10, an improvement in dissolution rate was observed. Further decrease in the ratio of microcrystalline cellulose:silica from 10 to 5 resulted in a significant reduction in dissolution rate. Increasing of PVP concentration in liquid medication caused a dramatic increase in dissolution rate at first 30 min. The results showed that the dissolution rate of liquisolid tablets was not significantly affected by storing the tablets at 25 °C/75% relative humidity for a period of 6 months. The results of DSC and X-ray crystallography did not show any changes in crystallinity of the drug and interaction between carbamazepine and exipients during the process.

Preparation of agglomerated crystals for improving flowability and compactibility of poorly flowable and compactible drugs and excipients

Agglomerates of naproxen, carbamazepine and lactose were developed by two spherical crystallization techniques, i.e., a spherical agglomeration method for carbamazepine and an emulsion diffusion method for naproxen and lactose. Physical characteristics of the crystals were studied for the morphology of crystals using scanning electron microscope, for the identification of polymorphism by X-ray powder diffraction (XRPD) and for thermodynamic properties using differential scanning calorimetery (DSC). The results showed that the flow and packing properties of agglomerates, represented in terms of the angle of repose and changes in tapping density, were much improved by these techniques compared with those of conventional crystals. This may be due to the spherical shape of agglomerated particles, since the area of contact in the powder bed for spherical agglomerates was smaller than that for other crystal shapes. Under static compression the acceptable tablet with a sufficient strength was produced successfully without capping, although the capping occurred with the original unagglomerated crystals. The improved compactibility of agglomerates was attributed to their structural characteristics. Scanning electron microscope showed that the agglomerates were comprised of small crystals and this particular structure was responsible for large relative volumes change which occurred during the early stage of the compression process, as a consequence of fragmentation. XRPD and DSC results showed that during the agglomeration process, naproxen did not undergo any polymorphic changes. XRPD and DSC results for carbamazepine and lactose revealed that during the agglomeration process, carbamazepine Form III changed to Form I and some of α-lactose monohydrates were converted to anhydrous β-lactose.

The influence of various excipients on the conversion kinetics of carbamazepine polymorphs in aqueous suspension

The influence of various excipients on the conversion of carbamazepine polymorphs to the dihydrate in aqueous suspension has been investigated. Ten excipients having functional groups which were potentially able to form hydrogen bonds with carbamazepine (group 1: methylcellulose, hypromellose (hydroxypropyl methylcellulose), hydroxypropylcellulose (HPC), 2-hydroxyethylcellulose (HEC), carmellose sodium (sodium carboxymethylcellulose), cellobiose; group 2: povidone (polyvinylpyrrolidone), povidone-vinyl acetate copolymer (povidone/VA) and N-methyl-2-pyrrolidone; group 3: macrogol (polyethylene glycol) and polyethylene oxide-polypropylene oxide copolymer (PEO/PPO)) were selected. Carbamazepine polymorphic forms III and I were dispersed separately into each aqueous excipient solution (0.1%, w/v) for 30 min at room temperature. The inhibition effect of each excipient was quantified using Raman spectroscopy combined with multivariate analyses. The solubility parameter of each excipient was calculated and used for categorizing excipients. Excipients in groups 1 and 2, which had both low solubility parameters (< 27.0 MPa(1/2)) and strong hydrogen bonding groups, inhibited the conversion completely. With increasing solubility parameter, the inhibition effect decreased for group 1 excipients, especially for carbamazepine form I, which had a higher specific surface area. Also, the excipients of group 3, lacking strong hydrogen bonding groups, showed poor inhibition although they had low solubility parameters (< 21.0 MPa(1/2)). This study indicated the importance of both hydrogen bonding interaction and a suitable hydrophobicity (expressed by the solubility parameter) in the inhibition of the conversion of carbamazepine to the dihydrate.

Extended-Release Formulations for the Treatment of Epilepsy

This review analyses the concept of extended-release (ER) formulations in epilepsy and evaluates ER formulations of carbamazepine, valproic acid and a modified-release (MR) formulation of oxcarbazepine. ER formulations are usually designed to reduce dose frequency and maintain relatively constant or flat plasma drug concentration. It is questionable whether flat plasma concentrations of an antiepileptic drug (AED) improve antiepileptic efficacy compared with fluctuating plasma concentrations. More certainly, they minimise concentration-related adverse effects, and the dosing flexibility and consistency of plasma concentrations may simplify the management of antiepileptic drug therapy. Neurologists would like ER formulations that can be administered once- and/or twice-daily to tailor therapy for the individual patient; however, switching dosage schedules from multiple dosages per day to once daily, although more convenient, will not generally improve therapeutic coverage (maintenance of effective drug concentration in biological fluids and tissue). Pharmacokinetically, the impact of a missed dose is greater the larger the dose and the less frequent the administration. Therefore, the risk of breakthrough seizure is higher during AED once-daily administration than twice-daily administration. Consequently, the increased compliance observed with fewer dosages per day should be weighed against the impact or forgiveness of omitted dose(s) and the shorter 'forgiveness' period associated with once-daily administration. Currently, the trend is to treat patients with epilepsy with ER formulations because of the better compliance, convenience and flat plasma concentration versus time curve. Thus, it seems that the term 'flatter is better' for AED plasma profiles has precipitated in the last 10-15 years among neurologists and epilepsy caregivers, and is being promoted by marketing forces of pharmaceutical companies. Data from the literature support the trend to treat epileptic patients with twice-daily administration of the existing ER formulations of valproic acid and carbamazepine, and oxcarbazepine-MR; however, the author of this article is not convinced that these ER formulations can guarantee a complete therapeutic coverage throughout the 24-hour dosing interval following once-daily administration. Epilepsy is a single-episode disease, and the convenience and possible better compliance associated with once-daily administration must be weighed against the shorter 'forgiveness' period and possible higher risk of breakthrough seizure due to sub-therapeutic plasma levels and/or omitted doses. Data suggest just a small difference in compliance between once- and twice-daily administration, with no significant difference in efficacy. Therefore, the increased compliance following once-daily administration may be counter-productive in minimising the occurrence of sub-therapeutic drug concentrations. Weighing up the advantages and disadvantages for once- versus twice-daily administration of ER formulations in epilepsy leads to a conclusion in favour of twice-daily administration.

1-O-alkylglycerol stabilized carbamazepine intravenous o/w nanoemulsions for drug targeting in mice

Carbamazepine (CBZ) is used in the treatment of generalized tonic clonic and partial seizures. In seizure disorder the focal point of treatment is brain. At present no commercial parenteral formulation of CBZ is available. We developed o/w nanoemulsions of CBZ stabilized by 1-O-alkylglycerol/lecithin for intravenous administration and evaluated the brain targeting potential of these formulations. The nanoemulsions were characterized for globule size, zeta potential (ZP), CBZ content and in vivo tissue distribution in mice. The in vivo data revealed a significant uptake of CBZ in all tissues. Among the nanoemulsions, 1-O-decylglycerol stabilized system showed significantly higher tissue levels and availability of CBZ. Particularly for this system 2.37 times higher brain availability and a brain/serum concentration ratio of 3.0 at 30 min is an important finding. This indicates the brain targeting potential. A systematic formulation development of CBZ nanoemulsions employing 1-O-alkylglycerols might pave way to achieve selective brain delivery of this important antiepileptic drug.

Performance comparison of a co-crystal of carbamazepine with marketed product

The carbamazepine: saccharin co-crystal ( 1) was studied in terms of a series of attributes, including suitability for multi-gram scale-up, propensity for crystal polymorphism, physical stability, in vitro dissolution and oral bioavailability, with the goal of comparing 1 with the marketed form of carbamazepine (Tegretol ®). Preparation of 1 was achieved on a 30 g scale with a conventional cooling crystallization process from alcohol solution without seeding. The compound is not overtly polymorphic. This finding is in contrast to the form diversity of pure carbamazepine, which has four known polymorphs and a host of solvates, including a dihydrate, which is the stable form in the presence of water. Physical and chemical stability of the co-crystal is also shown to be quantitatively similar to the pure drug in the marketed product (Tegretol ®). Finally, comparison of oral bioavailability of 1 with Tegretol ® tablets in dogs shows the co-crystal to be a viable alternative to the anhydrous polymorph in formulated solid oral products. The balance of properties and performance of 1 as a model co-crystal is discussed.

An Automated Parallel Crystallisation Search for Predicted Crystal Structures and Packing Motifs of Carbamazepine

An automated parallel crystallisation search for physical forms of carbamazepine, covering 66 solvents and five crystallisation protocols, identified three anhydrous polymorphs (forms I–III), one hydrate and eight organic solvates, including the single-crystal structures of three previously unreported solvates (N,N-dimethylformamide (1:1); hemi-furfural; hemi-1,4-dioxane). Correlation of physical form outcome with the crystallisation conditions demonstrated that the solvent adopts a relatively nonspecific role in determining which polymorph is obtained, and that the previously reported effect of a polymer template facilitating the formation of form IV could not be reproduced by solvent crystallisation alone. In the accompanying computational search, approximately half of the energetically feasible predicted crystal structures exhibit the C=O···H—N RR22(8)dimer motif that is observed in the known polymorphs, with the most stable correctly corresponding to form III. Most of the other energetically feasible structures, including the global minimum, have a C=O···H—N C(4) chain hydrogen bond motif. No such chain structures were observed in this or any other previously published work, suggesting that kinetic, rather than thermodynamic, factors determine which of the energetically feasible crystal structures are observed experimentally, with the kinetics apparently favouring nucleation of crystal structures based on the CBZ-CBZ RR22(8) motif.

P30.13 Mental processing in epilepsy in children and adolescents

Long latency auditory evoked potentials, especially P300, are an objective and non-invasive procedure and a recommended standard for clinical evaluation of mental processing. Aim of the study: In order to evaluate the results of epilepsy treatment in children and adolescents the influence of two antiepileptic drugs (AED) carbamazepine (CBZ) and valproates (VPA) on cognitive functions was analyzed. Materials and methods: The examination was performed in 30 newly diagnosed patients with epilepsy 8–18 years old before AED therapy and in 62 patients to whom both formulations of CBZ or VPA was administered in monotherapy. Neuropediatric status as well as the neuroimaging in the groups were unremarkable. All showed normal mentality measured by psychological tests. Control group consisted of 66 healthy children and adolescents of the same age. According to the IFCN standards, we applied the oddball paradigm to elicit P300. Results: Significant prolongation of P300 and N2 latency was observed and the increase of N1–P2, P2–N2 and N2–P3 amplitude values in all epileptic patients in comparison to healthy controls was detected. There were also significant changes of N1 and P2 latency recorded in children receiving CBZ. P300 latency was longer in patients with newly diagnosed epilepsy than in control group. It was also shown that patients with partial seizures demonstrated longer P300 and N2 latency than recorded in case history as well as N2–P3 amplitude was higher than in patients with generalized seizures. There was not any statistically significant relation between parameters of P300 and the age of the child at the moment of epilepsy being diagnosed, the duration of the disease and the level of AED in blood serum. Conclusions: There were significant differences indicated in parameters of P300 in epileptic children and adolescents in comparison to control group. The type of epileptic seizures and the choice of AED influence their values significantly.

Practical considerations for carbamazepine use in bipolar disorder

Carbamazepine (CBZ) has a long history of successful use in epilepsy and, therefore, has a safety profile that is well characterised. Additionally, an extended-release formulation of CBZ (CBZ-ERC; Equetro™, Shire US) has recently been approved for use in bipolar disorder. The most frequent adverse events associated with CBZ are somnolence, fatigue, dizziness and headache. Rash and leukopoenia may occur in ~ 10% of patients, but are benign and transient in most cases. Rare serious adverse effects include agranulocytosis, aplastic anaemia, Stevens-Johnson syndrome and toxic epidermal necrolysis. Although changes in lipid profiles have been noted, hyperglycaemia does not occur with CBZ, and clinically significant weight gain is uncommon. Proper monitoring and careful titration of the extended-release formulation should allow for successful use of CBZ in psychiatric patients.

Towards a Universal Dissolution Medium for Carbamazepine

ABSTRACTThe aim of this study was to develop a dissolution medium for assessment of various carbamazepine (CBZ) formulations with different strengths. The design of a system inhibiting transformation of the anhydrous CBZ (CBZ A) to the dihydrate form (CBZ D), with minimum surface-active properties and suitable sink was investigated. The effect of pH, different concentrations of sodium lauryl sulphate (SLS), polyvinylpyrrolidone (PVP), and methyl cellulose (MC) on dissolution rate, solubility, dissolution solubility, and polymorphic transformation of CBZ was assessed. Solution-mediated transformation of CBZ A into CBZ D was monitored using optical microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry. Results showed that different strengths (100, 200, 400 mg) of the same CBZ tablet formulation exhibited different dissolution patterns, in 1% SLS (USP system). Such differences were reduced in 0.5% SLS solution which provided sufficient sink for up to 200 mg CBZ. It was also shown that solubility of CBZ A could not be detected in the media under study (water, SGF, SIF, and SLS solutions) due to its rapid transformation into CBZ D. The use of 3% PVP solution protected CBZ A from conversion for 75 min, while 0.01% MC completely inhibited the transformation up to 24 h. Therefore, a medium consisting of 0.5% SLS and 0.01% MC was selected. The medium provided: a) protection against transformation of CBZ A to CBZ D, b) increased solubility of CBZ A (204 mg % compared to 128 mg % of CBZ D in 0.5% SLS), c) suitable sink for up to 400 mg CBZ and d) overlapping dissolution profiles of various strengths of the same CBZ formulation. The suggested system may be a step in the way of solving CBZ dissolution problems that forced the USP to specify two similar dissolution tests with two different limits for conventional 200 mg CBZ tablets.

Extended-release carbamazepine for acute bipolar mania: A review

In December 2004, an extended-release capsule formulation of carbamazepine was approved by the U.S. Food and Drug Administration for the treatment of acute manic or mixed episodes associated with bipolar I disorder. This formulation allows twice-daily dosing and minimizes plasma carbamazepine fluctuations. The efficacy, safety and tolerability of the product were demonstrated with two pivotal randomized, placebo-controlled, double-blind monotherapy trials. These studies showed efficacy in bipolar I mania in patients with acute manic or mixed episodes. Pooled post hoc analyses documented a significant onset of effect within seven days, an incremental response of about 25% over placebo and a moderate effect size of 0.61 with no treatment-emergent depression. Carbamazepine's mode of action in mania is unknown, but a variety of effects on receptors, neurotransmitters, ion channels and binding sites have been documented. It has a complex pharmacokinetic profile due to autoinduction and a long-acting active metabolite. Carbamazepine's most frequent adverse events comprise dizziness, somnolence, nausea and vomiting, although these tend to diminish over time. It is effectively weight neutral and can provide an acceptable and efficacious treatment option for bipolar I mania.

Extended-Release Carbamazepine Capsules in Bipolar I Disorder1

An extended-release capsule formulation of carbamazepine is approved for use in adult patients experiencing an acute manic or mixed episode associated with bipolar I disorder. A capsule of extended-release carbamazepine contains three types of bead: immediate release, extended release and enteric release, constituting 25%, 40% and 35% of the dose, respectively.black triangle Extended-release carbamazepine capsules 200--1600 mg/day demonstrated superior antimanic efficacy to placebo in two 3-week, well designed trials in adult patients with bipolar I disorder and acute manic or mixed episodes. At study end, reductions from baseline in Young Mania Rating Scale scores were significantly greater with carbamazepine than with placebo (primary endpoint). The active treatment was effective from the end of the first week of treatment (post hoc analysis).black triangle In the 3-week trials and a 6-month extension study, most treatment-emergent adverse events observed with extended-release carbamazepine were of mild or moderate severity. In the 3-week trials, although significantly greater reductions in white blood cell count occurred with extended-release carbamazepine than with placebo, only one case of leukopenia was deemed serious. There were no reports of agranulocytosis or aplastic anaemia with up to 6 months' treatment.

Thermally Reversible In Situ Gelling Carbamazepine Liquid Suppository

Carbamazepine (CBZ), indicated for the control of epilepsy, undergoes extensive hepatic first-pass elimination after oral administration. A rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Gellan gum was also tried instead of 20% poloxamer. All formulations contained 10% CBZ. The characteristics of the suppositories differed depending on the formulation. The formula containing 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol showed reasonable gelation temperature, gel strength and bioadhesive force. The analysis of release mechanism showed that CBZ released from the suppositories by Fickian diffusion. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. However, there was no statistical significant difference (p > 0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC0 - ∝, 17.9 and 18.8 μ g.h/ml, respectively. These results suggested that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.

Antiepileptic Drugs: All Ages

Antiepileptic Drugs: All Ages

Carbamazepine extended-release capsules: a new treatment option for bipolar I disorder

Carbamazepine has a long history in psychiatry and neurology. More recently, carbamazepine extended-release capsules have been approved by the US Food and Drug Administration for the treatment of manic and mixed episodes associated with bipolar I disorder. This decision represents a significant step forward for the agent, which was first described to have efficacy in the disorder in the early 1970s. Approval of carbamazepine extended-release capsules was aided by two large placebo-controlled, 3-week trials. Using nearly identical protocols, these trials demonstrated that monotherapy with carbamazepine extended-release capsules was effective for the treatment of acute mania in patients with bipolar I disorder. Recent data collected based on this new formulation of carbamazepine illustrate the need for education about the utility of this compound in bipolar disorder.

Temperature dependent terahertz pulsed spectroscopy of carbamazepine

In this study for the first time temperature dependent terahertz pulsed spectroscopy was performed on a pharmaceutical drug. The polymorphic conversion process of carbamazepine form III to I was studied at varying temperatures. Furthermore, the solid-state transformation at isothermal conditions below the melting point of carbamazepine was investigated. The ability to study solid-state reactions with terahertz pulsed spectroscopy could be demonstrated.

Improved tolerability and efficacy in epilepsy patients with extended-release carbamazepine

The authors conducted a 3-month, prospective, open-label study assessing the effects of switching from immediate-release carbamazepine formulations to an equal total daily dose of carbamazepine extended-release capsules (CBZ-ERC) in adolescents and adults with epilepsy. Using validated, epilepsy-specific measures the authors found that switching to CBZ-ERC significantly improved patients' adverse events and quality-of-life measures. Switching to CBZ-ERC also improved seizure control.

Patterns of care, outcomes, and direct health plan costs of antiepileptic therapy: a pharmacoeconomic analysis of the available carbamazepine formulations

Although generic formulations of immediate-release carbamazepine (IR-CBZ) are available, extended-release delivery systems may offer important advantages, including the convenience of less-frequent administration and smaller peak-to-trough serum carbamazepine (CBZ) fluctuations. The aim of this study was to compare the patterns of pharmacotherapy, rates of adverse events, and the utilization costs among patients treated with the available CBZ formulations (ie, generic and branded IR-CBZ, and extended-release CBZ (ER-CBZ) capsules [Carbatrol, Shire US Inc., Wayne, Pennsylvania] and tablets [Tegretol-XR, Novartis Pharmaccuticals Corporation, East Hanover, New Jersey]). Data were retrieved from the PharMetrics patient-centric database (which contains integrated claims data for almost 36 million unique patients from 61 US health plans) for patients who were diagnosed with epilepsy and initiated CBZ between July 1999 and June 2001. Patient demographic and clinical characteristics, adverse events, discontinuations, CBZ therapy switches, and utilization and costs for related care subsequent to treatment initiation were recorded. Annual rates of adverse events and discontinuations were calculated, and the risks of these events were compared across treatment groups. Data were gathered for 1737 patients. The branded CBZ group was demographically and clinically different than the other groups (ie, migraine and cerebral palsy prevalence) and therefore was excluded from event-risk analyses. Results of the proportional hazards regression analysis indicated that Tegretol-XR patients were more likely to experience common central nervous system (CNS)-related adverse events relative to Carbatrol (hazard ratio, 1.67; P = 0.043). A lower percentage of subjects switched off ER-CBZ relative to IR-CBZ (Carbatrol, 5.2%; Tegretol-XR, 5.7%; generic IR-CBZ, 13.0%; branded IR-CBZ, 16.7%). Differences in mean payments for epilepsy-related health care services at 1 year among Carbatrol, Tegretol-XR, and branded or generic CBZ did not reach statistical significance. Among the available CBZ formulations, Carbatrol was associated with a lower incidence of common CNS adverse events. ER-CBZ formulations were also associated with reduced likelihood of therapy discontinuation or switching CBZ medications, relative to patients taking generic IR-CBZ, in this retrospective data analysis.